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Cited by 699Nanoparticle-Based Drug DeliveryDrug Solubulity and Delivery SystemsAdvanced Drug Delivery Systems

Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval.

Open access
Hwang, Duhyeong, Ramsey, Jacob D., Kabanov, Alexander V.·2020·Advanced drug delivery reviews
DOI 10.1016/j.addr.2020.09.009PMC PMC8173698
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Abstract

Over the last three decades, polymeric micelles have emerged as a highly promising drug delivery platform for therapeutic compounds. Particularly, poorly soluble small molecules with high potency and significant toxicity were encapsulated in polymeric micelles. Polymeric micelles have shown improved pharmacokinetic profiles in preclinical animal models and enhanced efficacy with a superior safety profile for therapeutic drugs. Several polymeric micelle formulations have reached the clinical stage and are either in clinical trials or are approved for human use. This furthers interest in this field and underscores the need for additional learning of how to best design and apply these micellar carriers to improve the clinical outcomes of many drugs. In this review, we provide detailed information on polymeric micelles for the solubilization of poorly soluble small molecules in topics such as the design of block copolymers, experimental and theoretical analysis of drug encapsulation in polymeric micelles, pharmacokinetics of drugs in polymeric micelles, regulatory approval pathways of nanomedicines, and current outcomes from micelle formulations in clinical trials. We aim to describe the latest information on advanced analytical approaches for elucidating molecular interactions within the core of polymeric micelles for effective solubilization as well as for analyzing nanomedicine's pharmacokinetic profiles. Taking into account the considerations described within, academic and industrial scientists are expected to develop novel polymer materials and optimal micelle formulations for clinical applications of poorly soluble small molecules.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes three decades of work on polymeric micelles for poorly soluble small-molecule drugs, spanning polymer design, drug-polymer interaction analysis, pharmacokinetics, manufacturing, regulation, and clinical translation. It concludes that micelles can improve drug loading, pharmacokinetics, and safety, but clinical success remains limited and their dynamic behavior complicates characterization and approval.

Key findings

  • Polymeric micelles can achieve high drug loading and reduce excipient-related toxicity. POx micelles solubilized paclitaxel up to 40 mg/mL and about 50% loading; the mouse maximum tolerated dose was 150 mg/kg versus 20 mg/kg for Taxol. POx combination micelles reached roughly 48.7% loading for paclitaxel:17-AAG:etoposide and 48.4% for paclitaxel:17-AAG:bortezomib.
  • Clinical translation is mixed. Genexol® PM and Nanoxel® M were approved in South Korea. Genexol® PM had a phase I maximum tolerated dose of 390 mg/m², higher than Taxol® (200 mg/m²) and Abraxane® (300 mg/m²); phase II metastatic breast cancer overall response was 58.5%, and with cisplatin in NSCLC it was 37.7% with median survival 21.7 months. NK105 completed phase III but did not meet non-inferiority for progression-free survival (8.4 vs 8.5 months; overall survival 31.2 vs 36.2 months; response rates 31.6% vs 39.0%), although peripheral sensory neuropathy was lower. NC-6004 completed a phase III trial with no reported results; SP1049C showed 47% response in evaluable patients and 43% in intent-to-treat, with median overall survival 10 months and progression-free survival 6.6 months.
  • Drug-polymer interactions are more complex than simple hydrophobic partitioning; hydrophilic shell blocks can also participate. Advanced methods include solid-state NMR, small-angle neutron scattering, fluorescence, molecular dynamics, and QSPR. QSPR predicted aqueous solubility with up to 75% accuracy, and the SITUA assay can quantify encapsulated, protein-bound, and unbound drug fractions, though its assumptions may not hold for dynamic micelles.
  • No polymeric micelle formulation was approved in the United States at the time of the review. Regulatory routes discussed include US 505(b)(1), 505(b)(2), and 505(j), plus the EU “nanosimilar” stepwise approach; robust control of size, morphology, release, and pharmacokinetics is emphasized.

Methods

  • Narrative review, not a systematic review or meta-analysis. It synthesizes published literature on block copolymer chemistry, drug loading, drug-polymer interactions, pharmacokinetics, manufacturing, regulatory pathways, and clinical trials.
  • Evidence comes from cited preclinical and clinical studies, tables of polymers and formulations, and selected trial examples; no new experiments or primary data collection are reported.
  • The main analysis is qualitative and conceptual, organizing the field into polymer design, interaction characterization, pharmacokinetics/distribution, and clinical/regulatory translation.

Limitations

  • Stated by the paper: polymeric micelles are dynamic, making pharmacokinetic analysis difficult; methods to measure encapsulated, protein-bound, and unbound drug fractions in tissues are lacking; SITUA may misclassify micelle-bound drug if exchange is rapid; crosslinked micelle translation is limited by crosslinking consistency; only PEG has been widely used as a clinical shell material; POx safety in humans needs further study; and no US-approved polymeric micelle exists.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy or formal quality appraisal; many conclusions rely on preclinical animal models; several clinical trials had unreported results; and the 2020 publication date means later clinical and regulatory developments are not captured.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.addr.2020.09.009

Cites

342 of 342 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

217 of 502 cited sources checked · 115 supported · 6 flagged · accuracy not yet measured

  • Interpretationcitation

    Side effects can be largely mitigated in preclinical and clinical studies by using polymeric micelle formulations.

    “Side effects could be largely mitigated in both preclinical and clinical studies by using polymeric micelle formulations.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [11] source
    • cites [17] source

      The Abstract (page unavailable) says the micellar formulation SP1049C had similar toxicology to conventional doxorubicin in mice and rats. The Toxicity section (page unavailable) says its overall adverse-event spectrum in patients was also similar to conventional doxorubicin, rather than largely mitigated. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    DOXIL has shown the ability to induce ABC in human patients mainly due to anti-PEG antibodies after initial treatment.

    “The clinically approved doxorubicin liposome formulation, DOXIL®, has also shown the ability to induce the ABC phenomenon in human patients mainly due to the development of anti-PEG antibodies in the body after the initial treatment of DOXIL® [82].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [82] source

      The Introduction says Doxil hypersensitivity reactions occur mostly at first exposure, without prior sensitization. The Patients and Complement activation by Doxil in vivo sections study first-time recipients and report complement activation after infusion, not accelerated blood clearance (ABC) after an initial treatment. The cited paper therefore describes a different reaction and does not support anti-PEG antibodies as the claimed mechanism. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Findingcitation

    The NK105 paclitaxel polymeric micelle formulation was reported to have lower toxicity in clinical trials compared to Taxol.

    “Some other paclitaxel polymeric micelle formulations, such NK105, were also reported to have lower toxicity in clinical trials compared to Taxol® [238].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [238] source

      The Discussion (page not available in our copy) says NK105’s observed toxicities were similar to those expected for conventional paclitaxel, not lower. It says whether NK105 causes less peripheral neuropathy requires future trials; the lower-toxicity finding it mentions came from animal experiments, not this clinical trial. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Flash precipitation can be optimized by increasing mixing times to obtain drug-containing polymeric micelles and block copolymer coated drug nanoparticles with desired size and coating.

    “It can be optimized by increasing mixing times to obtain drug-containing polymeric micelles and block copolymer coated drug nanoparticles with desired size, coating, and other characteristics [269].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [269] source

      The Principles section (page unavailable) says the opposite of the claimed optimization: longer mixing times promote particle growth, so flash nanoprecipitation requires a higher mixing rate and shorter mixing time. The MIVM section (page unavailable) does discuss producing drug polymeric micelles, but that does not support increasing mixing times to obtain the desired particles. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Hydrophilic blocks can play a substantial role in drug-polymer interaction, especially in highly drug-loaded polymeric micelles.

    “The Luxenhofer group has shown that hydrophilic blocks can play substantial role in drug polymer interaction especially in highly drug loaded polymeric micelles [30].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [30] source

      The Introduction (page unavailable) describes hydrophilic pMeOx blocks in both micelles and reports high curcumin loading, while the Results and Discussion (page unavailable) examines drug–polymer interactions in the micellar core. The paper does not show that the hydrophilic blocks play a substantial role in those interactions, especially at high drug loading. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • May combine two claims. 216
  • Classified as probably not a substantial claim. 99
  • The quote only partly states this claim. 4
  • Borderline: one of the tests for a substantial claim is unclear. 1

  • May combine two claims.

    Premisecitation

    In that study, for copolymers with varying core composition, furosemide solubility positively correlated with trimethylene carbonate content, consistent with χFH-based miscibility prediction.

    “For the block copolymers with varying composition of the core-forming block the solubility of a single drug (furosemide) positively correlated with the content of the trimethylene carbonate co-monomer in this block. This also was consistent with the drug-polymer miscibility prediction based on χFH.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [196] source

      Section 2.4 (p. 502) reports that furosemide solubility decreases as CL content falls—that is, as TMC content rises. Table 6 shows a decline from 3.17 mg/mL at 10% TMC to 1.88 mg/mL at 90% TMC. The paper says this decline agrees with its drug–polymer compatibility prediction, contrary to the claimed positive correlation with TMC. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A completed phase III study in South Korea evaluated efficacy and safety of Genexol PM at 260 mg/m2 versus paclitaxel at 175-200 mg/m2 in recurrent or MBC, but results have not been reported yet.

    “A completed phase III study in South Korea further evaluated the efficacy and safety of Genexol® PM (260 mg/m2) compared to paclitaxel (175–200 mg/m2) in recurrent or MBC (ClinicalTrials.gov: NCT00876486) [302], but the results of this trial have not been reported yet.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [302] source

      The Introduction identifies this phase III trial as NCT00876486, and the Treatment section gives starting doses of 260 mg/m2 for Genexol-PM and 175 mg/m2 for Genexol. But the Results section reports efficacy and safety findings, contrary to the claim that the trial’s results had not been reported. Our copy also specifies 175 mg/m2, not a 175–200 mg/m2 comparator range. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a Phase I refractory gout study, about one third of patients with prior pegylated therapy had anti-PEG antibodies, resulting in lower AUC and poor efficacy of PEG-uricase.

    “In a Phase I study of refractory gout, patients were treated with a PEG-uricase therapy. About one third of the treatment group, who had previously been treated with pegylated therapies at some point, had previously developed anti-PEG antibodies in the body. This resulted in lower AUC’s and poor efficacy of the PEG-uricase treatment [80].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [80] source

      The Abstract and Results (Immunogenicity; page unavailable) report that five of 13 refractory-gout subjects developed anti-PEG antibodies after PEG-uricase injection, not that they had antibodies from prior PEGylated therapy. Results (Two pharmacokinetic patterns of PEG-uricase elimination; page unavailable) associate those five subjects with earlier drug elimination and a shorter-lasting urate-lowering effect; area-under-curve calculations are mentioned but not shown. Thus the approximate proportion and reduced exposure and durability are supported, but the claimed prior treatment and pre-existing antibodies are not. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ring-opening polymerization of cyclic esters commonly produces high molecular weight polyesters with narrow polydispersity.

    “Synthesis of polyesters is commonly done by ring-opening polymerization of cyclic esters and this synthetic strategy is known to produce high molecular weight polyesters with narrow polydispersity [105].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [105] source

      The Introduction (p. 3) describes ring-opening polymerization of cyclic esters as a route to aliphatic polyesters. The Discrete cores section (p. 7) reports narrow polydispersities for selected star-polymer samples, but also notes deviations in molecular-weight distributions; its table includes a high-molecular-weight sample with a PDI of 1.90. The review therefore does not support the unqualified claim that this strategy commonly produces polyesters that are both high in molecular weight and narrow in polydispersity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In vivo degradation of the polyester backbone prevents polymer accumulation in the body and lowers chronic toxicity risk.

    “The in vivo degradation process of the polyester backbone prevents the undesired accumulation of the polymer in the body, thus reducing the risk of chronic toxicity [60].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [60] source

      Section 2.2.1 describes hydrolysis of polyester ester bonds, and the adjacent PLGA discussion says the polymer is eventually degraded in vivo and cleared. This supports the point about avoiding accumulation for PLGA, but the copy does not explicitly link that clearance to a reduced risk of chronic toxicity or establish it for all polyesters. No page number is available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A POx diblock copolymer with a triazine-ring hydrophobic block exhibits hydrophobic interaction and likely pi-pi stacking capabilities.

    “Also, we have recently reported a POx based diblock copolymer which has a hydrophobic block consisting of a triazine ring and exhibits both hydrophobic interaction and likely pi-pi stacking capabilities [28].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Interpretationcitation

    Poly(histidine) can be a core-forming block that is hydrophobic at extracellular pH but becomes positively charged and soluble upon acidification, enabling local drug release.

    “Therefore, poly(histidine) can be used as a core-forming block in the polymeric micelles that is hydrophobic at the extracellular pH but becomes positively charged and soluble upon acidification, which can result in the local release of an incorporated drug [131].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    PMeOx is more hydrophilic than PEG, is well-hydrated in the shell of highly drug-loaded POx micelles, and interacts less with loaded drug than PEtOx.

    “For example, PMeOx (which is more hydrophilic than PEG) was well-hydrated in the shell of highly drug-loaded POx micelles and had less interaction with loaded drug compared to PEtOx (which is similarly hydrophilic to PEG).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Etoposide, third-generation taxanes, vismodegib, and multiple drug combinations were solubilized in the POx micelle system with high loading.

    “A number of other hydrophobic drugs such as etoposide, 3rd generation of taxanes, and vismodegib as well as multiple drug combinations were shown to be solubilized in the POx micelle system with high loading [113, 117, 118].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [113]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [117] source

      The Discussion reports high loading of etoposide in POx micelles, and the Conclusions report high-loading binary and ternary drug formulations (page numbers not supplied). The paper discusses paclitaxel and docetaxel, but our copy does not establish the claimed third-generation taxanes or vismodegib. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [118] source

  • May combine two claims.

    Premisecitation

    Poly(histidine) imidazole groups are uncharged at pH 7.4 and become protonated at acidic pH.

    “On the other hand, the imidazole groups in poly(histidine) are uncharged at the physiologic pH 7.4 and become protonated at acidic pH.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Chemical crosslinking of the shell or core improves stability and circulation time of self-assembled polymeric micelles, and drug release can be modulated by cleaving crosslinks.

    “Chemical crosslinking approaches were also employed to improve the stability and circulation time of self-assembled polymeric micelles. Either the shell or core could be crosslinked, and the drug release could be modulated by cleavage of the crosslinks [160–163].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [160] source
    • cites [161] source
    • cites [162] source

      The Results and Discussion (page not provided) state that core crosslinking stabilized the micelles, and report prolonged circulation for the resulting PEG-coated particles. The paper mentions shell-crosslinked micelles but does not establish that shell crosslinking improves circulation; it raises the possibility that shell crosslinking limits the mobility of a protective layer. It does not report drug release controlled by cleavage of crosslinks. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [163] source

      The Introduction (pp. 2–3) says cross-linking stabilizes micelles against disintegration in the bloodstream and describes a cross-linkable shell. It does not establish longer circulation time, discuss core cross-linking, or say drug release is modulated by cleaving crosslinks. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The same concept led to development of NK911, which was evaluated clinically.

