Co-delivery of Paclitaxel and Cisplatin in Poly(2-oxazoline) Polymeric Micelles: Implications for Drug Loading, Release, Pharmacokinetics and Outcome of Ovarian and Breast Cancer Treatments

May combine two claims.

Sequential PTX followed by a platinum-based regimen is currently first-line therapy for ovarian cancer and a common treatment for breast cancer.

“The combination chemotherapy using sequential administration of paclitaxel (PTX) followed by a platinum-based regimen is currently the first-line therapy for ovarian cancer as well as common treatment for breast cancer [1, 2].”

• cites [1] Ozols, 2004, Advanced ovarian cancer: a clinical update on first-line treatment, recurrent disease, and new agents, J. Natl. Compr. Canc. Netw.Not checked — no full text of the source
• cites [2] Rhee, 2002, Efficacy of combination chemotherapy with paclitaxel and cisplatin in patients with advanced non-small cell lung cancer, Cancer Res. Treat. sourcePartly supported

  The treatment-methods passage (결론 section; page unavailable) describes paclitaxel given before cisplatin, but the patients had advanced non-small-cell lung cancer. The discussion in the same section says paclitaxel is effective against ovarian and breast cancers; it does not say the sequential combination is first-line therapy for ovarian cancer or a common breast-cancer treatment. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

PTX POx micelles have about 4 to 100 times higher drug loading and about 10 to 20 times higher drug concentration than Taxol, Genexol-PM, and Abraxane.

“Specifically, PTX POx micelles have ca. 4 to 100 times higher drug loading and ca. 10 to 20 times higher drug concentration than the current PTX clinical formulations Taxol, Genexol-PM, and Abraxane.”

• cites [13] Han, 2012, Synergistic combinations of multiple chemotherapeutic agents in high capacity poly(2-oxazoline) micelles, Mol. Pharm. sourcePartly supported

  The Discussion reports 43.6% PTX loading in POx micelles, versus about 1% in Taxol and 10% in Abraxane, supporting an approximately 4- to 44-fold loading comparison. Its nearly 100-fold figure refers to less excipient, not higher drug loading. The paper reports a POx PTX concentration of 38.7 g/L but does not establish a 10- to 20-fold concentration comparison with the named clinical formulations or provide a Genexol-PM comparison. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [14] He, 2015, Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation, J. Contr. Release sourceNot checked — no full text of the source

May combine two claims.

Aqueous POx micelle solutions can be prepared containing 10 to 50 g/L of extremely poorly soluble drug and are stable for days and weeks.

“For many drugs, the aqueous POx micelle solutions can be readily prepared that contain 10 to 50 g/L of extremely poorly soluble drug and are stable for days and weeks.”

• cites [13] Han, 2012, Synergistic combinations of multiple chemotherapeutic agents in high capacity poly(2-oxazoline) micelles, Mol. Pharm. sourcePartly supported

  Results §3.1 reports aqueous POx micelles containing nearly 40 g/L of PTX or DTX, while Discussion §4 reports that many formulations remained stable for as long as two weeks. The claimed upper concentration of 50 g/L is not supported: in the reported high-concentration formulations, 50 g/L refers to the copolymer, not the drug. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [14] He, 2015, Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation, J. Contr. Release sourceNot checked — no full text of the source

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

Platinum anticancer drugs such as cisplatin enter cancer cell nuclei and form DNA adducts that lead to apoptosis.

“Platinum anticancer drugs, such as cisplatin, the most potent member of the platinum drug family, penetrate into the nucleus of cancer cells and form adducts with DNA leading to apoptosis [4].”

• cites [4] Florea, 2011, Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects, Cancers (Basel) sourcePartly supported

  The Cytotoxicity section says cisplatin forms DNA adducts, and the Drug Resistance Mechanisms section says DNA damage from those adducts triggers cell-cycle arrest and apoptosis. Our copy does not establish the citing sentence’s additional claim that cisplatin is the most potent platinum drug, or explicitly describe its passage into cancer-cell nuclei. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Several preclinical formulations of multiple drugs co-loaded into various nanoparticle carriers have been evaluated and shown some promise for cancer treatment.

“Moreover, several preclinical formulations of multiple drugs co-loaded into various nanoparticle carriers have also been evaluated and shown some promise for the treatment of cancers [9, 10].”

• cites [9] Ma, 2013, Nanoparticles for combination drug therapy, ACS Nano sourceSupported
• cites [10] Tian, 2017, Nanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer, Nanomedicine sourceSupported

May combine two claims.

