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

In the paper

“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.”

What the sources say

• Disputed

  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.

  cites [196] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Disputed

  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.

  cites [302] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [80] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [105] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [60] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Discussion (page unavailable) identifies PMeOx-PcBOx as a diblock copolymer with a triazine-containing side chain in its hydrophobic block. It discusses hydrophobicity in drug solubilization and says the triazine groups may enable pi-pi stacking, matching the claim’s qualified wording. (LLM, conf=0.87)

  cites [28] source

In the paper

“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].”

What the sources say

• Supported

  The Results and discussion (§3.3) reports that PHIS-PEG/DSPE-PEG micelles remain stable at tumor extracellular pH but disintegrate at endosomal pH as PHIS becomes protonated. The in vitro drug release studies (§3.6) explain that acidification makes PHIS more hydrophilic, separates it from the micelle core, and releases the drug. (LLM, conf=0.92)

  cites [131] source

In the paper

“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).”

What the sources say

• Supported

  The ¹H-NMR Spectroscopy section reports that pEtOx interacts more strongly with loaded curcumin than pMeOx and loses hydration as drug loading increases, while the pMeOx signal remains visible. The Additional information section describes PEG as similar to pEtOx in amphiphilicity; together with the paper’s comparison of pMeOx and pEtOx hydration, this supports the hydrophilicity comparison. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [119] source

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [113]
• Partly supported

  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)

  cites [117] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [118] source

In the paper

“On the other hand, the imidazole groups in poly(histidine) are uncharged at the physiologic pH 7.4 and become protonated at acidic pH.”

What the sources say

• Supported

  The Results and discussion (§3.3) attribute the micelles’ positive charge at pH 5.5 to protonation of poly(histidine) imidazole rings. Section 3.6 reports that poly(histidine) becomes almost completely protonated near pH 5.0, contrasting this with stable micelles at pH 7.4. Together, these passages support the stated pH-dependent change, although they do not directly measure the charge of individual imidazole groups at pH 7.4. (LLM, conf=0.88)

  cites [131] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [160] source
• ?Not checked — no full text of the sourcecites [161] source
• Partly supported

  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)

  cites [162] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [163] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Discussion (page not provided) describes NK911 as a new polymeric micelle preparation developed from earlier micellar doxorubicin work; the cited references include work by Kataoka and colleagues. The Patients and Methods and Results sections (pages not provided) document its clinical evaluation in 23 patients. (LLM, conf=0.90)

  cites [146] source
• ?Not checked — no full text of the sourcecites [147] source

In the paper

“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.”

What the sources say

• ?Not matched

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

  cites [176]
• ?Not checked — no full text of the sourcecites [177] source
• Partly supported

  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)

  cites [178] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Abstract says the Flory–Huggins parameters predicted greater indomethacin compatibility with PCL cores, while measured drug loading was higher in PεDL micelles. The Discussion qualifies this apparent contradiction: per unit micelle volume, PCL cores loaded more drug, consistent with the prediction. (LLM, conf=0.90)

  cites [200] source

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [46]
• Supported

  The structural-model discussion (indexed under Abstract; page unavailable) describes curcumin interacting with the hydrophobic core-forming block at low loading and increasingly with hydrophilic blocks at higher loading. It places curcumin at the core–shell interface and says it blocks hydrogen-bond acceptor sites within the shell, supporting partial shell incorporation. (LLM, conf=0.92)

  cites [65] source

In the paper

“The resulting rankings agreed reasonably well with the experimentally measured drug solubilities in the micelles.”

What the sources say

• Supported

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

  cites [196] source

In the paper

“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.”

What the sources say

• Supported

  The Results section, “Virtual screening of DrugBank and experimental evaluation,” says four drugs predicted to have high solubilization and four predicted to have low solubilization were selected for experimental testing. The Discussion states that predicted loading values for three positive and three negative hits were confirmed experimentally; the fourth negative hit, simvastatin, was a false negative. (LLM, conf=0.94)

  cites [116] source

In the paper

“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].”