    “This same concept was used by Kataoka and colleagues in a series of works leading to development of polymeric micelle NK911, which was evaluated clinically [146, 147].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [146] source
    • cites [147] source

  • May combine two claims.

    Premisecitation

    Increased blood circulation time and tumor distribution, decreased toxicity, and improved anti-tumor effects were reported for drugs in core-crosslinked micelles.

    “Increased blood circulation time and tumor distribution of drugs incorporated in such core-crosslinked micelles along with decreased toxicity and improved anti-tumor effects of the micellar drugs were reported.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [176]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [177] source
    • cites [178] source

      The Introduction (page unavailable) says cross-linking can enable prolonged nanogel circulation and greater drug accumulation at the target site. The Results and Discussion (page unavailable) report greater tumor accumulation, less toxicity, and stronger antitumor effects for drug-loaded nanogels than for free cisplatin. The paper describes cross-linked nanogels rather than establishing these outcomes for core-crosslinked micelles specifically, and it presents prolonged circulation as a possibility, not a measured result. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Kakde et al. found that χFH estimates predicted lower indomethacin solubility in poly(ε-decalactone) core than in PCL core, contradicting experimental data.

    “The χFH values estimated in this work predicted that the drug solubility in poly(ε-decalactone) core was less than that in PCL core, which contradicted the experimental data.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Drug-polymer interactions in polymeric micelles can involve both hydrophobic core-forming blocks and hydrophilic shell-forming blocks, and some drugs can be partly incorporated into the shell.

    “In some cases, these interactions can involve not only the core-forming hydrophobic blocks but also the shell-forming hydrophilic blocks and selected drugs can be at least partially incorporated in the shell of the micelle [46, 65].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [46]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [65] source

  • The quote only partly states this claim.

    Premisecitation

    Latere Dwan'Isa et al. found that including interaction parameters for both hydrophilic and hydrophobic blocks produced rankings that agreed reasonably well with experimental drug solubilities in PEG-b-poly(ε-caprolactone-co-trimethylene carbonate) micelles.

    “The resulting rankings agreed reasonably well with the experimentally measured drug solubilities in the micelles.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    In Alves et al., virtual screening selected eight drugs predicted to have good or poor solubilization, and three putative positives and three putative negatives were confirmed experimentally.

    “These models were employed for virtual screening of drug libraries, and eight drugs predicted to have either good or poor solubilization in these polymeric micelles were selected. Three putative positives, as well as three putative negative hits, were confirmed experimentally.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    QSPR modeling is based on statistical analysis of data sets and has been frequently used in medicinal chemistry and chemical toxicology to predict efficacy and/or toxicity of small molecules.

    “QSPR modeling is based on the statistical analysis of the data sets and has been frequently used in the field of medicinal chemistry and chemical toxicology for the prediction of efficacy and/or toxicity of small molecules [220].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Wu et al. developed QSPR models to assess doxorubicin loading in polymeric micelles using genetic function approximation, and the approach established a quantitative relationship between polymer structure and drug loading.

    “Wu et al. reported the development of a series of QSPR models to assess the loading of doxorubicin in polymeric micelles using the genetic function approximation algorithm [209, 210].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [209] source
    • cites [210] source

  • May combine two claims.

    Premisecitation

    Erlebach et al. found that Flory-Huggins parameters from MD simulations correctly accounted for block length and PEG:PDLLA ratio effects and were in reasonable agreement with experimental encapsulation data for pyrene, Nile red, and indomethacin in mPEG-b-PDLLA micelles.

    “The predictions from those Flory−Huggins parameters correctly accounted for the effects of the block length and the PEG:PDLLA ratio and were in reasonable agreement with the experimental data for the encapsulation of several hydrophobic molecules (pyrene, Nile red, and indomethacin).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [204] source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Lower-loaded Callari et al. micelles had greater uptake and in vitro cytotoxicity than higher-loaded micelles.

    “The lower loaded micelle had greater uptake and in vitro cytotoxicity, presumably due to the softer micellar structure facilitating interactions between the micelles and the cells.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Findingcitation

    PEtOx was much less efficient as a hydrophilic shell; the respective micelles did not solubilize as much curcumin and were less stable at higher loading.

    “On the contrary, PEtOx was much less efficient as a hydrophilic shell and the respective micelles did not solubilize as much curcumin and were less stable at higher loading.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Findingcitation

    After adding powder polymer to micelle formulations, curcumin fluorescence increased in both POx and POzi polymers, indicating mobility and dynamic exchange of these polymer systems.

    “After this addition, in both the POx and POzi polymers, the curcumin fluorescence increased indicating the mobility and dynamic exchange/behavior of these polymer systems.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The POzi polymer has an additional methylene unit in the hydrophobic block, conferring added flexibility and enabling alternative non-radiative decay pathways for excited-state curcumin.

    “The POzi has an additional methylene unit in the hydrophobic block background which confers an added degree of flexibility and enables alternative non-radiative decay pathways for excited state curcumin.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [30] source

      The Results and Discussion (page unavailable) state that pPrOzi has an additional methylene group in its backbone and is more flexible than pBuOx. That section links polymer flexibility to curcumin’s non-emitting internal conversion, and the Conclusions attribute curcumin’s faster decay in pPrOzi micelles at very low drug loading partly to greater flexibility. The paper does not establish distinct alternative decay pathways, and the claim presents this proposed mechanism more definitively and generally than the source does. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationreasoning

    The higher fluorescence intensity in POx means that the fluorescence quantum yield is higher in POx due to a decrease in non-radiative decay pathways.

    “This must mean that the fluorescence quantum yield is higher in the POx polymer due to a decrease in non-radiative decay pathways.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Findingcitation

    The absorption band at 345 nm completely disappeared when curcumin was encapsulated in both polymers, possibly due to hydrogen bonding between curcumin keto/enol groups and polymer carbonyl groups, indicating that hydrogen bonding plays a key role in curcumin solubilization.

    “The absorption band at 345 nm completely disappeared when encapsulated in both polymers which may be due to hydrogen bonding between the keto and enol groups of curcumin and the carbonyl groups on the polymer, which indicates that hydrogen bonding plays a key role in curcumin solubilization.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [30] source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    A shift in absorbance maximum from 432 nm to 414 nm was observed as curcumin concentration in POzi-based micelles increased, indicating drug localization in a less polar microenvironment and further exclusion of water from the core.

    “Additionally, a shift in the absorbance maximum from 432 nm to 414 nm was observed as the concentration of curcumin in the POzi-based polymeric micelle increased indicating drug localization in a less polar microenvironment and the further exclusion of water from the core with increased curcumin loading.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [30] source

      The Results and Discussion reports a shift from 432 nm to 414 nm as curcumin loading increased in A-pPrOzi-A micelles and associates the shift with a less polar microenvironment. It proposes that water may be expelled from the core as loading increases, but presents that explanation as a hypothesis rather than an established finding. No page number is provided in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Curcumin is a very hydrophobic drug with fluorescent properties, such as peak positions and quantum yield, that are highly dependent on the local microenvironment.

    “Curcumin is a very hydrophobic drug with fluorescent properties, such as peak positions and quantum yield, which are highly dependent on the local microenvironment [30].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Findingcitation

    Over 24 hours, paclitaxel was not completely released from the PBuOx polymer but was completely released from the triazine-ring-based polymer.

    “Their work showed that over 24 hours paclitaxel was not completely released from the PBuOx polymer while it was completely released from the triazine ring-based polymer.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] source

      The Results (Solubilization of poorly soluble small molecules; page not available) report that after 24 hours, less than 50% of paclitaxel had been released from P2, the PBuOx-containing polymer, while most had been released from the triazine-containing PcBOx polymer. They report over 80% release from PcBOx, not complete release; the Discussion calls its release profile “more complete,” not complete. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    High drug loading increases the amount of drug per micelle, which can increase the amount of drug internalized into cells.

    “A high LC also increases the amount of drug per micelle, which can increase the amount of drug internalized into cells [114].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [114] source

      The Discussion reports increased loading capacity and improved cellular uptake for co-loaded micelles compared with a mixture of single-drug micelles. It does not establish that a greater amount of drug per micelle caused the increased uptake; the authors instead propose that delivering both drugs in fewer particles may explain it. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In Hwang et al.'s study, bruceantin release rate was approximately the same from triazine-ring-based and PMeOx-b-PBuOx-b-PMeOx micelles, while paclitaxel release was drastically different.

    “While the rate of release of bruceantin from both types of the micelles was approximately the same, the rate of release of paclitaxel was drastically different.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Interpretationcitation

    SITUA enables analysis of drug subpopulations derived from nanomedicines in systemic circulation in pharmacokinetic studies and can also be used clinically.

    “This approach enables the analysis of the aforementioned subpopulations of drugs derived from nanomedicines in the systemic circulation in PK studies and can also be used clinically [247].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    For the Taxol formulation, Cremophor EL micelles bind in rapid equilibrium with unbound drug; this binding was observed as an increase in protein binding that correlated with formulation concentration and influenced paclitaxel pharmacokinetics by decreasing clearance and volume of distribution.

    “This was the case for the SITUA when it was applied to the Taxol formulation in which Cremophor EL micelles bind in rapid equilibrium with unbound drug; this Cremophor EL micelle binding was observed as an increase in protein binding that correlated with formulation concentration, and influenced paclitaxel PK by decreasing both clearance and volume of”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [247] source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The POx-vismodegib formulation showed a 1.6-times increase in tumor AUC and overall improved delivery to the brain.

    “The POx-vismodegib formulation showed a 1.6-times increase in tumor AUC and overall improved delivery to the brain.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [113] source

      The Results section, “POx micelles improve the brain and tumor delivery of vismodegib without penetrating CNS” (page unavailable), reports significantly higher tumor AUC and improved distribution across the blood–brain barrier with POx-vismodegib. Our copy does not give a 1.6-times increase in tumor AUC; the numerical comparison it provides here is the tumor-to-plasma AUC ratio, 0.569 versus 0.439. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The micelle formulation also resulted in a lower volume of distribution, which could lead to fewer off-target effects than the conventional formulation's less than ideal distribution to peripheral tissues.

    “The micelle formulation also resulted in a lower Vd which could lead fewer off-target affects than the conventional formulation’s less than ideal distribution to peripheral tissues [113].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Particles larger than 200 nm could be caught by the liver, while nanoparticles smaller than 10 nm would be easily cleared by the kidney.

    “Particles with size ranging over 200 nm could be caught by the liver, while smaller nanoparticles less than 10 nm would be easily cleared by the kidney [239].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [239] source

      Section 9.2 discusses particle size in relation to cellular entry, and section 8.1 describes uptake of particles around 200 nm and larger by HeLa cells. Neither addresses liver capture of particles over 200 nm or kidney clearance of particles under 10 nm; searches for those thresholds and organ-specific clearance found no supporting passage in our copy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Some studies have shown that drug release and lower drug/polymer ratios allow incorporation of water into the micelle core, which increases hydrodynamic size.

    “Some studies have shown that the release of drug, and lower Drug/Polymer ratios allow the incorporation of solvent (water) into the micelle core which increases the hydrodynamic size [30].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [30] source

      In Results and Discussion (page unavailable), the authors propose that micelle cores may contain water at low curcumin loading and report that micelles initially shrink as loading increases. This supports an association between lower loading and a larger size, but the paper does not show that drug release causes water to enter the core or establish water incorporation as the cause of the size change. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the Wan et al. study, the modeling approach was applied using a POx-paclitaxel polymeric micelle formulation.

    “In the Wan et al. study, this modeling approach was applied using a POx-paclitaxel polymeric micelle formulation.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [188] source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Sizes from 50 nm to 100 nm are effective in preclinical models, suggesting ideal particle size distribution is necessary for efficacy of polymeric micelles.

    “In some previous studies, it was shown that sizes from 50 nm–100 nm are effective in preclinical models, suggesting ideal particle size distribution is necessary for efficacy of polymeric micelles [253, 254].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [253] source

      The Results and Discussion describe preclinical testing of 50–150 nm polymeric nanoparticles and report that they were effective radiosensitizers, with a trend toward greater efficacy at 100 nm. The paper does not establish that an ideal size distribution is necessary for efficacy, and it studies polymeric nanoparticles rather than identifying its formulations as polymeric micelles. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [254] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent study by the authors' lab explored the complex, dynamic nature of POx polymeric micelles and the pharmacokinetic activity of these formulations.

    “A recent study by our lab explored the complex, dynamic nature of POx polymeric micelles and the PK activity of these formulations [188].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Frequently employed combinations are several chemotherapies, chemotherapy with tumor microenvironment modifiers, or immunotherapy with anticancer agents.

    “Frequently employed combinations are 1) a combination of several chemotherapies for killing cancer cells, 2) a combination of chemotherapy with additional agents, such as tumor microenvironment modifiers, or more recently 3) a combination of immunotherapy with anticancer agents [259].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [259] source

      The Results (page unavailable) describe chemotherapy combined with chemosensitizers and Resiquimod immunotherapy combined with anti–PD-1, supporting examples of two combination types. The paper does not establish that the three listed types are frequently employed, or document combinations of several chemotherapies or chemotherapy with tumor-microenvironment modifiers. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Combination therapy has been largely exploited for treatment of various cancers based on related pathways of oncogenesis or using agents that affect the tumor microenvironment.

    “Combination therapy has been largely exploited for the treatment of various types of cancer based on related pathways of oncogenesis or utilizing a combination of agents which affect the tumor microenvironment [257, 258].”
    Quote in the paperNot a substantial claim2 of 2 sources checked

  • May combine two claims.

    Premisecitation

    Combination polymeric micelles had superior anti-tumor activity in preclinical lung cancer models along with a strong synergistic effect.

    “Along with the strong synergistic effect of the combination, a superior anti-tumor activity of combination polymeric micelles was observed in preclinical lung cancer models.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Oil-in-water emulsions are common in pharmaceutical development and can be applied to polymer micelle preparation.

    “Another technique, oil in water emulsions, is common in pharmaceutical development and can be applied to polymer micelle preparation.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [278] source

      The Introduction and Materials and Methods describe an oil-in-water emulsion used to make polymeric nanoparticles, and the Results and Discussion describe emulsion solvent evaporation as a method used in drug-delivery nanoparticle formulation. They do not support the claim about preparing polymer micelles: the Results and Discussion explicitly say the particles produced are not micellar, while the Methods say incidental micelles are removed. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [279] source

  • May combine two claims.

    Premisecitation

    The organic solvent selected affects polydispersity, highlighting the need to evaluate multiple solvent systems to optimize formulation stability.

    “The selection of organic solvent used also had an effect on polydispersity once again highlighting the need to evaluate multiple solvent systems in order to optimize formulation stability.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [274] source

      Section 3.6 reports broader particle-size distributions with DMSO and THF than with the other two solvents, supporting an effect of solvent choice on polydispersity. The paper compares four solvents, but it does not establish that testing multiple solvent systems is needed to optimize formulation stability; Section 3.6 instead says all the particles were stable against small dilution. Page numbers were not supplied for these passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Solvent selection is a key parameter in thin film hydration; both drug and polymer must dissolve in the chosen organic solvent, but not all good solvents yield stable, uniform micelles.