A recent study reported that co-loading etoposide and C6CP in POx micelles considerably decreased release rates and increased tumor distribution of both drugs, along with increased anticancer activity compared with single-drug micelles.

“Our recent study reported that co-loading of etoposide and C6CP in POx micelles resulted in considerable decrease in the release rates and increase in the tumor distribution of both drugs along with the increased anticancer activity of the co-loaded formulation compared to the single drug micelles [20].”

• cites [20] Wan, 2018, Drug combination synergy in worm-like polymeric micelles improves treatment outcome for small cell and non-small cell lung cancer, ACS Nano sourceSupported

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

A decrease in drug release kinetics was also reported to be accompanied by decreased hepatotoxicity of CLS NP wortmannin.

“It was also reported that a decrease in drug release kinetics was accompanied by a decrease in the hepatotoxicity of CLS NP wortmannin.”

• cites [31] Sethi, 2014, Effect of drug release kinetics on nanoparticle therapeutic efficacy and toxicity, Nanoscale sourceSupported

Classified as probably not a substantial claim.

The relationship between nanoparticle drug release kinetics and the therapeutic efficacy and toxicity of delivered drugs has been previously reported.

“The relationship between the drug release kinetics from the nanoparticles and the therapeutic efficacy and toxicity of the drugs delivered using these nanoparticles has been previously reported [31].”

• cites [31] Sethi, 2014, Effect of drug release kinetics on nanoparticle therapeutic efficacy and toxicity, Nanoscale sourceSupported

May combine two claims.

In that prior study, co-loading also drastically changed particle shape, complicating dissection of the release-kinetics effect.

“However, in that study the co-loading also resulted in a drastic change of the particles shape, which has complicated dissecting the effect of the release kinetics.”

• cites [20] Wan, 2018, Drug combination synergy in worm-like polymeric micelles improves treatment outcome for small cell and non-small cell lung cancer, ACS Nano sourceSupported

May combine two claims.

Serum-bound drug is active against tumors: release of PTX to serum is a putative mechanism of Taxol anti-tumor activity, and Abraxane is a complex of PTX with serum albumin.

“There is no doubt that the serum bound drug is active upon tumors as the release of the drug, in particular PTX, to the serum is a putative mechanism of the anti-tumor activity of Taxol [34], and another blockbuster PTX-based drug, Abraxane, represents the complex of PTX with serum albumin [35].”

• cites [34] Paal, 2001, High affinity binding of paclitaxel to human serum albumin, Eur. J. Biochem. sourceNot checked — no full text of the source
• cites [35] Miele, 2009, Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer, Int. J. Nanomed. sourceSupported

May combine two claims.

Prior studies suggest that tumor permeability and nanoparticle size are critically important for nanoparticle drug distribution to tumors and resulting anticancer effects.

“This conclusion is consistent with the prior studies suggesting that the tumor permeability as the well as the size of the nanoparticles (including polymeric micelles of different type) are critically important for nanoparticle drug distribution to tumors and the resulting anticancer effects [36–38].”

• cites [36] Cabral, 2011, Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size, Nat. Nanotechnol. sourceNot checked — no full text of the source
• cites [37] Yokoi, 2015, Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier, J. Contr. Release sourcePartly supported

  The Concluding remarks (page not provided) say that transport properties of the tumor microenvironment and vascular barrier are critical to nanotherapeutic delivery and may help explain efficacy. The Drug transport model section says its model accounts for particle size, but the paper does not establish that nanoparticle size is critically important to tumor distribution or anticancer effects, nor does it examine polymeric micelles. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [38] Yokoi, 2014, Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment, Cancer Res. sourcePartly supported

  The Introduction links particle size to tumor accumulation and drug payload, while the Discussion describes size-dependent passage through tumor-vessel collagen. The Results on cell proliferation also link drug extravasation to an anticancer effect. The paper studies liposomes, however, and does not establish the parenthetical claim about different types of polymeric micelles. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

The trend of ratio-dependent synergy/antagonism was observed for each cisplatin derivative but was most pronounced for PTX/C6CP PM.

“This trend was observed for each cisplatin derivative but was perhaps the most pronounced for the PTX/C6CP PM (Figure 3b,c).”

May combine two claims.

Overall LC values in these PM formulations were high ~28%, but not maximal.

“The overall LC values in these PM formulations were high ~28 %, but not maximal for this PM system.”

May combine two claims.

CP incorporation was nearly complete except for PTX/C6CP PM (20/5/50), where LC decreased to ~33.5%.

“As far as the incorporation CP is concerned it was nearly complete except for the PTX/C6CP PM (20/5/50), for which the LC decreased to ~33.5 %.”

May combine two claims.