What the sources say

• Supported

  In “Predictive Toxicology and Quantitative Structure-Activity Relationships (QSARs) for Industrial Chemicals” (page not provided), the paper describes structure–activity relationships in pharmacology and toxicology as mathematical relationships linking chemical properties to toxicity or therapeutic response, and describes QSAR as a predictive screening tool. Its discussion of fish acute toxicity syndromes also describes statistical analysis of data sets used to develop predictive models. (LLM, conf=0.85)

  cites [220] source

In the paper

“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].”

What the sources say

• Supported

  The Abstract says the authors developed a series of QSPR models for micelle drug-loading capacity using genetic function approximation. The Introduction specifies that the models used doxorubicin (DOX)-loading data, and the Conclusions describe the relationship between polymer structure and loading capacity. (LLM, conf=0.94)

  cites [209] source
• ?Not checked — no full text of the sourcecites [210] source

In the paper

“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).”

What the sources say

• Partly supported

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

  cites [204] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The bioactivity results (pp. 8441–8445) report lower IC50 values and greater cellular uptake for low-loaded (LL) than high-loaded (HL) micelles in both tested cancer cell lines. The summary links the LL micelles’ greater efficacy to their softer structure and greater potential to interact with cells. (LLM, conf=0.94)

  cites [226] source

In the paper

“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.”

What the sources say

• Supported

  Tables S2 and S3 in the Formulation data section show lower maximum curcumin solubilization with pEtOx rather than pMeOx as the hydrophilic block. Table S6 shows that curcumin remaining solubilized by pEtOx-containing micelles falls sharply at higher drug feeds, and the discussion describes agglomeration of the pEtOx-containing formulation. These passages support the comparison and the claim of reduced stability at higher loading; page numbers are not available in our copy. (LLM, conf=0.91)

  cites [46] source

In the paper

“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.”

What the sources say

• Supported

  The Results and Discussion (page unavailable) report that dry POx or POzi polymer was added to curcumin formulations and that the resulting spectral properties depended on the polymer-to-curcumin ratio, regardless of whether that ratio was reached by addition or direct formulation. The paper describes this as evidence of highly dynamic micelles. It explicitly reports a strong fluorescence increase after POx addition; its fluorescence results also report higher intensity at lower curcumin loading for both polymers. (LLM, conf=0.86)

  cites [30] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [30] sourceExperimental — accuracy not yet measured

In the paper

“This must mean that the fluorescence quantum yield is higher in the POx polymer due to a decrease in non-radiative decay pathways.”

What the sources say

• Supported

  The Results and Discussion state that, at identical CUR content and absorbance, higher fluorescence intensity corresponds to higher quantum yield and link that increase to reduced non-emitting internal conversion. The same section reports longer fluorescence lifetimes for POx-based than corresponding POzi-based CUR formulations. (LLM, conf=0.91)

  cites [30] source

In the paper

“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.”

What the sources say

• Partly supported

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

  cites [30] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [30] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Introduction describes curcumin’s extremely low water solubility and gives its logP as 3.28. The Conclusions call curcumin solvatochromic and report shifts in its optical properties; the Results and Discussion link its fluorescence quantum yield to its immediate environment. (LLM, conf=0.93)

  cites [30] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [28] sourceExperimental — accuracy not yet measured

In the paper

“A high LC also increases the amount of drug per micelle, which can increase the amount of drug internalized into cells [114].”

What the sources say

• Partly supported

  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)

  cites [114] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Results section reports similar bruceantin release rates from PMeOx-PcBOx and the reference P2 micelles, but very different paclitaxel release rates. The same section identifies P2 as PMeOx-b-PBuOx-b-PMeOx, and the Discussion identifies the PcBOx side chain as triazine-based. Page numbers are not available in our copy. (LLM, conf=0.94)

  cites [28] source

In the paper

“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].”