    “Additionally, solvent selection is a key parameter which is explored in several studies [116, 193, 264]. First of all, both the drug and polymer must be soluble in the selected organic solvent. However, this does not necessarily mean that all good solvents for a polymer-drug system will produce stable, uniform polymeric micelles.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [116] source

      The Methods section (‘Polymeric micelle preparation’) says the drug and polymer were dissolved in an organic solvent for thin-film hydration. The Results (‘Cheminformatics analysis’) identifies solvent choice as important to drug loading. The copy does not establish the further claim that an organic solvent that dissolves both components may fail to produce stable, uniform micelles. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [193] source
    • cites [264] source

  • May combine two claims.

    Premisecitation

    POx-based micelles solubilized multi-drug combinations with loading capacities up to 50%, including 48.7% for a 1:1:1 ratio of paclitaxel:17-AAG:etoposide and 48.4% for a 1:1:1 ratio of paclitaxel:17-AAG:bortezomib.

    “POx-based polymeric micelles were able to solubilize multi-drug combinations with an extremely high LC of up to 50 % (48.7 % LC for 1:1:1 ratio of paclitaxel:17-AAG:etoposide and 48.4 % LC for 1:1:1 ratio of paclitaxel:17-AAG:bortezomib).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The combination polymeric micelle had nanosized and worm-like morphology, which had rarely been reported previously for drug-loaded polymeric micelles.

    “The combination polymeric micelle featured nanosized and worm-like morphology which was rarely reported previously for drug-loaded polymeric micelles.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Drug release from the combination polymeric micelle was slower, presumably because co-loading drugs formed stable micelle formulations.

    “Interestingly, drug release from combination polymeric micelle was slower, presumably due to the formation of stable micelle formulations with the co-loading of drugs.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [114] source

      The Results report slower release of both drugs from co-loaded micelles than from single-drug micelles and separately report that the co-loaded micelles remained stable in solution for at least two weeks. The Discussion tentatively links reduced release and improved retention to increased miscibility of the drug pair, but does not identify formulation stability as the reason for slower release. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PEG-b-PDLLA micelles containing two- or three-drug combinations such as paclitaxel/17-AAG, etoposide/17-AAG, docetaxel/17-AAG, and paclitaxel/etoposide/17-AAG had sizes around 30-40 nm and increased drug solubility up to 3-4 mg/mL in aqueous media.

    “Polymeric micelles of 2- and 3-drug combinations such as paclitaxel/17-AAG, etoposide/17-AAG, docetaxel/17-AAG and paclitaxel/etoposide/17-AAG were small (~30–40 nm) and displayed enhanced drug solubility up to 3–4 mg/mL in aqueous media [260].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    3-in-1 PEG-b-PDLLA micelles containing 17-AAG, paclitaxel, and rapamycin had a hydrodynamic size of about 40 nm and improved drug solubility to approximately 3 mg/mL in aqueous solution.

    “The 3-in-1 micelle featured 40 nm hydrodynamic size and improved drug solubility (approximately up to 3 mg/mL in aqueous solution).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The paclitaxel/alkylated cisplatin combination was effectively solubilized in a POx-based block copolymer with high loading capacity over 50%, forming stable two-drug polymeric micelles.

    “The drug combination was effectively solubilized in a POx-based block copolymer with high LC (over 50 %) and stable polymeric micelles for two-drug combinations were formed.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [188] source

      The Results and Discussion (page unavailable) confirm that paclitaxel and cisplatin prodrugs were co-loaded in stable POx micelles. They report a maximum loading capacity of about 46%, however, not over 50%; the over-50% figure appears in the abstract but conflicts with those body-text measurements. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Resiquimod in polymeric micelles stimulated antigen-presenting cells in the tumor microenvironment, resulting in mobilization of an anti-tumor CD8+ immune response.

    “Investigation of the in vivo immune status following resiquimod in polymeric micelles treatment showed that resiquimod-based stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of anti-tumor CD8+ immune response [259].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Drug-coloaded micelles released drug components more slowly into plasma and improved exposure of both drugs to the tumor site.

    “Drug-coloaded micelles had slower release of the drug components to plasma and improved drug exposure of both drugs to the tumor site (Table 5).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Han et al. reported synergistic solubilization of multiple drugs in a single micelle system with high loading capacity, producing ultra-high loaded polymeric micelle drug formulations.

    “Han et al. reported the synergistic solubilization of multiple drugs in a single micelle system with high LC resulting in formation of ultra-high loaded polymeric micelle drug formulations.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [117] source

      The Results (§3.1) and Discussion (§4) report co-solubilizing binary and ternary drug combinations in POx micelles with high loading capacities, reaching about 48–49% for ternary formulations. They do not establish synergistic *solubilization*: the Discussion says solubilization of drug blends was “similar or better” than for single drugs. The paper’s reported synergy concerns drug effects on cancer cells, not solubilization. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A nanosimilar formulation must show comparable character at each step and cannot rely on in vitro or preclinical animal model data alone, making some level of clinical evaluation necessary.

    “The nanosimilar formulation must show comparable character at each step of the process and cannot rely on in vitro or preclinical animal model data alone, making a case for having some level of clinical evaluation to be necessary for nanosimilars.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [293] source
    • cites [299] source

      The section on the EMA’s evaluation of nanosimilars says that demonstrating similarity in quality, safety, and efficacy requires stepwise comparability studies. It does not say that in vitro and preclinical animal data are necessarily insufficient or that clinical evaluation is required for nanosimilars. The “Versus Development Timeline” section describes exploratory human trials in some cases, but not as a requirement for nanosimilars; page numbers were unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The SITUA method developed by the NCL has potential to probe complex PK behaviors of nano-based pharmaceuticals and can provide strong evidence for similarity of two nanomedicines.

    “For example, the SITUA method (See section 4.2) developed by the NCL has shown the potential to probe the complex PK behaviors of nano-based pharmaceuticals [247]. This kind of analysis can provide strong evidence for the similarity of two nanomedicines.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The 505(j) generic approval pathway requires demonstration of "sameness" with only small formulation changes and can be more challenging for nano-based pharmaceuticals than traditional small molecule formulations due to nanomaterial complexity.

    “The 505(j) pathway for the approval of generics requires the demonstration of “sameness” with only small changes to formulation allowed. This pathway can be more challenging for nano-based pharmaceuticals than traditional small molecule formulations due to the added complexity inherent when working with nanomaterials.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [293] source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The 505(b)(2) pathway allows use of clinical data from the Reference Listed Drug but still requires demonstration of some improved outcome.

    “Utilizing the 505(b)(2) pathway then allows for the use of clinical data from the Reference Listed Drug (RLD). However, by following the 505(b)(2) pathway, one must still demonstrate some kind of improved outcome whether therapeutic, improved shelf-life/stability, increased convenience, reduced metabolic burden, or some other quality which distinguishes it from the innovator product.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [293] source

      Section 2 (page unavailable) says the 505(b)(2) pathway could be used for NBCD/nanosimilar follow-on versions. It does not say that the pathway permits use of clinical data from a Reference Listed Drug or requires an improved outcome of the kinds listed; searches for those terms found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The impact of nanocarriers on safety and efficacy profiles calls for increased scrutiny and rigor in regulatory review.

    “Regulatory appraisal has to deal with its impact on safety and efficacy profiles. This calls for increased scrutiny and rigor in the review process [288, 291, 292].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [288] source
    • cites [291]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [292] source

  • May combine two claims.

    Premisecitation

    The USFDA does not rely on preclinical animal data for nanosimilars and instead focuses on extensive physicochemical characterization followed by clinical PK data.

    “On the other hand, the USFDA does not rely on pre-clinical animal data and instead focuses on extensive physicochemical characterization followed by clinical PK data [291, 293].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [291]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [293] source

      Section 2 says that, for follow-on iron nanocolloids, the FDA favors extended physicochemical characterization together with plasma pharmacokinetics over nonclinical animal evaluation. The claim generalizes that approach to nanosimilars as a whole; the same section notes that animal studies are listed among factors in another FDA nanomaterials document. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The traditional US application process for NDAs of novel human pharmaceuticals, including nanomaterials, occurs through the 505(b)(1) pathway; the 505(b)(2) pathway applies to products closely related to innovators.

    “The traditional application process in the US for New Drug Application (NDA) of novel human pharmaceuticals, including those containing nanomaterials, occurs through the 505(b)(1) regulatory pathway. In addition, the 505(b)(2) pathway exists and applies to products closely related to the innovators.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [293] source

      Section 2 (page unavailable) says that 505(b)(2) is within the NDA framework and could be used for NBCD or nanosimilar follow-on versions, supporting the claim about products related to innovators. The available text does not state that novel pharmaceuticals containing nanomaterials follow the 505(b)(1) pathway, and it describes 505(b)(2) as a possibility rather than an unqualified rule. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ICH Q8 and Q11 guidelines provide knowledge on scientific approaches and quality risk management for product development and manufacturing.

    “International Conference on Harmonisation (ICH) guidelines Q8 Pharmaceutical Development of the European Medicines Agency (EMA) and Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) of the USFDA provide such guidelines to provides knowledge on the application of scientific approaches and quality risk management for the development of a”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [286]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [287] source

  • May combine two claims.

    Premisecitation

    If an API is reformulated into a new nanocarrier, it may proceed through 505(b)(1) with a non-similar PK profile to the innovator or 505(b)(2) if the PK profile is similar.

    “If an API has been reformulated into a new ‘nanocarrier’, then it may proceed along either the 505(b)(1) with non-similar PK profile to the innovator or the 505(b)(2) route if the PK profile is similar.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [293] source

      Section 2 (page unavailable) says that 505(b)(2) could be used for NBCD/nanosimilar follow-on versions. It does not say that a reformulated API's route is determined by whether its PK profile is similar to the innovator's, or establish the claimed 505(b)(1) alternative. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    SP1049C is a doxorubicin-loaded Pluronic-based formulation developed by Supratek Pharma and was the first polymeric micelle drug formulation to enter clinical trials in 1999.

    “SP1049C is a doxorubicin-loaded Pluronic®-based formulation which was developed by Supratek Pharma Inc. and was the first polymeric micelle drug formulation to enter clinical trials in 1999 [17].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] source

      The Discussion describes SP1049C as doxorubicin incorporated into Pluronic L61/F127 micelles, and the Treatment section says Supratek Pharma supplied its carrier solution (page numbers unavailable). The paper calls this the first clinical trial of SP1049C, but does not establish that it was the first polymeric micelle drug formulation to enter clinical trials, that entry occurred in 1999, or that Supratek developed it. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a phase I trial, SP1049C exhibited a similar PK profile of doxorubicin to conventional doxorubicin and a similar MTD of 70 mg/m2 in patients with metastatic or recurrent solid tumors.

    “In the phase I clinical trial, SP1049C exhibited a similar PK profile of doxorubicin to the conventional doxorubicin formulation and a similar MTD of 70 mg/m2 in the patients with metastatic or recurrent solid tumors [17].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] source

      The Discussion (page unavailable) reports an SP1049C MTD of 70 mg/m² and says its pharmacokinetic profile was similar to conventional doxorubicin, but with slower terminal clearance. The Abstract (page unavailable) also emphasizes slower clearance. The trial enrolled patients with advanced cancer refractory to conventional treatment or lacking a suitable treatment; the paper does not define the whole cohort as having metastatic or recurrent solid tumours. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NC-6004 exhibited stable micelles in solution and slowly released cisplatin over 150 hours in physiological saline; it had a narrow size distribution of 28 nm and cisplatin loading up to 39% LC.

    “NC-6004 exhibited stable micelles in solution and slowly released cisplatin from the micelle for over 150 h in physiological saline. NC-6004 exhibited a narrow size distribution in solution with a size of 28 nm and loading of cisplatin in NC-6004 was up to 39% LC [153].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [153] source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In July 2016, an open-label phase III non-inferiority trial of NK105 in metastatic or recurrent breast cancer was completed (NCT01644890); 436 patients received either NK105 at 65 mg/m2 or conventional paclitaxel at 80 mg/m2.

    “In July 2016, an open-label phase III non-inferiority trial of NK105 in patients with metastatic or recurrent breast cancer was completed (ClinicalTrials.gov: NCT01644890) [307]. Four hundred thirty-six patients were enrolled in the study and administered either NK105 (65 mg/m2) or conventional paclitaxel (80 mg/m2).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [307] source

      The Study design and Treatment sections describe the open-label phase III non-inferiority trial and the stated doses; the trial registration is NCT01644890. Results > Patients reports that 436 patients were randomised, but only 427 were included in the safety analysis, so the paper does not support saying all 436 received treatment. Our copy does not establish that the trial was completed in July 2016. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The phase III trial failed to meet the primary endpoint of statistical non-inferiority of progression-free survival; median PFS was 8.4 vs 8.5 months, median OS 31.2 vs 36.2 months, and overall response rates 31.6% vs 39.0% for NK105 vs paclitaxel.

    “The results of the phase III trial revealed that the primary endpoint (statistical non-inferiority of progression-free survival) was not met (the median progression free survival (PFS) of 8.4 and 8.5 months for NK105 and paclitaxel, respectively, and the median overall survival of 31.2 and 36.2 months, and overall response rates of 31.6% and 39.0%, respectively) [307].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    NC-6004 exhibited extended half-life and increased AUC compared to cisplatin infused as an aqueous solution due to prolonged blood circulation of NC-6004.

    “Also, NC-6004 exhibited extended half-life and increased AUC compared to cisplatin infused as an aqueous solution due to the prolonged blood circulation of NC-6004.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In a phase I trial of NK105, 19 patients with various cancers were recruited to examine safety and PK; doses ranged from 10 to 180 mg/m2 without premedication; the MTD was 180 mg/m2 due to neutropenia; plasma AUC of paclitaxel from NK105 at 150 mg/m2 was approximately 15-fold higher than from Taxol at 210 mg/m2; NK105 was well tolerated with reduced hypersensitivity reactions.

    “In a phase I trial of NK105, nineteen patients with various type of cancers (pancreatic, bile duct, gastric, and colonic) were recruited to examine the safety and PK of NK105. NK105 doses ranging from 10 mg/m2 to 180 mg/m2 was administered to patients without premedication. The MTD of NK105 was determined to be 180 mg/m2 due to dose limiting hematological toxicity (neutropenia). The PK profile of”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    NK105 is composed of paclitaxel and modified mPEG-b-P(Asp) block copolymer with mPEG 12,000 g/mol and P(Asp) 8,000 g/mol, where half of the carboxylic groups of the P(Asp) block are modified with hydrophobic 4-phenyl-1-butanol to increase hydrophobicity and improve drug incorporation.

    “NK105 is composed of paclitaxel and modified mPEG-b-P(Asp) block copolymer (mPEG = 12,000 g/mol and P(Asp) = 8,000 g/mol) where half of the carboxylic groups P(Asp) block is modified with hydrophobic 4-phenyl-1-butanol to increase its hydrophobicity and improve drug incorporation [7].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    NK105 exhibited 23% drug loading with a hydrodynamic size of approximately 90 nm.

    “NK105 exhibited 23% of drug loading with a hydrodynamic size of approx. 90 nm [7].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The incidence of peripheral sensory neuropathy among NK105-treated patients was decreased compared to paclitaxel, indicating an improved toxicity profile.