Co-loading the drugs in micelles slows their release to serum, improves pharmacokinetics, and increases tumor distribution for both drugs.

“The drugs co-loading in the micelles result in a slowed-down release to serum, improved pharmacokinetics and increased tumor distribution for both drugs.”

May combine two claims.

C6CP was released faster than PTX from both single and combination drug micelles; C8CP release rates were close to PTX; C10CP was released slower than PTX.

“As a result while for C6CP was released faster than PTX form both single and combination drug micelle (Figure 2a,b) for the C8CP these rates were close to each other (Figure 2c), while for C10CP the situation was inverse and with this hydrophobic cisplatin derivative being released slower than PTX (Figure 2d).”

May combine two claims.

In PTX/C6CP PM (2/2/10), plasma Cmax increased about 2.0-fold for C6CP and about 1.4-fold for PTX compared with the single-drug micelles.

“The Cmax in the plasma was increased ~2.0 fold for C6CP and ~1.4 fold for PTX, when compared to the single drug micelles.”

May combine two claims.

XPS analysis suggests CP prodrug contains Pt(IV) and Pt(II) ~76:24, which can be reduced by ascorbate to ~29:71.

“The XPS analysis suggests that the CP prodrug contains both Pt(IV) and Pt(II) ~76:24, which can be reduced by ascorbate to ~29:71.”

May combine two claims.

In PTX/C6CP PM (2/2/10), PTX plasma AUC increased about 1.9-fold, clearance decreased about 1.5-fold, and Vdobs increased about 1.3-fold.

“Moreover, there was ~1.9 fold increase in the plasma AUC of PTX (~1.5 fold decrease in CL) as well as ~1.3 fold increase Vdobs of this drug.”

May combine two claims.

Micelles with feed ratios 1/3/10 and 2/2/10 displayed no or minimal synergy, while 3/1/10, 20/3/50, and 40/3/50 showed pronounced synergy with CI < 1 over Fa 0.1 to 1.0.

“The micelles with feed ratios 1/3/10 and 2/2/10 displayed no or minimal synergy, while the higher PTX content micelles 3/1/10 and high-loaded micelles 20/3/50 and 40/3/50 were showing pronounced and clear synergistic effect with CI value < 1 over a wider range Fa values from 0.1 to 1.0 (Figure 3b,c).”

May combine two claims.

In the first range, PTX/CP molar ratios varied from ~0.2 to ~1.9 for PTX/C6CP or ~0.25 to ~2.25 for PTX/C10CP, close to clinical dose ratios.

“As a result, the PTX/CP molar ratios varied from ~0.2 to ~1.9 PTX/C6CP or ~0.25 to ~2.25 for PTX/C10CP, and were close to PTX/cisplatin dose ratios used in the clinical chemotherapy regimens [18].”

• cites [18] Rosati, 2000, A phase II study of paclitaxel/cisplatin combination in patients with metastatic breast cancer refractory to anthracycline-based chemotherapy, Tumori sourceNot checked — no full text of the source

May combine two claims.

No significant differences in particle morphology were found between various PM; shapes were nearly spherical by TEM.

“No significant differences in the particle morphology was found between various PM as their shapes were nearly spherical by TEM (Figure 1g–j).”

May combine two claims.

All prepared PM formulations remained stable in dispersion with little if any particle size change and no drug precipitation for at least 12 days.

“All prepared PM formulations remained quite stable in dispersion displaying little if any changes of the particle sizes and no drug precipitation for at least as long as 12 days (Figure 1b–f).”

May combine two claims.

In PTX/C6CP PM (2/2/10), tumor Cmax increased about 2.3-fold for C6CP and about 1.6-fold for PTX compared with the single-drug micelles.

“Specifically, the Cmax increased by ~2.3 fold for C6CP and ~1.6 fold for PTX (Table 2).”

May combine two claims.

The slowed release effect was most pronounced for PTX in all combination formulations, and noticeable for high loaded PTX/C6CP PM and combination micelles with more hydrophobic cisplatin prodrugs.

“This effect was the most pronounced for PTX in all combination formulations, was quite noticeable for high loaded PTX/C6CP PM as well as combination drug micelles containing two more hydrophobic cisplatin prodrugs (Figure 2).”

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

In the second range, PTX/C6CP molar ratios varied from ~1.4 to ~15.8, and overall LC and total drug concentration reached ~46% and ~43 g/L.

“As a result, the overall LC and the total drug concentration in these formulations were maximized reaching as much as ~46 % and ~43 g/L, respectively.”

May combine two claims.

Co-loaded PTX and CP were quantitatively recovered by HPLC and each drug retention time was the same as respective free drug standard.