What the sources say

• Supported

  The Discussion states that SITUA measures systemic drug fractions simultaneously and compares their pharmacokinetic profiles. It also discusses the sample-processing requirements for clinical studies, supporting the claim that the method can be used clinically, while noting a logistical and financial burden. (LLM, conf=0.85)

  cites [247] source

In the paper

“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”

What the sources say

• Partly supported

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

  cites [247] sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly supported

  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)

  cites [113] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Results section, “POx micelles improve the brain and tumor delivery of vismodegib without penetrating CNS,” reports that the nanoparticle formulation decreased vismodegib’s volume of distribution. It interprets this as lower distribution to peripheral tissues that could perhaps mitigate systemic toxicity, matching the claim’s qualified suggestion about fewer off-target effects. (LLM, conf=0.93)

  cites [113] source

In the paper

“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].”

What the sources say

• ?Could not verify

  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)

  cites [239] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [30] sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Methods section describes a three-compartment pharmacokinetic simulation for drugs administered in polymeric micelles. The Results apply that model to micellar paclitaxel, and the Conclusion identifies the formulations as POx micelles containing paclitaxel, including ones co-loaded with a cisplatin prodrug. (LLM, conf=0.91)

  cites [188] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [253] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [254] source

In the paper

“A recent study by our lab explored the complex, dynamic nature of POx polymeric micelles and the PK activity of these formulations [188].”

What the sources say

• Supported

  The Discussion (page not provided) examines how drugs redistribute among POx micelles, serum proteins, and other circulating forms, and how that redistribution affects pharmacokinetics. It also compares the pharmacokinetics of the drugs and POx copolymer to investigate micelle behavior in vivo. (LLM, conf=0.92)

  cites [188] source

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [259] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Introduction says combinations of therapeutics are often used in cancer therapy. Section 2 describes combinations targeting different pathways, while Section 6.1 describes pairing a tumor-targeting regimen with one that targets the tumor microenvironment. (LLM, conf=0.91)

  cites [257] source
• Supported

  Section 2 describes combination chemotherapy as an established cancer treatment, explains its rationale in interconnected disease pathways, and gives examples in ovarian and lung cancer. Section 3.1 also describes combining chemotherapy with an anti-angiogenesis agent that acts on tumor blood vessels, supporting the tumor-microenvironment part of the claim. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [258] source

In the paper

“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.”

What the sources say

• Supported

  The Results report drug synergy in H69AR cells and a clear synergistic effect for the co-loaded formulation in 344SQ/Luc. cells (CI < 0.5). The Discussion reports considerably greater antitumor activity for co-loaded micelles than for single-drug micelles, their mixture, or free-drug combinations across three SCLC and NSCLC tumor models. (LLM, conf=0.92)

  cites [114] source

In the paper

“Another technique, oil in water emulsions, is common in pharmaceutical development and can be applied to polymer micelle preparation.”

What the sources say

• Partly supported

  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)

  cites [278] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [279] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [274] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [116] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [193] source
• ?Not checked — no full text of the sourcecites [264] source

In the paper

“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).”

What the sources say

• Supported

  The Abstract reports that POx micelles solubilized multi-drug combinations with total loading capacities up to 50 wt.%. Table 1 in Results §3.1 lists 48.7% for PTX/17-AAG/ETO and 48.4% for PTX/17-AAG/BTZ; the measured amounts of each drug in both combinations are approximately equal. (LLM, conf=0.95)

  cites [117] source

In the paper

“The combination polymeric micelle featured nanosized and worm-like morphology which was rarely reported previously for drug-loaded polymeric micelles.”

What the sources say

• Supported

  The Results describe co-loaded micelles measuring approximately 75–103 nm and retaining an elongated, worm-like shape. The Discussion calls this morphology “very rare for drug loaded micelles,” directly supporting the claim about its rarity. (LLM, conf=0.94)

  cites [114] source

In the paper

“Interestingly, drug release from combination polymeric micelle was slower, presumably due to the formation of stable micelle formulations with the co-loading of drugs.”

What the sources say

• Partly supported

  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)

  cites [114] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

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

  cites [260] source

In the paper

“The 3-in-1 micelle featured 40 nm hydrodynamic size and improved drug solubility (approximately up to 3 mg/mL in aqueous solution).”