    “However, the incidence of peripheral sensory neuropathy among patients treated with NK105 was decreased compared to that of paclitaxel, indicating an improved toxicity profile of the drug in NK105 [307].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    In a phase I trial, 17 patients with advanced solid tumors received NC-6004 at 10-120 mg/m2; toxicities occurred at 90 mg/m2, and the MTD was 120 mg/m2 due to renal impairment and hypersensitivity reactions.

    “In a phase I clinical trial, a total of 17 patients with various type of advanced solid tumors were recruited to evaluate the efficacy and safety of NC-6004 [308]. NC-6004 was administered in doses ranging from 10 mg/m2 to 120 mg/m2. Drug toxicities were observed at the dose of 90 mg/m2 of NC-6004, and 120 mg/m2 of NC-6004 was determined as the MTD due to renal impairment and hypersensitivity”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims. The quote only partly states this claim.

    Findingreasoning

    Polymeric micelles have enhanced efficacy and a superior safety profile for therapeutic drugs.

    “Polymeric micelles have shown improved pharmacokinetic profiles in preclinical animal models and enhanced efficacy with a superior safety profile for therapeutic drugs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pharmacokinetic improvements observed in preclinical animal models for polymeric micelle drugs will translate to improved clinical outcomes in humans.

  • May combine two claims.

    Findingcitation

    As PEO chain length increased, apparent penetration of PEO chains into the poloxamer micelle core increased and the core environment became less hydrophobic.

    “As the length of PEO chain increased the apparent penetration of PEO chain in the core also increased and the core environment became less hydrophobic.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

  • May combine two claims.

    Findingcitation

    SANS has been used to reveal the microstructure of the core and shell of drug-free polymeric micelles and more recently extended to drug-loaded micelles.

    “This method has been previously used to reveal the microstructure of the core and shell of drug-free polymeric micelles [228] and more recently extended to the thorough characterization of drug-loaded micelles.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] source

  • May combine two claims.

    Findingreasoning

    Studies performed in serum often show quicker release profiles because hydrophobic drugs can directly transfer from micelles to serum protein molecules, which serve as carriers to the external solution.

    “Studies performed in serum will often show quicker release profiles as hydrophobic drugs can directly transfer from the micelle to the serum protein molecules and the latter can serve as carrier for the drug to the external solution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Taxol has shown anti-cancer efficacy in human patients and is still approved for humans, but its excipients cause toxicity and limit the ability to dose Taxol.

    “Though Taxol® has shown anti-cancer efficacy in human patients and is still approved for humans, these excipients cause toxicity and limit the ability to dose Taxol® [237].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [237]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation

    The Cremophor EL-free Genexol PM formulation of paclitaxel was much safer than Taxol in cancer patients and had less concern of hypersensitivity reactions.

    “For instance, it was shown that the Cremophor EL-free Genexol® PM formulation of paclitaxel (approved in South Korea and several other countries) was much safer than Taxol® in cancer patients (390 and 200 mg/m2 doses approved, respectively) and there were much less concern of hypersensitivity reactions compared to those that can be observed during Taxol® treatment [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Polyesters are frequently used as hydrophobic polymer candidates in polymeric micelle formulation design.

    “Polyesters are other exemplary hydrophobic polymer candidates which are frequently used in the formulation design of polymeric micelles.”
    Quote in the paperNot a substantial claim

  • Borderline on S4 (based): unclear from the text.

    Premisenone given

    Hydrophobic segments of block copolymers play an essential role in solubilizing and encapsulating poorly soluble drugs in the core of polymeric micelles.

    “Hydrophobic segments of block copolymers play an essential role in solubilizing and encapsulating poorly soluble drugs in the core of polymeric micelles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Ideal polymeric micelles are expected to reduce the toxicity of encapsulated drugs.

    “Furthermore, ideal polymeric micelles are expected to reduce the toxicity of the therapeutic compounds.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The hydrophilic shell of polymeric micelles helps avoid drug loss from serum components and prevents complement opsonization that would otherwise cause rapid clearance.

    “Structural features of polymeric micelles, such as the hydrophilic shell, help to avoid both unexpected drug loss from serum components and prevent opsonization by the complement system which typically result in the rapid clearance of drugs from systemic circulation [15, 16].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] source
    • cites [16] source

  • May combine two claims.

    Premisecitation

    Block copolymer design aims to encapsulate therapeutic compounds into polymeric micelles through molecular interactions, protecting the cargo and improving pharmacokinetics.

    “The design of block copolymers is intended to effectively encapsulate therapeutic compounds into polymeric micelles by various molecular interactions which results in the protection of the cargo from the external environment and improvements of the pharmacokinetic (PK) profile [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Over the past thirty years, polymeric micelles have become a promising platform for delivering therapeutic compounds.

    “Over the last three decades, polymeric micelles have emerged as a highly promising drug delivery platform for therapeutic compounds.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    An improved safety profile of compounds in polymeric micelles can expand the therapeutic window and improve outcomes.

    “The safety profile of compounds within polymeric micelles could improve therapeutic outcomes by expanding the therapeutic window.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The hydrophobic block of block copolymers solubilizes poorly soluble drugs in the core and controls drug release from micelles.

    “The hydrophobic block of block copolymers is intended to solubilize poorly soluble drugs in the core and control the release of the drug from the polymeric micelles [36–38].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] source
    • cites [37] source
    • cites [38] source

  • May combine two claims.

    Premisenone given

    The core holds the micelle together and solubilizes poorly soluble small molecules.

    “The core holds the micelle together and solubilizes poorly soluble small molecules.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PEG with molecular weights from 1 to 6 kDa is ideal for endowing nanoparticles with efficient anti-fouling properties and is frequently used in block copolymers for drug delivery.

    “PEG with molecular weights ranging from 1 to 6 kDa are an ideal molecular weight for endowing nanoparticles with efficient anti-fouling properties and are frequently being employed to prepare block copolymers for drug delivery [34, 69, 70].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] source
    • cites [69] source
    • cites [70] source

  • May combine two claims.

    Premisecitation

    Pidhatika et al. found that PMeOx maintained anti-fouling properties for long-term exposure while PEG did not.

    “However, for a long-term exposure to media, it was found that only PMeOx, but not PEG, could maintain the anti-fouling properties.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] source

  • May combine two claims.

    Premisecitation

    Anti-PEG antibodies did not affect the pharmacokinetics of PEG-b-PBLA polymeric micelles, while PEG-liposomes had significantly decreased circulation times after repeated dosing.

    “According to Shiraishi et al., anti-PEG antibodies did not affect the PK of PEG-b-poly(b-benzyl L-aspartate) (PEG-b-PBLA) polymeric micelles, while the PK profile of PEG-liposomes was marked by significantly decreased circulation times after repeated dosing [84].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] source

  • May combine two claims.

    Premisenone given

    The shell prevents aggregation and precipitation of micelles and protects the therapeutic cargo.

    “The shell prevents aggregation and precipitation of the micelles while also protecting the therapeutic cargo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Polymeric micelles are dynamic systems that release drug to their target more easily than rigid solid nanoparticle systems.

    “Polymeric micelles are dynamic systems. Because of this, they release the drug to their target much easier than many more rigid, “solid” nanoparticle systems.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The pyrrolidone moiety and amide groups in the side chain are closely related to PVP's anti-fouling properties, but comprehensive mechanisms are still unknown.

    “Allegedly, both the pyrrolidone moiety and amide groups in the side chain are closely related to the anti-fouling properties of PVP, but comprehensive mechanisms of these properties are still unknown [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] source

  • May combine two claims.

    Interpretationreasoning

    This allows encapsulated drug to stably reside in the core during systemic circulation and gradually be released to the external environment.

    “This allows encapsulated drug to stably reside in the core during systemic circulation and gradually be released to the external environment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    PBLA and PBLG are commonly used hydrophobic poly(amino acid)s.

    “Commonly used hydrophobic poly(amino acid)s are poly(β-benzyl-l-aspartate) (PBLA) and poly(γ-benzyl-α, l-glutamate) (PBLG).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    That PEG-b-PBLA micelle formulation had doxorubicin loading of 15-20% and size distribution of 57-70 nm.

    “The micelle formulation exhibited 15–20% of doxorubicin loading and a 57–70 nm of size distribution.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] source

  • May combine two claims.

    Premisecitation

    PPO and poly(butylene oxide) have hydrophobic properties and, when incorporated in block copolymers, can solubilize hydrophobic drugs.

    “PPO and poly(butylene oxide) have shown hydrophobic properties and, when incorporated in block copolymers, have the capacity to solubilize hydrophobic drugs [4, 103].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] source
    • cites [103] source

  • May combine two claims.

    Premisecitation

    Those PEG-SS-PBLG micelles had sizes of 20-125 nm and drug loading up to 12%.

    “The micelles displayed 20–125 nm size and the drug loading capacity was up to 12 %.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] source

  • May combine two claims.

    Premisecitation

    In that study, Pluronic block copolymer micelles solubilized haloperidol and were conjugated with insulin or antibody to neurospecific antigens to deliver the neuroleptic to the brain.

    “In that study Pluronic® block copolymer micelles were used to solubilize a neuroleptic drug, haloperidol, and the micelles were conjugated with insulin or antibody to neurospecific antigens to deliver this neuroleptic to the brain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premiseown data

    These block copolymers were the first used for delivery of non-covalently incorporated drug in polymeric micelles.

    “In fact these block copolymers were the first used for the delivery of non-covalently incorporated drug in polymeric micelles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PEG-SS-PBLG can solubilize camptothecin and form micelles in solution.

    “According to Thambi et al., PEG-b-PBLG bearing the disulfide bond (PEG-SS-PBLG) could solubilize poorly soluble camptothecin and form micelles in solution [59].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The concept of a micellar microcontainer, now called a micellar nanocontainer, was introduced by our group in the late 1980s.

    “This concept was introduced by our group in the late 1980s and was initially termed “micellar microcontainer”, but is now widely known as a “micellar nanocontainer” [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Commonly employed hydrophobic polymers are polyethers and polyesters.

    “Commonly employed hydrophobic polymers are polyethers and polyesters.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    In weakly acidic environments, PBAE protonates, the micelle core swells, and the drug is rapidly released.

    “In weakly acidic environments the PBAE protonates, the micelle core swells, and the drug is rapidly released.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Endosomes and the tumor microenvironment have slightly acidic local pH and are targeted by pH-sensitive polymers.

    “Endosomes and the tumor microenvironment where the local pH is slightly acidic are the targeted spaces for such pH-sensitive polymers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Paclitaxel was highly soluble in PMeOx-b-PBuOx-b-PMeOx but less soluble in its POzi analog.

    “Meanwhile, paclitaxel was highly soluble in PMeOx-b-PBuOx-b-PMeOx but is less soluble its POzi analog [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] source

  • May combine two claims.

    Premisecitation

    POx-based polymers show little degradation in biological fluids in the short term, but POx can degrade long-term via oxidative degradation.

    “POx-based polymers have shown little degradation in biological fluids in the short-term, but it was reported that POx can be degraded in the long-term via oxidative degradation [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] source

  • May combine two claims.

    Premisecitation

    Paclitaxel was solubilized in POx up to 40 mg/mL in aqueous solution, forming spherical micelles smaller than 50 nm.

    “For example, paclitaxel was extremely well-solubilized in POx up to a paclitaxel concentration of 40 mg/mL in aqueous solution to form well-defined spherical micelles with a size of less than 50 nm [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    ELPs are polypeptides with elastin-like properties that can induce LCST phase transition behavior.

    “ELPs are polypeptides composed of amino acids which exhibit elastin like properties that potentially induce LCST phase transition behavior.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    PBAEs are insoluble at neutral pH but degrade to soluble fragments in acidic and alkali environments due to tertiary amine groups.

    “Due to the tertiary amine groups in the polymer structure, PBAEs exhibit pH-sensitive behavior with the polymer being insoluble at neutral pH but degrading to soluble fragments in acidic and alkali environments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    PMeOx in the shell can support very high drug loading and stabilize the micelle structure in solution.

    “With highly hydrophilic properties, PMeOx in the shell could support super high drug loading micelle formulation and stabilize the micelle structure in solution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Temperature-responsive polymers with LCST are hydrophilic and water-soluble below LCST, but above LCST they dehydrate, become hydrophobic, and phase-separate from solution.

    “At temperatures below LCST such polymers are hydrophilic and water-soluble, but above LCST they dehydrate and transform to hydrophobic polymers that phase-separate from a solution.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PBAE-based copolymers have also been used as carriers for nucleic acids because of their cationic charge.

    “Due to the presence of the cationic charge, PBAE-based copolymers were also employed as carriers for nucleic acids [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] source

  • May combine two claims.

    Premisecitation

    PMAA carboxylic groups are ionized and charged at pH 7.4, making the polymer soluble, while at acidic pH they protonate and the polymer becomes insoluble due to methyl groups in the backbone.

    “For example, the carboxylic groups in PMAA are ionized and charged at the physiologic pH 7.4 which renders the polymer soluble, while at acidic pH these groups protonate and the polymer becomes insoluble due to the presence of methyl groups in the backbone of the main chain [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] source

  • May combine two claims.

    Premisecitation

    A 16-arm star block copolymer with inner PCL and outer PEG blocks, stPCL-PEG16, exhibited etoposide loading up to 22% w/w and no toxicity on porcine kidney epithelial cells.

    “The micelle formulation from the resulting 16-arm star-block copolymer, stPCL-PEG16 exhibited high loading of a hydrophobic drug, etoposide up to 22% w/w and did not show toxicity on porcine kidney epithelial cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] source

  • May combine two claims.

    Premisecitation

    In the early 1980s, Ringsdorf used PEG-polypeptide block copolymers with hydrophobic and cyclophosphamide-containing side groups; drug conjugation made the conjugate block hydrophobic and the copolymer amphiphilic, leading to micelle self-assembly.

    “In early 80-ies, Ringsdorf used PEG-polypeptide block copolymers with hydrophobic and cyclophosphamide-containing side groups, where upon conjugation of the drug, the drug conjugate block becomes hydrophobic and the entire block copolymer becomes amphiphilic resulting in drug-conjugate self-assembly into the polymeric micelles [143].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Clinical translation of cross-linked micelle designs has not yet occurred, and in the authors' view a major challenge is consistency of cross-linking chemistry and characterization of crosslink number and spatial distribution.

    “However, the clinical translation of the cross-linked micelle designs has not occurred yet, with one of the greatest challenges in our view being consistency of the cross-linking chemistry and characterization of the chemical composition including the number and spatial distribution of the crosslinks in the resulting crosslinked micelles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The conjugated drug was not easily released from the micelle core, causing negligible drug activity, but toxicity decreased and circulation time increased.

    “However, the conjugated drug was not easily released from the micelle core, resulting in negligible drug activity; albeit, the toxicity to the body was also decreased and circulation time greatly increased [149].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149]

  • May combine two claims.

    Premisereasoning

    Below the CMC, micelles in solution tend to dissociate and loaded drug may be dispersed unexpectedly.

    “Below the CMC, micelles in solution tend to dissociate and the loaded drug may be unexpectedly dispersed in the solution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cross-linked micelles are single nanoscale molecules that are stable upon dilution, shear forces, and environmental variations such as pH, ionic strength, and solvents.