“Moreover, the co-loaded PTX and CP were quantitatively recovered by HPLC and each drug retention time was the same as that of the respective free drug analytical standard.”

May combine two claims.

A wide range of drug mixing ratios and very high two-drug loading, exceeding 50 wt.% drug, were achieved in a stable micellar solution.

“A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50 wt.% drug in a stable micellar solution is demonstrated.”

May combine two claims.

In the LCC-6-MDR model, PTX/C6CP PM (40/3/50) had the greatest effect, surpassing all treatment groups in both tumor growth inhibition and lifespan prolongation.

“The combination drug micelles PTX/C6CP PM (40/3/50) had the greatest effect surpassing any of the treatment groups in both the inhibition of the tumor growth and in the prolongation of the lifespan to a median of (Figure 5e,f, Supplementary Tables S3 and S4).”

May combine two claims.

In healthy 6-8 week old female nude mice with a q4d x 4 regimen, MTD values were 20 mg PTX/kg and 20 mg CP/kg for PTX/CP PM (2/2/10), 60 mg/kg PTX and 4.5 mg/kg C6CP for PTX/C6CP PM (40/3/50), and 3 mg/kg for free cisplatin.

“The MTD values were determined in healthy 6–8 week old female nude mice using a q4d x 4 regimen. These MTD were 1) 20 mg PTX/kg and 20 mg CP/kg for PTX/CP PM (2/2/10), and 2) 60 mg/kg PTX and 4.5 mg/kg C6CP for PTX/C6CP PM (40/3/50). The MTD of the free cisplatin was 3 mg/kg.”

May combine two claims.

In PTX/C8CP PM (2/2/10), plasma Cmax of C8CP slightly decreased about 1.1-fold while PTX Cmax increased about 2.0-fold.

“Likewise, although there was a slight (~1.1 fold) decrease in the Cmax of C8CP in the plasma, the Cmax of PTX increased ~2.0 fold.”

May combine two claims.

In PTX/C8CP PM (2/2/10), PTX plasma AUC increased about 2.2-fold, clearance decreased about 1.7-fold, and Vdobs increased slightly about 1.1-fold.

“The improvement in the PK of PTX in the PTX/C8CP PM formulation was further evidenced by ~2.2 fold increase in the plasma AUC of this drug (~1.7 fold decrease in CL) and slight (~1.1 fold) increase in the Vdobs.”

May combine two claims.

Co-loading PTX and CP in POx micelles produced formulations with drug loading from about 28% to about 46% of total drug in the dispersed phase and total drug concentration from about 3 g/L to over 40 g/L.

“In this study, we co-loaded PTX and CP in POx micelles resulting in the micellar formulations with LC from ~28 % to ~46 % of the total drug in the dispersed phase, and the total drug concentration in the solution from about 3 g/L to over 40 g/L.”

May combine two claims.

In PTX/C6CP PM (2/2/10), tumor AUC increased about 2.9-fold for C6CP and about 1.3-fold for PTX.

“The tumor AUC were increased ~2.9 fold for C6CP and ~1.3 fold for PTX.”

May combine two claims.

The tumor-to-plasma AUC ratio for C8CP in PTX/C8CP PM (2/2/10) exceeded that for C8CP in single-drug C8CP PM (2/10) by about 1.4 times, and for PTX by about 1.1 times.

“The tumor to plasma AUC ratios for C8CP in the co-loaded drug micelles, PTX/C8CP PM (2/2/10), exceeded the ratio for C8CP in the single drug micelles, C8CP PM (2/10), by ~1.4 times; and ~1.1 times exceeded for PTX.”

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

Pt(IV) appears to be partially reduced to Pt(II) during preparation of the samples.

“However, the process of incorporation of CP in the micelles would need to be optimized in the future as Pt(IV) appears to be partially reduced to Pt(II) during preparation of the samples.”

May combine two claims.

In PTX/C8CP PM (2/2/10), C8CP plasma AUC slightly decreased while Vdobs increased almost 2.1-fold.

“Again, the plasma AUC of C8CP in the co-loaded micelles was slightly decreased, although, surprisingly, these was almost ~2.1 fold increase in Vdobs.”

May combine two claims.

In PTX/C8CP PM (2/2/10), the effects of co-loading were less pronounced and were seen mainly for PTX, not for C8CP.

“In case of PTX/C8CP PM, the effects of co-loading were less dramatic and seen mainly for PTX but not for C8CP (Table 3).”

May combine two claims.

In PTX/C8CP PM (2/2/10), tumor Cmax of PTX increased about 2.0-fold while C8CP tumor Cmax remained unchanged compared with single-drug micelles.