What the sources say

• Supported

  Results §3.1 reports a hydrodynamic diameter of about 44 nm for the 3-in-1 micelles, consistent with approximately 40 nm. It reports aqueous solubilities of 3.36, 3.86, and 2.09 mg/mL for paclitaxel, 17-AAG, and rapamycin, respectively—approximately 3 mg/mL per drug, not in total. (LLM, conf=0.91)

  cites [240] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [188] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Discussion reports that resiquimod in polymeric micelles polarized antigen-presenting cells in the lung adenocarcinoma tumor model and increased CD8+ T-cell infiltration, supporting a cytotoxic T-cell response. The Results also report an increase in tumor CD8+ T cells after treatment. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [259] source

In the paper

“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).”

What the sources say

• Supported

  The Results section reports that both drugs were released more slowly from co-loaded micelles than from single-drug micelles. The Discussion reports improved tumor Cmax and AUC for both drugs in the PTX/C6CP formulation, while noting that the improvement was less pronounced for PTX/C8CP. (LLM, conf=0.90)

  cites [188] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [117] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Abstract describes a stepwise assessment of nanosimilar similarity, moving from quality characterization through nonclinical assessment to clinical evaluation. Section 2 says nonclinical data are required in addition to human bioequivalence or pharmacokinetic data for iron nanomedicines, supporting the point that in vitro and animal data alone are insufficient. The paper treats further clinical studies as case-dependent, not universally required. (LLM, conf=0.88)

  cites [293] source
• Partly supported

  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)

  cites [299] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Abstract says the NCL developed SITUA and describes its use in distinguishing complex nanomedicine pharmacokinetics. The Discussion reports that it characterized similar drug-fraction PK profiles for two liposomal doxorubicin formulations and describes its potential for evaluating bioequivalence. (LLM, conf=0.91)

  cites [247] source

In the paper

“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.”

What the sources say

• Partly supported

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

  cites [293] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [293] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [288] source
• ?Not matched

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

  cites [291]
• Supported

  The “Positioning and Premises of the New Draft Guidance Document” section links nanomaterial attributes to product safety and efficacy and describes a risk-based approach. The “CQA Assessment for Complex Drug Products” section calls for assessing attributes that may affect safety or efficacy and using experimental and clinical-performance data to validate that assessment. Together, these support the paraphrase about rigorous regulatory review; page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites [292] source

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [291]
• Partly supported

  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)

  cites [293] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [293] sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not matched

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

  cites [286]
• Supported

  The introduction (p. 1) identifies Q8 as Pharmaceutical Development and says Q11 applies concepts from Q8 and Q9, the Quality Risk Management guideline, to drug-substance manufacturing. “Does the guideline introduce additional regulatory expectations?” (p. 2) explicitly discusses systematic development approaches and quality-risk-management tools. (LLM, conf=0.88)

  cites [287] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [293] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [17] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  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)

  cites [17] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

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

  cites [153] sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly supported

  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)

  cites [307] sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

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

  cites [307] source

In the paper

“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.”

What the sources say

• Supported

  The Clinical Studies pharmacokinetics passage reports a longer half-life and higher AUC for NC-6004 than for cisplatin at an equivalent dose, and attributes the difference to prolonged blood circulation after incorporation into micelles. The copy describes the comparator as a cisplatin injection rather than explicitly calling it an aqueous solution; page numbers are unavailable. (LLM, conf=0.90)

  cites [308] source

In the paper

“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”

What the sources say

• Supported

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

  cites [238] source

In the paper

“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].”

What the sources say

• Supported

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

  cites [7] source

In the paper

“NK105 exhibited 23% of drug loading with a hydrodynamic size of approx. 90 nm [7].”

What the sources say

• Supported

  The Results (Preparation and characterisation of NK105; page not provided) state that NK105 contained approximately 23% paclitaxel by weight and had a weight-average diameter of approximately 85 nm. The Figure 1 caption identifies dynamic light scattering as the size-measurement method, so approximately 90 nm is a reasonable rounding. (LLM, conf=0.92)

  cites [7] source

In the paper

“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].”