    “The resulting cross-linked micelles are, in essence, single molecules of nanoscale size that are stabile upon dilution, shear forces and environmental variations (e.g. changes in pH, ionic strength, solvents etc.) [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    DACHPt was attached via coordination bonding of platinum to carboxylic groups of P(Glu), and active drug was released via ligand exchange with chloride ions.

    “Similarly to CDDP, DACHPt was attached via coordination bonding of the platinum to the carboxylic groups of P(Glu) block and the active drug was released via ligand exchange of DACHPt with chloride ions in environment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Unimolecular micelles are topologically similar to self-assembled micelles but consist of single polymer molecules with covalently linked amphiphile block copolymer chains.

    “Unimolecular micelles are topologically similar to self-assembled micelles, but consist of single polymer molecules with covalently linked amphiphile block copolymer chains [155].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In that study, PDLLA and PLLA cores differed drastically in drug solubilization, which SPs did not reflect because they do not distinguish stereoisomers.

    “Interestingly, there was a drastic difference in the drug solubilization in the micelles with PDLLA and PLLA core forming blocks. This was not reflected in the SPs which do not distinguish between stereoisomers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The extent of drug partitioning is determined by the partition coefficient, which depends on aqueous drug solubility and drug-polymer interactions in the micelle core.

    “The extent of the partitioning is defined by the value of the partitioning coefficient, which depends on the drug solubility in the aqueous solution and drug-polymer interactions in the micelle core.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    In Hansen solubility parameter theory, two components are predicted miscible when the difference in SPs is less than or equal to the interaction sphere radius.

    “In the case of Hansen’s SP, two components are predicted to be miscible when the difference in SPs is less than (or equal) to the interaction sphere radius defined by Equation 5:”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Several studies found that enthalpies of mixing from Hansen SP calculations could predict solubilization of hydrophobic drugs by amphiphilic block copolymers, though predictions were unsatisfactory in some cases.

    “Several studies on drug and macromolecule compatibilities revealed that the enthalpies of mixing derived from the calculation of Hansen’s SP could predict the solubilization of hydrophobic drugs by amphiphilic block copolymers. Although, in some cases the predictions were not satisfactory (Table 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Kinetic stability reflects the dynamic nature of micelles in aqueous media and their stability over time.

    “Kinetic stability of the assembled micelles reveals the dynamic character of the micelles in aqueous media and its stability in solution over time [23, 182].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] source
    • cites [182] source

  • May combine two claims.

    Premisereasoning

    Molecular interactions between encapsulated drugs and hydrophobic blocks assist micelle formation and further stabilize the micelle structure in solution.

    “The molecular interactions between encapsulated drugs and hydrophobic blocks not only assist the formation of the micelle, but also further stabilize micelle structure in solution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    When a micellar drug formulation is diluted in water, drug partitions into the external solution; once copolymer concentration falls below the CMC, micelles disintegrate into unimers and release remaining drug.

    “Upon micellar drug dilution in water, the drug partitions itself in the external solution. Once the block copolymer concentration drops below the CMC the micelle disintegrates into single block copolymer molecules (“unimers”) releasing the remaining drug.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In that study, computational methods were sometimes misleading, especially for non-solubilizable drugs, and could not account for small side-chain changes or differentiate between two drugs using SPs alone.

    “However, the computational methods in some cases were misleading, especially in the case of non-solubilizable drugs. They also could not account for small changes in the chemical structure of the side chains of the polymers that had tremendous impact on polymer−drug compatibility. No differentiation between two different drugs would have been possible using these SPs only.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] source

  • Classified as probably not a substantial claim.

    Premisecitation

    In that study, high drug loading and supersaturation of micelles may have contributed to the lack of correlation with SPs.

    “In this case the drug loading was high and the micelles were supersaturated with the drug, which could have contributed to the lack of correlation with the SPs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Experimental validation of predictions from these computational approaches has been performed.

    “Experimental validation of the prediction data from the aforementioned approaches has been performed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In that study, prodrug derivatives of geldanamycin with varying alkyl chain lengths were prepared to lower χFH and improve solubilization, and prodrugs with lower interaction parameters showed enhanced solubilization.

    “Then they prepared a series of prodrug derivatives of geldanamycin with varying alkyl chain lengths in an attempt to lower χFH and thereby improve the solubilization in the micelle. This approach was shown to be successful as the prodrugs with the lower interaction parameters indeed demonstrated enhanced solubilization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hansen SPs can be determined experimentally or estimated by group contribution methods.

    “The Hansen’s SPs of various substances can be determined experimentally or estimated using the group contribution method (GCM), which estimates CED as the sum of partial contributions from all functional and structural groups of a molecule (see [213] for further review).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Danquah et al. found that bicalutamide solubilization in mPEG-b-poly(carbonate-co-lactide) exceeded that in mPEG-b-PLLA, consistent with Flory-Huggins prediction.

    “The drug solubilization in mPEG-b-poly(carbonate-co-lactide), containing additional carbonate groups in the core-forming block, exceeded that in mPEG-b-PLLA, which was again consistent with the prediction based on the Flory-Huggins interaction parameter.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] source

  • May combine two claims.

    Premisecitation

    PDLLA and PLLA also differed in aggregation behavior and crystallinity, which likely affected drug placement in the core.

    “The PDLLA and PLLA also differed in their aggregation behavior and degree of crystallinity that most likely affected the placement of the drug in the core.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] source

  • May combine two claims.

    Interpretationreasoning

    In most cases, classic χFH theory can only be used for ranking polymer-drug interactions to reveal possible trends in drug solubilization, and in some cases it can be false.

    “As a result, in most cases the classic theory χFH can only be used for polymer-drug interactions ranking to reveal possible trends in drug solubilization and in some cases it can be false.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In that study, ellipticine release was closely related to SPs: PCL sustained release over 6 days, while PDLLA released faster and completed within 3 days.

    “Specifically, a compatible polymer, such as PCL, sustained the release of ellipticine for over 6 days, while a less compatible polymer, such as PDLLA, showed a faster release of ellipticine which was complete within 3 days.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] source

  • May combine two claims.

    Premisecitation

    Hydrogen bonding and pi-pi interactions can affect CMC values of drug-loaded polymeric micelles and enhance micelle stability.

    “Other molecular interactions such as hydrogen bonding or pi-pi interactions are known to affect CMC values of drug-loaded polymeric micelles and facilitate enhanced stability of the micelles [186].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    According to Flory-Huggins theory, two components are predicted miscible if χFH < 0.5 and phase separated if χFH > 0.5.

    “According to the Flory-Huggins theory, two components are predicted to be miscible if χFH is less than 0.5, or phase separated if χFH > 0.5.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    A traditional view holds that solubilization is primarily driven by hydrophobic interactions between incorporated molecules and hydrophobic domains in the micelle core.

    “A traditional view is that the solubilization process primarily driven by hydrophobic interactions between the incorporated molecules and the hydrophobic domains of the micelles formed by segregated copolymer blocks in the micelle core.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mahmud et al. found that the interaction parameter correctly predicted the trend of cucurbitacin I loading in three micelle systems, but release profiles were not predictable and depended on core viscosity.

    “They also found that the interaction parameter correctly predicted the trend of the drug loading. However, in this case the release profiles of the drug from the micelle were not predictable. Rather, the release of the drug depended on the core viscosity which likely controls the drug diffusion from the micelle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The CMC and drug partitioning between micelle and external milieu have long been considered thermodynamic measures of micelle stability as a drug carrier under equilibrium conditions.

    “The CMC and the partitioning of the drug between the micelle and the external milieu has long been considered a thermodynamic measure of the stability of the micelle as a drug carrier in equilibrium conditions [29, 187].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] source
    • cites [187] source

  • May combine two claims.

    Premisecitation

    Patel et al.'s simulations suggested differential drug localization within micelles depending on drug and block copolymer ratio; nimodipine at high loading localizes deeper in PCL, while fenofibrate clusters around both PCL and PEG.

    “For example, nimodipine at high drug loading has higher solubility in PCL and localizes deeper within the core, whereas fenofibrate clusters around both PCL and PEG.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [201] source
    • cites [202] source
    • cites [203] source

  • May combine two claims.

    Premisecitation

    MD and DPD simulations of pH-sensitive mPEG-b-PBAE suggested that protonation of PBAE block causes transition from hydrophobic to hydrophilic, accompanied by aggregate shape transition from spherical to disk-like micelles to vesicles.

    “This multi-scale simulation suggests that the PBAE block upon protonation undergoes the transition from hydrophobic to hydrophilic. This is accompanied by a transition of the shape of the polymeric aggregates from spherical to disk-like micelles and finally to vesicles, as dictated by the counterbalance of free energies for the formation of shell, interface, and core.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] source

  • May combine two claims.

    Interpretationcitation

    Overall, MD studies elucidated molecular interactions in the core of drug-containing micelles and suggested MD simulation can be useful for analyzing important trends of drug solubilization in polymeric micelle systems.

    “Overall, these studies elucidated the molecular interactions occurring in the core of the drug-containing micelles and suggested that MD simulation can be useful for analyzing some important trends of drug solubilization in polymeric micelle systems.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The classic Flory-Huggins method fails to consider molecular geometry, excluded volume interactions, and cannot distinguish isomers with identical chemical structures but different constitution/configuration.

    “The classic method fails to take into consideration the geometry of the molecules involved, the excluded volume interactions that are especially prevalent for long-chain copolymers, and cannot distinguish between isomers that have identical chemical structures but different constitution and configuration [201].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] source

  • May combine two claims.

    Interpretationcitation

    Increased PEO length allows greater distribution of ethylene oxide units and water into the micellar core, decreasing its hydrophobicity and lowering the partitioning coefficient.

    “The authors detailed that an increase in the PEO length allowed increased distribution of ethylene oxide units and water into the micellar core, decreasing its hydrophobicity and lowering the partitioning coefficient [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patel et al. predicted an opposite solubilization trend for nimodipine and fenofibrate, which have only hydrogen bond acceptors and could not bind effectively with the branched multiblock copolymer, but no experimental evidence validated these predictions.

    “An opposite trend in solubilization was predicted for nimodipine and fenofibrate that have the hydrogen bond acceptors only and could not bind effectively with the branched multiblock copolymer, although no experimental evidence was provided to validate these predictions in this study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] source

  • May combine two claims.

    Premisecitation

    MD simulation of itraconazole in PEG-b-PLGA micelles showed that drug loading primarily occurred at water-polymer interfaces while the micelle core tended to remain empty.

    “The results demonstrated that the drug loading primarily occurred at the water-polymer interfaces, while the core of the micelle tends to remain empty.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] source

  • May combine two claims.

    Premisenone given

    The classic Flory-Huggins method tends to underestimate polar and Coulomb interactions and lacks a straightforward way to account for drug interactions with both core- and shell-forming blocks.

    “It also tends to underestimate polar and coulomb interactions, and does not provide a straightforward approach for accounting for the drug interactions with both core- and shell-forming block.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    MD simulations can account for drug interactions with both shell and core forming blocks and for interactions of the blocks with each other.

    “Moreover, the MD simulations can also account for drug interactions with both shell and core forming blocks as well for the interactions of the blocks with each other.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In that simulation, camptothecin loading predicted by Flory-Huggins parameter and MD was in good agreement with experimental values, with drug loaded into both hydrophobic core and core interface with hydrophilic shell loading.

    “The loading of a drug (camptothecin) in such aggregates predicted by the Flory-Huggins parameter and MD simulation was in good agreement with the experimental values. The drug was loaded into both hydrophobic core and core interface with hydrophilic shell loading.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lubtow et al. also concluded that Hansen SP values could better predict some trends in identifying good and poor solubilizers among the block copolymers.

    “As discussed in the previous section, they also concluded that the Hansen SP values could better predict some trends in identifying good and poor solubilizers among the block copolymers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] source

  • May combine two claims.

    Premisecitation

    Patel et al. found that Flory-Huggins interaction parameters computed by MD successfully predicted experimental solubility of fenofibrate, nimodipine, cucurbitacin B, and cucurbitacin I in mPEG-b-PCL micelles, whereas GCM-calculated parameters deviated from experiments.

    “They found that Flory-Huggins interaction parameters computed by MD simulations could successfully predict the experimental solubility of the drugs in the micelles, whereas those calculated by the GCM deviate from the experimental observations.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [201] source
    • cites [202] source
    • cites [203] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In general, sink conditions are around 5 times the volume necessary for saturation of the drug in the system.

    “Literature varies on the definition of sink conditions, but in general the value is around 5 times the volume necessary for saturation of the drug in the system [229].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] source

  • May combine two claims.

    Interpretationreasoning

    Because the same limitation exists during in vivo circulation, use of sink conditions for in vitro release is still a good initial assessment of drug release behavior.

    “However, this same kind of limitation exists during in vivo circulation, so the use of sink conditions for in vitro release is still a good initial assessment of drug release behavior [229].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sink conditions ensure that complete dissolution of the drug from the polymeric micelle system is feasible.

    “Sink conditions ensure that complete dissolution of the drug from the polymeric micelle system is feasible.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] source

  • May combine two claims.

    Premisereasoning

    Sink conditions address potential saturation of drug in the system but not potential saturation of drug in the dosage form.

    “Sink conditions address the potential for saturation of the drug in the system, but not for the potential of saturation of drug in the dosage form.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    2D HMQC ssNMR provides additional structural insights and, combined with 1D NMR, SANS, MD, and other advanced techniques, yields a better understanding of drug-polymer interactions.

    “Therefore, 2D HMQC ssNMR provides additional structural insights, and in combination with 1D NMR, SANS, MD, and other advanced characterization techniques, yields a better understanding of drug-polymer interactions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Nanomedicines introduce additional complexities to traditional pharmacokinetic studies, modeling, and analysis.

    “The advent of nanomedicines introduces additional complexities to traditional PK studies, modeling, and analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The flaw of the Wilhelm et al. analysis is that percent injected dose in tumor does not relate tumor exposure to systemic exposure as the AUC ratio does, and is therefore not a true measure of tumor delivery efficiency.

    “Therefore, the flaw of the Wilhelm et al. analysis is that %ID in tumor does not relate tumor exposure to systemic exposure, as AUC ratio does, and is therefore not a true measure of the tumor delivery efficiency.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A rigorous nanoparticle pharmacokinetic analysis of tumor drug delivery should account for Cmax in the tumor, nanoparticle drug release, tumor free drug exposure, and overall exposure time.

    “Moreover, a rigorous nanoparticle PK analysis of tumor drug delivery should have accounted for Cmax in the tumor, nanoparticle drug release, tumor free drug exposure and overall exposure time.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    SITUA should be cautiously applied to polymeric micelle drug systems, and additional considerations such as dependence of the bound tracer fraction on formulation concentration should be taken into account.

    “Until then, the SITUA assay should be cautiously applied to polymeric micelle drug systems and additional considerations such as dependence of the bound D* fraction on the formulation concentration should be taken in account.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationcitation

    It is best to measure the distinct drug fractions individually because the released drug fraction correlates with toxicity and efficacy.