What the sources say

• Supported

  The Results (Safety and patient-reported outcomes; page not specified) report peripheral sensory neuropathy in 52.8% of NK105 patients versus 70.0% of paclitaxel patients, with significantly lower cumulative incidence for NK105. The Discussion also describes NK105’s neuropathy toxicity profile as better, while noting that overall safety profiles were similar. (LLM, conf=0.94)

  cites [307] source

In the paper

“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”

What the sources say

• Supported

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

  cites [308] source

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [29] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [228] source

In the paper

“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.”

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [237]

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [11] source

In the paper

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

In the paper

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

In the paper

“Furthermore, ideal polymeric micelles are expected to reduce the toxicity of the therapeutic compounds.”

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [15] source
• ?Not checked — no full text of the sourcecites [16] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [14] source

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [36] source
• ?Not checked — no full text of the sourcecites [37] source
• ?Not checked — no full text of the sourcecites [38] source

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [34] source
• ?Not checked — no full text of the sourcecites [69] source
• ?Not checked — no full text of the sourcecites [70] source

In the paper

“However, for a long-term exposure to media, it was found that only PMeOx, but not PEG, could maintain the anti-fouling properties.”

What the sources say

• ?Not checked — no full text of the sourcecites [88] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [84] source

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [99] source

In the paper

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

In the paper

“Commonly used hydrophobic poly(amino acid)s are poly(β-benzyl-l-aspartate) (PBLA) and poly(γ-benzyl-α, l-glutamate) (PBLG).”

In the paper

“The micelle formulation exhibited 15–20% of doxorubicin loading and a 57–70 nm of size distribution.”

What the sources say

• ?Not checked — no full text of the sourcecites [2] source

In the paper

“PPO and poly(butylene oxide) have shown hydrophobic properties and, when incorporated in block copolymers, have the capacity to solubilize hydrophobic drugs [4, 103].”

What the sources say

• ?Not checked — no full text of the sourcecites [4] source
• ?Not checked — no full text of the sourcecites [103] source

In the paper

“The micelles displayed 20–125 nm size and the drug loading capacity was up to 12 %.”

What the sources say

• ?Not checked — no full text of the sourcecites [59] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [4] source

In the paper

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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [59] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [4] source

In the paper

“Commonly employed hydrophobic polymers are polyethers and polyesters.”

In the paper

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

In the paper

“Endosomes and the tumor microenvironment where the local pH is slightly acidic are the targeted spaces for such pH-sensitive polymers.”

In the paper

“Meanwhile, paclitaxel was highly soluble in PMeOx-b-PBuOx-b-PMeOx but is less soluble its POzi analog [63].”

What the sources say

• ?Not checked — no full text of the sourcecites [63] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [45] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [22] source

In the paper

“ELPs are polypeptides composed of amino acids which exhibit elastin like properties that potentially induce LCST phase transition behavior.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“Due to the presence of the cationic charge, PBAE-based copolymers were also employed as carriers for nucleic acids [140].”

What the sources say

• ?Not checked — no full text of the sourcecites [140] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [136] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [158] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [143] source

In the paper

“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.”

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [149]

In the paper

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

In the paper

“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].”

What the sources say

• ?Not matched

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

  cites [155]

In the paper

“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.”

In the paper

“Unimolecular micelles are topologically similar to self-assembled micelles, but consist of single polymer molecules with covalently linked amphiphile block copolymer chains [155].”

What the sources say

• ?Not matched

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

  cites [155]

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [193] source

In the paper

“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.”

In the paper

“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:”

In the paper

“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).”

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [23] source
• ?Not checked — no full text of the sourcecites [182] source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [64] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [193] source

In the paper

“Experimental validation of the prediction data from the aforementioned approaches has been performed.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [194] source

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites [213]

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [199] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [193] source

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [192] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [186] source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [198] source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [29] source
• ?Not checked — no full text of the sourcecites [187] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [201] source
• ?Not checked — no full text of the sourcecites [202] source
• ?Not checked — no full text of the sourcecites [203] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [208] source

In the paper

“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.”

In the paper