    “Therefore, it is always best to measure these distinct fractions individually as it is the released drug fraction that correlates with toxicity and efficacy [245].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [245]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    The percent injected dose in tumor metric reduces time-concentration data to a single average, neglects overall exposure time, and does not relate tumor and systemic exposure.

    “This metric reduces the time-concentration data to a single average value, neglects overall exposure time and does not relate the tumor and systemic exposure [242, 243].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [242] source
    • cites [243] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Applying basic pharmacokinetic principles to nano-based pharmaceuticals is not trivial and requires additional considerations.

    “However, the application of basic PK principles to nano-based pharmaceuticals is not trivial and requires some additional considerations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    There is a significant need for evaluation of micelle drug exchange phenomena.

    “While micelle drug exchange may occur at a slower rate than protein drug exchange, this was not the case for Taxol, and there is a significant need for the evaluation of this phenomena.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The protein bound drug fraction in target tissues can differ from that in blood.

    “Additionally, the protein bound drug fraction in target tissues can be different than when in the blood.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The SITUA study could have been improved by using a higher animal number and a crossover study design to increase data variability.

    “This study could have been improved by using a higher animal number and a crossover study design to increase data variability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Both excipient biocompatibility and high drug loading are required to minimize toxicity derived from excipients.

    “that both the biocompatibility of excipients and high LC are required to minimize excipient-derived toxicity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    To obtain the full pharmacokinetic picture, one must measure all three drug fractions in all tissues.

    “Thus, one must measure all three fractions in all tissues in order to obtain the full PK picture.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both the biocompatibility of excipients and high loading capacity are required to minimize excipient-derived toxicity.

    “This study indicates that both the biocompatibility of excipients and high LC are required to minimize excipient-derived toxicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both unbound and nanoparticle bound drug can enter tumor microenvironments, but only unbound drug is pharmacologically active, so nanoparticles must release encapsulated drug to the tumor microenvironment after local uptake.

    “Both unbound and nanoparticle bound drug can enter tumor microenvironments, but only the unbound drug is pharmacological activity, thus the nanoparticles must release their encapsulated drug to the tumor microenvironment after local uptake.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Polymeric micelle formulations exist as dynamic structures in which drugs are loaded via non-covalent interaction, resulting in gradual drug release to the external environment, and can be reabsorbed by the micelles.

    “It is important to consider that, in contrast to other common nanoformulations, polymeric micelles formulations exist as dynamic structures in which drugs are loaded via non-covalent interaction resulting in gradual drug release to the external environment and can be reabsorbed by the micelles [246].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [246] source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Polymeric micelles have shown potential to deliver drugs with high drug loadings, minimizing excipient use and improving overall drug pharmacokinetics and therapeutic indices.

    “Polymeric micelles have shown the unique potential to deliver critically important drugs with high drug loadings thereby minimizing excipient use and improving overall drug PK and therapeutic indices.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The lower complement activation could also be due to increased biocompatibility and/or decreased immunoactivation in response to POx polymer.

    “This could also be due to an increased biocompatibility and/or decreased immunoactivation in response to POx polymer [118].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    A higher drug loading could improve micelle stability in circulation.

    “A higher drug loading could improve micelle stability in circulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    The dynamic nature of polymeric micelles presents many additional considerations and opportunities in analytical processing of samples and pharmacokinetic modeling.

    “While nanomedicine PK is highly complex, it is clear that the dynamic nature of polymeric micelles presents many additional considerations and opportunities in analytical processing of samples and the PK modeling of drug systems.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    When polymer concentration drops below the critical micelle concentration, redistribution of drug into unbound fractions can increase observed clearance, depending on rate-limiting metabolic processes.

    “When polymer concentration drops below the CMC, the redistribution of drug into the unbound fractions can then increase the observed clearance (but not necessarily depending on rate limiting metabolic processes).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    When drug is encapsulated in small polymeric micelles of about 30 nm, both penetration into desmoplastic tumors and anti-tumor effect of the drug can be improved.

    “Kataoka and colleagues have shown that when the drug is encapsulated in small polymeric micelles (~30 nm), both the penetration of the micelles into the desmoplastic tumors and anti-tumor effect of the drug can be improved [255].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [255] source

  • May combine two claims.

    Interpretationreasoning

    Only unbound drug can be metabolized, so as polymer concentration decreases below the critical micelle concentration, the equilibrium shifts as drug is slowly removed from the micellar compartment and unbound concentration can increase, making more drug available for metabolism.

    “Only unbound drug can be metabolized, so as polymer concentration is decreased below the CMC, the equilibrium shifts as drug is slowly removed from the “micellar compartment” and the unbound concentration can increase making more drug available for metabolism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    It is important for formulation designers to maximize drug retention in micelles to improve overall tumor drug exposure profiles.

    “Thus, it is important for formulation designers to maximize the drug retention in the micelles to improve overall tumor drug exposure profiles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    There is an immense need for further work and characterization of fundamental pharmacokinetic processes of polymeric micelles.

    “This is still an area where there is an immense need for further work and characterization of these fundamental PK processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The unbound drug fraction is minimal in systemic circulation, so neglecting its measurement in a model is inconsequential because this fraction generally mimics the total unencapsulated drug profile.

    “However, the unbound drug fraction is minimal in systemic circulation and neglecting its measurement in a model is inconsequential as this fraction is generally, and thus mimics the total unencapsulated drug profile.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Proper pharmacokinetic metrics, such as the tumor/plasma AUC ratio, should be used, and novel metrics should be validated against traditional analyses.

    “For now, we must be sure to utilize proper PK metrics, such as the tumor/plasma AUC ratio, and validate novel metrics against traditional analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    This indicates that unimers were cleared by the kidneys while micelles bypassed glomerular filtration.

    “This indicates that unimers were cleared by the kidneys while micelles bypassed glomerular filtration.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bulitta et al. developed similar models to represent regular micelle and emulsion systems.

    “This has also been studied earlier by Bulitta et al., who came to develop similar models to represent the regular micelle and emulsions systems [248].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [248] source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    A proper understanding of complex pharmacokinetics and design of polymeric micelle pharmacokinetic analysis will ensure that literature moving forward is reliable and truly represents the field.

    “A proper understanding of this complex PK and design of polymeric micelle PK analysis will ensure that literature moving forward is reliable and truly represents the field.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Surface charge of polymeric micelles could affect their biodistribution.

    “Additionally, surface charge of polymeric micelles could affect their biodistribution.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    If this size increase is large enough, it could affect key pharmacokinetic parameters such as clearance and volume of distribution as well as penetration of micelles into tumors.

    “If this size increase is large enough, this could affect key PK parameters such as clearance and volume of distribution as well as penetration of micelles in the tumors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Other factors, particularly better retention of co-loaded drugs compared to single-drug micelles, rather than shape alone, could have contributed to the higher tumor AUC from worm-like micelles.

    “However, other factors, in particular better retention of co-loaded drugs compared to single-drug micelles, rather than the shape alone could have also contributed to this phenomenon as discussed below.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Dilution of polymeric micelles by plasma could result in a concentration below the critical micelle concentration causing disassembly, or could lead to changes in size and morphology above the critical micelle concentration.

    “This dilution as discussed above could possibly result in a concentration below the CMC causing the disassembly of the polymeric micelles altogether but could also lead to changes size and morphology of the micelles above the CMC.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The critical micelle concentration of a micelle system could depend on the drug loading in the micelle.

    “It is also important to note that the CMC of a micelle system could depend on the drug loading in the micelle.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The Wan et al. model did not measure free, unbound drug, which is a shortcoming because unbound drug is pharmacologically active and contributes to drug transfer between compartments.

    “There was no measurement of the free, unbound drug which is the shortcoming of this model as the unbound drug is pharmacologically active and contributes to the transfer of drug between compartments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Further comparison of highly loaded spherical and worm-like polymeric micelles is needed to understand how morphology affects circulation, biodistribution, accumulation, and targeting.

    “The further comparison of highly loaded spherical and worm-like polymeric micelles is needed to consider morphology of micelles and how this may affect circulation, biodistribution, accumulation, and targeting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Micelle disassembly upon dilution below the critical micelle concentration is thermodynamically favored but can take hours, especially in micelles with glassy cores.

    “While the micelle disassembly upon dilution below the CMC is thermodynamically favored, the disassembly process can take hours, especially in micelles with “glassy cores” [250, 251].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [250]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [251] source

  • May combine two claims.

    Premisenone given

    Aqueous solubility is one of the main factors determining pharmacokinetic profiles of small molecule drugs and hinders parenteral administration.

    “One of the main factors that determine PK profiles of small molecule drugs is the aqueous solubility which hinders administration of such molecules via the parenteral route.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Not all processes for producing polymeric micelles are equally suitable; a process that works for one polymer-drug system may not be feasible for another, and not all processes are conducive to manufacturing scale.

    “However, not all processes are created equal. That is, what works for one polymer-drug system may not be feasible in another, and not all processes are conducive to a manufacturing scale.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Drugs that form highly stable single-drug micelles, such as paclitaxel, can increase the stability of drugs that do not form stable single-drug micelles.

    “Alternatively, drugs which form highly stable single drug systems (like paclitaxel), could increase the stability of those drugs which do not form stable single drug micelles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Effective solubilization of hydrophobic small molecules and co-encapsulation of drug combinations in a single micelle is important for successful combination therapy.

    “For this reason, the effective solubilization of hydrophobic small molecules and co-encapsulation of drug combinations in a single micelle is important for successful combination therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    This study demonstrates the promise of optimally delivered and nanoformulated immunomodulating agents, and possibly their combinations with chemotherapy, for metastatic NSCLC.

    “This study demonstrates the promise of optimally delivered and nanoformulated immunomodulating therapeutic agents and possibly their combinations with chemotherapy for treatments of metastatic NSCLC.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Ideal combination therapy requires precise drug exposure to induce synergistic therapeutic effects.

    “Ideal combination therapy requires precise drug exposure to induce synergistic therapeutic effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Multiple drug components in the micelle core may further stabilize polymeric micelle systems.

    “Presumably, multiple drug components in the core of polymeric micelle could further stabilize the polymeric micelle systems.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    As of today, no polymeric micelle formulation for combination therapy is USFDA approved, but design of pharmacologically effective drug combinations in polymeric micelles is highly warranted.

    “Although, as of today no polymeric micelle formulation for combination therapy is USFDA approved, but the design of pharmacologically effective drug combinations in polymeric micelles is highly warranted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In POx micelles, combining poorly compatible drugs with well-compatible drugs such as paclitaxel enables their encapsulation and raises aqueous solubility, altering the pharmacokinetics of both drugs.

    “In POx micelles, the inclusion of poorly compatible drugs with well-compatible, such as paclitaxel, allows for their encapsulation and increased aqueous solubility. This alters the PK of both paclitaxel and the other drug.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Flash precipitation allows synthesis of uniform nanoparticles and has been scaled by BASF for producing β-carotene nanoparticles.

    “In flash precipitation, an aqueous and organic phase are mixed rapidly with engineered geometries in a special “jet mixer” instrument which allows for the synthesis of uniform nanoparticles [266, 267]. This process has been brought to scale by BASF for the generation of β-carotene nanoparticles [268].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [266]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [267] source
    • cites [268] source

  • May combine two claims.

    Premisecitation

    A study comparing sonication and thin film hydration found that the process forming more stable micelles depends on the polymer, with block copolymer composition, block lengths, and polymer/drug ratio as key factors.

    “In that study, when comparing the sonication method and thin film hydration technique, they determined that the process which forms more stable micelles is polymer dependent. Some key factors are the block copolymer chemical composition, block lengths, and the polymer/drug ratio.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] source

  • May combine two claims.

    Premisereasoning

    The flash precipitation process is not universal and has challenges for drugs with relatively low logP values that dissolve faster than they incorporate into nanoparticles.

    “However, the process is not universal and has challenges especially for drugs with relatively low logP values that tend to dissolve faster than they incorporate into nanoparticles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Intimate mixing is needed to prevent drug crystallization during thin film formation, and this cannot be achieved in every solvent.

    “There must be intimate mixing to avoid crystallization of the drug during the thin film formation, and this cannot be achieved in every solvent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In vitro cytotoxicity assays confirmed synergistic cytotoxicity of micellar etoposide/17-AAG and micellar bortezomib/17-AAG in cancer cells.

    “An in vitro cytotoxicity assay confirmed synergistic cytotoxicity of micellar etoposide/17-AAG and micellar bortezomib/17-AAG in cancer cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Thin film hydration is a common drug-loaded polymeric micelle preparation technique and is fairly conducive to batch-wise scale-up.

    “One of the most common drug-loaded polymeric micelle preparation techniques is the thin film hydration method, which is fairly conducive to scale-up in a batch-wise manner.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In thin film hydration, achieving a dry thin film with no residual solvent is often critical.

    “In this technique, it is often critical that a dry thin film is achieved with no residual solvent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Administration and disposition of drug combinations to target tissue with the desired ratio of delivered agents is highly warranted.

    “Thus, the administration and subsequent disposition of combinations to target tissue with the desired ratio of the delivered agents is highly warranted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Combinations of the discussed preparation methods can potentially be used to prepare stable micelles.

    “It is also important to note that any combination of the aforementioned methods could potentially be used to prepare stable micelles. In these studies, organic solutions were added to an aqueous media, dialyzed, sonicated, and then freeze dried to produce stable formulations [273, 277].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [273] source
    • cites [277] source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The ability to solubilize multiple drugs in the same micelle can yield more predictable pharmacokinetic profiles and allow for solubility of new molecules and additional combination options.

    “The ability to solubilize multiple drugs in the same micelle can yield more predictable PK profiles and allow for the solubility of new molecules and additional combination options.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Dialysis is commonly used in laboratory micelle preparation but is not conducive to industrial scale-up.

    “One technique that is commonly used in laboratory micelle preparation which is not conducive to industrial scale up is dialysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Residual precipitated drug can be removed by brief centrifugation, and this applies to any of the discussed methods.

    “If there is any residual drug precipitated, then a brief centrifugation step can remove drug precipitates (this is applicable to any of the discussed methods).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cosolvent evaporation can produce stable aqueous micellar solutions by dissolving drug and polymer in organic solvent, adding the mixture to an aqueous phase, and heating or applying vacuum to remove volatile solvents.

    “Drug and polymer are dissolved in organic solvent and are added dropwise, or sometimes rapidly, to an aqueous phase. The solution can then be heated and/or placed under vacuum to remove the volatile organic solvents and produce stable aqueous micellar solutions [275, 276].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [275] source
    • cites [276] source

  • May combine two claims.

    Premisenone given

    With dialysis, processing times are long and complete removal of organic solvent and free unloaded drug is difficult.

    “With dialysis, the processing times are long and the complete removal of organic solvent and free, unloaded drug from the solution is difficult.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Both averaged molecular mass/mass distribution for block copolymers and mean size/PDI for micelles must be under tight control for optimal regulatory consideration.

    “Both of these must be under tight control for optimal consideration in the regulatory process.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Micelle morphology and zeta potential could play critical roles in interactions of polymeric micelles with cells and proteins.

    “Micelle morphology and zeta potential could also play critical roles in the interactions of polymeric micelles with cells and proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The EMA has developed a Scientific Advice procedure since 1995 that is useful for companies assessing evidence when designing clinical studies.

    “The EMA has developed since 1995 a Scientific Advise procedure that is very useful for companies to use, when assessing the relevance of the evidence gathered at the moment of designing their clinical studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    The tert-butanol freeze-drying process was unique to PVP-b-PDLLA and could not be applied to PEG-b-PDLLA because PEG is practically insoluble in tert-butanol.

    “However, the use of tert-butanol in this process was unique to the system of PVP-b-PDLLA block copolymer and could not be applied, for example, to PEG-b-PDLLA since PEG is practically insoluble in tert-butanol.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Minimizing manufacturing steps is desirable to increase loading efficiency and mitigate detrimental side effects such as formulation instability.

    “Minimizing the steps in the manufacturing process to increase LE and mitigate the detrimental side effects of manufacturing processes (e.g. formulation instability) is highly desirable.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    There is still a high attrition rate for new drugs, and new nano-based pharmaceuticals are subject to this as well.

    “However, there is still a high attrition rate for new drugs, and new nano-based pharmaceuticals are subject to this as well.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Understanding relationships between nano-based pharmaceutical physicochemical properties and in vivo behavior can help improve design and evaluation of nano-based pharmaceuticals, particularly block copolymer micelle systems.

    “Once thoroughly assessed, our understanding of these relationships can help to improve how we design and evaluate nano-based pharmaceuticals and, in particular, block copolymer micelle systems.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Development of new clinical models that better replicate patient pathophysiology is highly warranted to evaluate formulations and lower attrition of new medicines.

    “The development of new clinical models which better replicate patient pathophysiology are highly warranted, and this is a key place where physician-scientists can help to evaluate these formulations and push the field forward by lowering the attrition rate of new medicines.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Preclinical pharmacokinetic and anti-tumor results in animal models are predictive of clinical outcomes in humans.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Lyophilized powder is a better final formulation option because it may help avoid contamination or drug release/degradation of micelle formulations in aqueous media.

    “As the final formulation, the lyophilized powder form is the better option since it may be helpful to avoid contamination or drug release/degradation of micelle formulations in aqueous media.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mixing powdered polymeric micelles with excipients such as lactose makes the composition instantly dissolvable in water, allowing drying to a solid; this was used for SP1049C doxorubicin micelles.

    “To ensure the rapid dissolution of the powdered polymeric micelles, their mixing with excipients such as lactose makes this composition instantly dissolvable in water allowing the product to be dried to a solid. This approach was used, for example, for preparation of the dry from of SP1049C polymeric micelle formulation of doxorubicin [282].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [282]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The USFDA recommends that sponsors engage the Agency early in development and pre-submission to obtain timely guidance for studies critical for the drug product.

    “Since each new formulation has unique properties, the USFDA recommends sponsors engaging the Agency early in the development and pre-submission process so as to obtain timely and adequate guidance for studies critical for the given drug product.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    At larger production scale, manufacturing polymeric micelle products with reproducible physicochemical properties is important, requiring proper GMP and Quality by Design.

    “At a larger scale of production, the manufacturing of polymeric micelle products with reproducible physicochemical properties is of importance. For this purpose, proper establishment of the good manufacturing process (GMP) is necessary to follow industrial standards and ensure the quality of the final nanomedicine products.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In the US, new pharmaceuticals are reviewed and approved through a weight-of-evidence approach that considers each new drug case-by-case.

    “In the US, all new pharmaceuticals are reviewed and approved based on the well-established regulatory framework which is based on a weight-of-evidence approach. Such an approach considers each new drug on a case-by-case basis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Block copolymers and polymeric micelles do not consist of a single molecular weight or sized species but are distributions, so they should be described by averaged molecular masses and mass distribution for block copolymers and mean size and PDI for micelles.

    “Block copolymers and polymeric micelles do not consist of one single molecular weight or sized species. Rather, they consist as a distribution range and thus should be described by their averaged molecular masses and mass distribution for block copolymers and mean size and PDI for micelles as well as.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Freeze drying under particular conditions can remove small amounts of residual organic solvents, and freeze drying alone has been used to prepare stable micelle formulations.

    “Freeze drying, when done under particular conditions, can be used to remove small amounts of residual organic solvents. Moreover, freeze drying alone has been used to prepare stable micelle formulations.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [280] source
    • cites [281] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Nano-based pharmaceuticals are usually synthetic and do not fall under the biologics class, but some biologics are nanosized and exhibit unique properties due to their dimensions, creating a complex classification.

    “Nano-based pharmaceuticals are usually synthetic in origin and do not fall under the ‘biologics’ class of drugs. However, there are some biologics which are nanosized and exhibit unique properties due to these dimensions. This creates a highly complex classification of nanoscale drugs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Supercritical fluid methods allow faster processing, easy solvent removal, and no long freeze-drying or dialysis steps.

    “Using supercritical fluids in polymeric micelle preparation allows for faster processing times, easy solvent removal, and no long freeze drying or dialysis steps.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [283] source
    • cites [284] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In supercritical fluid micelle preparation, trifluoromethane and carbon dioxide are common solvents; pressure dissolves the polymer and drug, and rapid pressure removal forms micelles and evaporates solvent.

    “Common solvents for this are trifluoromethane and carbon dioxide. A solution is brought up to pressure to dissolve the polymer and drug as a supercritical fluid and then pressure is quickly removed allowing for micelles to form and the solvent to evaporate.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [283] source
    • cites [284] source

  • May combine two claims.

    Premisecitation

    Freeze drying is highly conducive to scale-up and can stabilize micelle formulations for longer periods.

    “The freeze drying process is highly conducive to scale up. Freeze drying after preparation of micelles can also be used to stabilize the formulation for longer periods of time [264].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [264] source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Thin film hydration may be the most plausible manufacturing option because it has the fewest steps, allows easy organic solvent removal during film formation, and avoids dialysis and potential water contamination.

    “For this purpose, the thin film hydration method could be the most plausible option since 1) there are the fewest steps 2) organic solvent removal is easy during film formation 3) it avoids dialysis and potential contamination from water.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Key parameters such as API and excipient amounts, solvent purity, impurities, and processing variables (time, temperature, pressure) can help define causes of unexpected quality issues or non-reproducibility.

    “The key parameters such as amount of API and excipients, purity of solvents, presence of impurities and processing variables (time, temperature and pressure) can be useful factors to define the cause of unexpected quality issues or non-reproducibility of the products during the production.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    Critical factors in micelle manufacturing processes include organic solvent selection, number of steps, yield from pure drug and excipient, sterilization for endotoxin-free formulation, and final formulation design.

    “As we have explained, several factors in these processes should be considered critical such as the selection of organic solvent, number of overall steps, yield of the polymeric micelle from the pure drug and excipient (de-facto LE), sterilization process for endotoxin-free formulation, and final formulation design (solution or lyophilized powder for reconstitution).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Nano-based pharmaceuticals and biologics are complex, heterogeneous formulations, making identical follow-on drugs impossible and demanding a more adequate regulatory approval route.

    “Nano-based pharmaceuticals and biologics represent the category of complex drug formulations which are often heterogeneous in nature. This heterogeneous nature makes it impossible to produce identical follow-on drugs and demands a more adequate route to regulatory approval.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Oil-in-water emulsions are commonly produced at manufacturing scales, but complete removal of organic solvent from them can be difficult.

    “Oil in water emulsions are commonly produced at manufacturing scales, but the complete removal of organic solvent from them can be difficult.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a phase I trial in South Korea, 21 patients received dose-escalated Genexol PM 135-390 mg/m2 without premedication; no acute hypersensitivity reactions occurred, while neuropathy, myalgia, and neutropenia limited the highest dose.

    “In a phase I clinical trial in South Korea, twenty-one patients entered into a dose-escalation study and were treated with Genexol® PM ranging from 135 mg/m2 to 390 mg/m2 without premedication of hydrocortisone and histamine blocker [11]. No acute hypersensitivity reactions were observed, while neuropathy, myalgia, and neutropenia were observed which limited the highest dose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    With some successful preclinical results, several polymeric micelle formulations have entered clinical trials, but only a few have received regulatory approval for human use.

    “With some successful preclinical results, several polymeric micelle formulations have entered clinical trials, but only a few have received regulatory approval for human use.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A Phase Ib/II trial of NC-6004 with gemcitabine in advanced solid tumors evaluated safety and tolerability (NCT02240238); NC-6004 was given at 60-180 mg/m2 with gemcitabine 1,250 mg/m2; the MTD was 135 mg/m2; common hematologic adverse events were leukopenia and thrombocytopenia; tumor shrinkage, partial responses, and stable disease were observed in 55%, 15%, and 70% of patients, respectively.

    “A Phase Ib/II trial of NC-6004 with gemcitabine was conducted in patients with advanced solid tumors to evaluate the safety and tolerability (ClinicalTrials.gov: NCT02240238) [309]. NC-6004 was administered to patients at 60 mg/m2 to 180 mg/m2 (on day 1) with gemcitabine (1,250 mg/m2, on days 1 and 8) every 3 weeks. A dose of 135 mg/m2 of NC-6004 was determined as the MTD and common hematologic”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [309] source

  • May combine two claims.

    Premisecitation

    In a phase II trial of NK105 in 57 patients with advanced gastric cancer after first-line chemotherapy failure, NK105 at 150 mg/m2 without anti-allergic premedication showed modest activity and tolerability; overall response rate was 25%, median PFS 3.0 months, and median OS 14.4 months.

    “A phase II trial of NK105 recruited 57 patients with advanced gastric cancer after the failure of first-line chemotherapy [300]. The patients were administered NK105 (at 150 mg/m2 paclitaxel) without anti-allergic premedication. The results of the phase II study revealed that NK105 showed modest activity and tolerability for paclitaxel. The overall response rate was 25% with median progress free”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [300] source

  • May combine two claims.

    Premisecitation

    Nanoxel M is a docetaxel-loaded polymeric micelle formulation developed by Samyang Biopharmaceuticals and received regulatory approval in South Korea in 2012.

    “Nanoxel® M is a docetaxel-loaded polymeric micelle formulation which was developed by Samyang Biopharmaceuticals Corp. and received regulatory approval in South Korea in 2012 (according to announcement from Samyang Biopharm (https://samyangbiopharm.com/eng/ProductIntroduce/injection) and Korea Pharmaceutical Information Center (http://www.health.kr/searchDrug/result_drug.asp?drug_cd=2012122700008)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In this phase II study, conventional drug was not administered because there was no standard of care for advanced gastric cancer, making interpretation of the results difficult.

    “In this study, conventional drug was not administered to patients since there was no standard of care for advanced gastric cancer. Thus, the interpretation of the results from the phase II study of NK105 is difficult.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Overall, NK105 successfully improved the PK and safety profiles of paclitaxel by incorporating the drug into a polymeric micelle formulation, but failed to improve the efficacy of paclitaxel in clinical trials.

    “Overall, NK105 successfully improved the PK and safety profiles of paclitaxel by incorporating the drug into a polymeric micelle formulation. However, NK105 failed to improve the efficacy of paclitaxel in clinical trials.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    There have been many challenges affecting the ability of polymeric micelles to navigate the regulatory pathway.

    “There have been many challenges affecting their ability to navigate the regulatory pathway, which we have worked to address in this review.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a phase II study of Genexol PM with cisplatin in advanced NSCLC in South Korea, the overall response rate was 37.7% and median survival was 21.7 months, indicating significant improvements compared to previous trials with Taxol 175-200 mg/m2 and cisplatin 75-80 mg/m2.

    “The overall response rate was 37.7% and the median survival period was 21.7 months, which indicated significant improvements compared to previous clinical trials conducted with Taxol® 175–200 mg/m2 and cisplatin 75–80 mg/m2 [301].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] source

  • May combine two claims.

    Premisecitation

    A Phase II trial demonstrated that SP1049C has notable single-agent activity and an acceptable safety profile in patients with advanced carcinoma of the esophagus and gastroesophageal junction.

    “Later, a Phase II trial demonstrated that SP1049C has a notable single-agent activity as well as an acceptable safety profile in patients with advanced carcinoma of the esophagus and gastroesophageal junction [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

  • May combine two claims.

    Premisecitation

    Genexol PM micelles are manufactured by solid dispersion using thin film hydration and are nano-sized spherical particles in aqueous media with 20-50 nm diameter and 16.7% LC paclitaxel.

    “The micelles are manufactured by the solid dispersion method using the thin film hydration approach and are nano-sized particles with well-defined spherical structure in aqueous media (20–50 nm in diameter and 16.7% LC of paclitaxel) [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

  • May combine two claims.

    Interpretationreasoning

    Overall, NC-6004 formed a stable polymeric micelle with sustained release of cisplatin; clinical trials demonstrated long circulation and sustained drug release in patients; NC-6004 could improve the drug toxicity profile, such as reducing nephrotoxicity.

    “Overall, NC-6004 formed a stable polymeric micelle with a sustained release of cisplatin. Clinical trials of NC-6004 demonstrated long circulation and sustained drug release of NC-6004 in patients. Also, NC-6004 could improve the drug toxicity profile, such as reducing nephrotoxicity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Polymeric micelles represent a much more complex system than early understanding suggests.

    “While simple at first pass, it is clear that polymeric micelles represent a much more complex system than early understanding suggests.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Overall, SP1049C may have several applications: as a new agent with a novel mechanism of action for combination therapy, as salvage therapy, and as a first-line single agent in doxorubicin indications.

    “Overall, SP1049C may have several applications: as a new agent with novel mechanism of action for combination therapy; salvage therapy; and as the first line single agent in doxorubicin indications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients treated with SP1049C at 75 mg/m2 had an objective response rate of 47% in the evaluable population and 43% in the intent-to-treat population, with median overall survival of 10 months and PFS of 6.6 months.

    “Patients treated with SP1049C at a dose 75 mg/m2 (doxorubicin equivalents) had an objective response rate of 47% in the evaluable patient population, and 43% in the intent-to-treat population along with the median overall survival of 10 months and PFS of 6.6 months.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

  • May combine two claims.

    Premisecitation

    In another phase II study in South Korea, Genexol PM in metastatic breast cancer with 41 patients at 300 mg/m2 every 3 weeks had an overall response rate of 58.5%, superior to Abraxane at 47.6% and Taxol at 21-54%.

    “Another phase II study in South Korea reported the clinical benefit of Genexol® PM in patients with metastatic breast cancer [9]. Forty-one patients were enrolled in the study and administered with a Genexol® PM infusion (300 mg/m2) every 3 weeks. The overall response rate was 58.5%, which is superior to that of Abraxane® (47.6%) and Taxol® (21–54%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The improved safety of Nanoxel M is believed to be due to removal of the toxicity of Polysorbate 80 contained in the conventional docetaxel formulation Taxotere.

    “This is believed to be due to the removal of toxicity of Polysorbate 80 that is contained in a conventional docetaxel formulation, Taxotere.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Although Genexol PM has shown some hypersensitivity reaction in the clinic, probably due to PEG, this is not nearly as much of a concern as for Taxol which contains Cremophor EL.

    “Although Genexol® PM has shown some hypersensitivity reaction in the clinic, probably due to the PEG, this is not nearly as much of a concern as for Taxol® which contains Cremophor EL [301].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    For nano-based pharmaceuticals, physicochemical sameness is more difficult to relate to therapeutic performance because the characteristics affecting performance are more complex and can affect performance in different ways.

    “In general, for the nano-based pharmaceuticals the physicochemical sameness is more difficult to relate to the same therapeutic performance because the physiochemical characteristics that may affect performance of a delivered drug are more complex and could affect therapeutic performance in different ways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Polymeric micelle formulations for poorly soluble small molecules have been extensively studied over three decades as a versatile platform for drug delivery.

    “Polymeric micelle formulations for poorly soluble small molecules have been extensively studied over three decades as a versatile platform for drug delivery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The MTD of Genexol PM was 390 mg/m2, higher than Taxol at 200 mg/m2 and Abraxane at 300 mg/m2.

    “The MTD was determined to be 390 mg/m2 for Genexol® PM, which is higher than that of the commercially available paclitaxel formulations Taxol® (200 mg/m2) and Abraxane® (300 mg/m2) [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] source

  • May combine two claims.

    Interpretationreasoning

    The tolerable dose of paclitaxel was increased by polymeric micelle formulation, resulting in an increased MTD.

    “The tolerable dose of paclitaxel was increased by virtue of polymeric micelle formulation, resulting in an increased MTD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ideal matrix for in vitro release studies is blood plasma, but a buffer containing albumin can be helpful when blood serum is unavailable.

    “The ideal matrix for these studies would be blood plasma, but a buffer containing albumin can be helpful as well, when blood serum is unavailable [221, 235].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [221] source
    • cites [235] source

  • May combine two claims.

    Interpretationreasoning

    Genexol PM could improve the dosing of paclitaxel and the safety of the drug in patients; in clinical trials it demonstrated improved therapeutic outcomes by limiting hypersensitivity reactions through elimination of toxic excipients.

    “In conclusion, Genexol® PM could improve the dosing of paclitaxel and the safety of the drug in patients. In clinical trials Genexol® PM demonstrated improved therapeutic outcomes as a formulation which limited hypersensitivity reactions in patients through the elimination of toxic excipients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NK105 is a paclitaxel-loaded polymeric micelle formulation developed by Kataoka's group and NanoCarrier, advanced to clinical trials with phase III completed (NCT01644890).

    “NK105 is a paclitaxel-loaded polymeric micelle formulation which was originally developed by Kataoka’s group and NanoCarrier Co., Ltd. in the early 1990s and advanced to clinical trials (phase III completed, ClinicalTrials.gov: NCT01644890).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Genexol PM is a Cremophor EL-free polymeric micelle formulation incorporating paclitaxel as the API.

    “Genexol® PM is a Cremophor EL-free, polymeric micelle formulation incorporating paclitaxel as the API.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nanoxel M is manufactured by thin-film hydration, producing uniform micelles with a hydrodynamic size of 25.4 nm.

    “It is manufactured by the thin-film hydration method, which produces uniform micelles with a hydrodynamic size of 25.4 nm [306].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [306] source

  • May combine two claims.

    Premisereasoning

    Genexol PM received regulatory approval in South Korea and was marketed there since 2007 for MBC, NSCLC, and ovarian cancers, and also received marketing approval in India, Serbia, Philippines, and Vietnam.

    “With improved therapeutic outcomes in clinical trials conducted in South Korea, Genexol® PM received regulatory approval in South Korea and was marketed there since 2007 for the treatment of MBC, NSCLC, and ovarian cancers. In addition to South Korea it received marketing approval in several other countries including India, Serbia, Philippines, and Vietnam.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Drug-oriented design can improve the efficiency of translation from lab to pre-clinical to clinical applications.

    “This drug-oriented design can improve the efficiency of translation from lab, to pre-clinical, to clinical applications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Only a few polymeric materials used for manufacturing micelles have reached the clinical stage; these include several hydrophobic polymers for core-forming blocks and just one hydrophilic polymer, PEG, for the shell.

    “Although many polymeric materials were studied during the previous three decades, there are only a few such materials used for the manufacturing of micelles which have reached the clinical stage of development. These include several hydrophobic polymers that are used to design the core-forming blocks of the polymeric micelles and just one hydrophilic polymer, PEG, used to manufacture the shell of”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Computational methods and AI have a role in the drug-oriented design of polymers.

    “In particular, we believe strongly in the role of computational methods and AI for the for the drug-oriented design of polymers.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    Polymeric micelle formulations hold clinical importance as a delivery platform for poorly soluble small molecules, and current systems have to further evolve to serve as efficient drug carriers.

    “Polymeric micelle formulations hold a clinical importance as a delivery platform for poorly soluble small molecules, and for this purpose current polymeric micelle formulation systems have to further evolve to serve as efficient drug carriers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    There are limitations to current materials including relatively poor drug incorporation, toxicity, and, for PEG, unfavorable immunological interactions such as antibody responses.

    “There are limitations to the use of the current materials including relatively poor drug incorporation in some cases, toxicity, and, in the case of PEG, unfavorable immunological interactions such as antibody responses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Comprehensive analysis of drug encapsulation and subsequent drug release profile in systemic circulation will provide insight for future design of novel polymeric micelle systems for human use.

    “We believe that the comprehensive analysis of drug encapsulation and subsequent drug release profile in systemic circulation will provide insight for the future design of novel polymeric micelle systems for human use.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Clinical investigations of polymeric micelle formulations have revealed promising therapeutic outcomes for human use, while there have also been a number of clinical trial failures from other polymeric micelle formulations.

    “Clinical investigations of polymeric micelle formulations have revealed promising therapeutic outcomes for human use, while we have also witnessed a number of clinical trial failures from other polymeric micelle formulations.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    All examples of clinically approved polymeric micelle drugs or polymeric micelle drugs in clinical development discussed here belong to the area of cancer therapy.

    “All examples of clinically approved polymeric micelle drugs or polymeric micelle drugs in clinical development discussed here belong to the area of cancer therapy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    A limited understanding of the complex dynamics of polymeric micelle formulations has hindered their translation into clinics.

    “A limited understanding of the complex dynamics of polymeric micelle formulations has hindered their translation into clinics.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Numerous preclinical animal studies using small molecule drugs in polymeric micelles for other diseases have shown improvements in solubility, stability, PK, bioavailability, decreased toxicity, increased pharmacological activity, and in some cases bioequivalence.

    “In these studies, the polymeric micelles were shown to greatly improve drug solubility and formulation stability, improve PK and bioavailability of the drug at the target site (e.g., longer systemic circulation after IV injection, increased brain exposure, enhanced drug disposition in skin or corneal permeability), decrease drug toxicity and unwanted side effects of treatments, increase specific”
    Quote in the paperNot a substantial claim
285 of 285

  • The paper relies on this without support.

    The anti-fouling performance of hydrophilic polymers observed in preclinical models predicts their ability to avoid clearance and improve circulation in humans.

    “Overall, hydrophilic POx polymers, and especially PMeOx, have emerged as highly attractive anti-fouling stealth polymers which have the potential to replace PEG in these applications.”

  • The paper relies on this without support.

    Pharmacokinetic improvements observed in preclinical animal models for polymeric micelle drugs will translate to improved clinical outcomes in humans.

    “Polymeric micelles have shown improved pharmacokinetic profiles in preclinical animal models and enhanced efficacy with a superior safety profile for therapeutic drugs.”

  • The paper relies on this without support.

    The performance of polymeric micelles depends on micelle stability, drug loading, release kinetics, circulation time, and biodistribution.

    “The performance of polymeric micelles is intimately related to micelle stability, drug loading, release kinetics, circulation time, and biodistribution.”

  • The paper relies on this without support.

    Polymeric micelles are significantly diluted upon administration into the body.

    “Since polymeric micelles are significantly diluted upon administration into the body, classical amphiphilic block copolymers may disassemble after injection, which results in the loss of micelle functionalities.”

  • The paper relies on this without support.

    The safety profile of amphiphilic block copolymers containing various hydrophobic POx or POzi blocks other than PMeOx-b-PBuOx-b-PMeOx has not been analyzed in humans.

    “Although extensive body of work in preclinical models is available about the safety profile of PMeOx-b-PBuOx-b-PMeOx (see for example [22]), the safety profile analysis of other amphiphilic block copolymers containing various hydrophobic POx or POzi blocks in humans has not been conducted.”

  • The paper relies on this without support.

    The typical free energy of transfer of a methylene group from water to a water-immiscible organic solvent is −3.1 kJ/mol.

    “Typically, the free energy of transfer from aqueous to a water-immiscible organic solvent of a methylene group is −3.1 kJ/mol.”

  • The paper relies on this without support.

    The tumor microenvironment is relatively acidic compared to circulating blood.

    “For example, the tumor microenvironment is relatively acidic compared to that of circulating blood.”

  • The paper relies on this without support.

    Excipient-derived toxicity has often occurred in patients and has been a dose-limiting factor in clinical treatments.

    “Excipient derived toxicity has often occurred in patients and was a dose limiting factor in clinical treatments.”

  • The paper relies on this without support.

    The complex interactions between solid tumor physiology and nano-sized drugs are not fully understood.

    “Despite a significant body of literature on the use of various nanoparticles for cancer drug delivery, the complex interactions between solid tumor physiology and nano-sized drugs are not fully understood.”

  • The paper relies on this without support.

    Most studies have measured only total drug, not the released drug that is pharmacodynamically active.

    “Another important issue is that most studies have only measured total drug (i.e., encapsulated plus released), and not the released drug which is pharmacodynamically active.”

  • The paper relies on this without support.

    Traditional pharmacokinetic analysis treats drug as protein bound or free unbound; unbound drug is pharmacodynamically active; protein bound drug is not pharmacologically active and not available for metabolism.

    “The PK analysis of traditional, excipient-based formulations usually treats the drug in two forms: that which is protein bound and that which is free and unbound. The unbound drug is the fraction which is considered pharmacodynamically active form. The protein bound drug is not pharmacologically active, and not available for metabolism.”

  • The paper relies on this without support.

    No methods exist at this time to measure encapsulated, protein bound, and unbound drug fractions in tissue.

    “However, to the best of our knowledge there are no methods at this time to measure encapsulated/protein bound/unbound drug fractions in tissue and this is an important area of research.”

  • The paper relies on this without support.

    The Cmax of the unbound drug form achieved in the tumor is strongly correlated with pharmacodynamic activity.

    “However, as general case both drug subpopulations should be accounted for as the Cmax of the unbound form achieved in the tumor is strongly correlated to pharmacodynamic activity.”

  • The paper relies on this without support.

    The size distribution of nano-sized particles may affect their biodistribution, resulting in either extended systemic circulation or faster clearance.

    “It is well-established that the size distribution of nano-sized particles may affect their biodistribution when administered, resulting in either extended systemic circulation or faster clearance from the body.”

  • The authors state this as an assumption.

    SITUA assumes that a tracer amount of isotopically labeled drug in plasma behaves identically to drug released from the nanomedicine with regard to protein binding.

    “The SITUA concept is based on an assumption that a tracer amount of isotopically labeled drug in plasma will behave identically to drug that is released from the nanomedicine with regard to protein binding.”

  • The authors state this as an assumption.

    SITUA assumes that the isotopically labeled drug only equilibrates with plasma protein bound drug and not with nanomedicine bound drug during the timescale of the assay.

    “The SITUA assay assumes the isotopically labeled drug, D*, only equilibrates with the plasma protein bound drug and not with the nanomedicine bound drug (polymeric micelle encapsulated in our case) during the timescale of this assay.”

  • The authors state this as an assumption.

    SITUA assumes that polymeric micelles are not behaving dynamically under the timespan of the assay, meaning there is no exchange between free labeled drug and drug encapsulated in the polymeric micelles.

    “Thus, the assay assumes that the polymeric micelles are not behaving dynamically under the timespan of the assay: that is, there is no exchange between free D* and drug which is encapsulated in the polymeric micelles.”

  • The authors state this as an assumption.

    The Wan et al. model assumes that all drug delivered to the tumor will be pharmacologically active.

    “The Wan et al. study did not discriminate between the micelle bound and released drug within the tumor assuming that all drug will be pharmacologically active if delivered to the tumor, which may be a fair assumption for the micelles used in the study.”

  • The authors state this as an assumption.

    The Wan et al. model assumes, based on experimental evidence, that clearance of plasma bound drug is higher than that of micelle bound drug.

    “This is because for both scenarios the clearance of plasma bound drug is assumed, based on experimental evidence, to be higher than that of micelle bound drug.”

  • The paper relies on this without support.

    Preclinical pharmacokinetic and anti-tumor results in animal models are predictive of clinical outcomes in humans.

    “Superior anti-tumor activity of combination therapy was confirmed in ovarian and breast cancer preclinical models.”
    “This study indicates to us that co-loading of drugs in a single micelle would be beneficial for the delivery of the combination therapy.”
20 of 20

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Polyelectrolyte micelles, with their charged cores, are adept at carrying a variety of charged drugs including DNA and RNA, and have advantageous stability offering a distinct application in gene delivery.

    “Polyelectrolyte micelles, with their charged cores, are adept at carrying a variety of charged drugs including DNA and RNA. These micelles have advantageous stability and offering a distinct application in gene delivery [109].”

    From From design to Deployment: The innovative role of nanomicelles in targeted ophthalmic therapeutics (2025) · cites this paper as [109]

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Self-check results appear here once an independent check has confirmed them.

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1021/bm070226v

    Info

    The cited work was retracted on 2024-12-09 (notice 10.1021/acs.biomac.4c01583), not before this paper was published (2020).

    Cited work 10.1021/bm070226v · retracted 2024-12-09 · notice 10.1021/acs.biomac.4c01583 · this paper published 2020

1 of 1

Cites

1 retracted

Flagged first, then by citations

11 of the 353 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Schulz, 2012, Poly (2-oxazoline) s as high-capacity multi-drug delivery systems, Polymer Prepr., 53, 305
  2. Lee, 2005, Methoxy poly (ethylene glycol)-block-poly (δ-valerolactone) copolymer micelles for formulation of hydrophobic drugs, Biomacromolecules, 6, 3119, 10.1021/bm050451h · DOI

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Related

Authors
Hwang, D., Ramsey, J. D., & Kabanov, A. V.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Kabanov, Alexander V.
ORCID
Venue
Advanced drug delivery reviews
Publisher
Elsevier BV
Published
2020
Volume
156
Pages
80-118
ISSN
0169-409X (ISSN-L)
DOI
10.1016/j.addr.2020.09.009
PMC
PMC8173698
OpenAlex
W3088981963
Cited by
699
References
353
Citations by year
2026: 113 · 2025: 167 · 2024: 154 · 2023: 126 · 2022: 97 · 2021: 40 · 2020: 2
FWCI
4.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Advanced Drug Delivery Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01NS102627, U01CA198910, U54CA198999)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
polymeric micelles, poorly water-soluble drugs, drug solubilization, drug encapsulation, pharmacokinetics, clinical trials, systemic drug delivery, nanocarriers
MeSH terms
Animals, Drug Compounding, Drug Interactions, Pharmaceutical Preparations, Humans, Micelles, Polymers, Solubility, Drug Delivery Systems, Nanoparticles

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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