“Consistent with the plasma PK, the Cmax of PTX in PTX/C8CP PM was increased ~2.0 fold while the Cmax of C8CP remained unchanged when compared to single drug micelles.”

May combine two claims.

For PTX/C6CP PM (40/3/50), mouse doses were 60 mg/kg PTX and about 2.55 mg/kg cisplatin equivalent, corresponding to human equivalent doses of about 180 mg/m2 PTX and 7.5 mg/m2 cisplatin.

“In this case the treatment doses in a mouse were 60 mg/kg for PTX and ~2.55 mg/kg for cisplatin equivalent, which correspond to HED of ~180 mg/m2 (~4.8 mg/kg) for PTX and ~7.5 mg/m2 (~0.89 mg/kg) for cisplatin.”

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

PTX and CP weight ratios were varied from a 3:1 excess of CP over PTX to a 45:1 excess of PTX over CP.

“We also varied the PTX and CP ratios (wt.) in a broad range from excess of CP vs. PTX (3:1) to a considerable excess of PTX vs. CP (45:1).”

May combine two claims.

The pattern of higher micelle AUC and lower serum-bound AUC occurs when micellar drug transfer to serum decreases, when reabsorption to micelles increases, or when both parameters are correspondingly altered.

“This pattern is seen 1) when the rate of the micellar drug transfer to serum decreases (A0 vs. A1, or A4; B0 vs. B1, or B4), or 2) when the rate of reabsorption to micelles increases (A1 vs. A2; B1 vs. B2), or 3) when both parameters are correspondingly altered (A0 vs. A3; B0 vs. B3).”

• AssumptionThe authors state this as an assumption: A drug's antitumor efficacy is directly proportional to the quantity of that drug that reaches the tumor.
• AssumptionThe authors state this as an assumption: The clearance rate of serum-bound drug is much faster than that of drug in polymeric micelles.

May combine two claims.

Tumor Cmax ratios were about 0.8 for both formulations, and tumor AUC ratios were 1.0 for PTX/C6CP and 1.1 for PTX/C8CP.

“Thus, the tumor Cmax ratios were ~0.8 for both formulations, and the tumor AUC ratios were 1.0 and 1.1 for PTX/C6CP and PTX/C8CP, respectively.”

May combine two claims.

Efficacy studies suggested that the co-loaded micelles are superior to any single-drug micelle formulation and even to the mixture of single-drug micelles given at the same dose.

“Consistent with this, the efficacy studies suggested that these co-loaded micelles are superior to any of the single drug micelle formulation and even the mixture of the single drug micelles administered at the”

May combine two claims.

In both basic PK model scenarios, as drug retention in micelles increases, concentration profiles and AUC values for the micelle compartment increase while those for the serum-bound drug compartment decrease.

“In both basic scenarios the concentration profiles and AUC values for PM compartment increase and the respective values for the serum-bound drug compartment decrease as the retention of the drug in the micelles increases (Table 4, Supplementary Figure S9).”

• AssumptionThe authors state this as an assumption: A drug's antitumor efficacy is directly proportional to the quantity of that drug that reaches the tumor.
• AssumptionThe authors state this as an assumption: The clearance rate of serum-bound drug is much faster than that of drug in polymeric micelles.

May combine two claims.

In the A2780/CisR model, single micelle drugs PTX PM, C6CP PM, and C8CP PM produced longer tumor growth delay and significantly increased median lifespan to about 18-20 days.

“The treatments with the single micelle drugs including PTX PM and both cisplatin prodrug forms, C6CP PM and C8CP PM resulted in a longer delay of the tumor growth and a significant increase in the median lifespan to ~18–20 days (see also Supplementary Tables S3 and S4).”

May combine two claims.

As drug retention in micelles increases, tumor Cmax decreases in scenario A but increases in scenario B.

“Specifically, as the drug retention in the micelles increases, Cmax decreases in scenario A, but increases in scenario B.”

• AssumptionThe authors state this as an assumption: A drug's antitumor efficacy is directly proportional to the quantity of that drug that reaches the tumor.
• AssumptionThe authors state this as an assumption: The clearance rate of serum-bound drug is much faster than that of drug in polymeric micelles.

May combine two claims.

In the LCC-6-MDR model, PTX PM (40/50) had a somewhat greater effect on tumor growth rate than other single-drug groups, but this effect and lifespan differences were not significant.

“Like in the previous case PTX PM (40/50) had a somewhat greater effect by decreasing the tumor growth rate compared to any other single drug group but this effect was not significant and neither were the difference in the lifespan compared to these treatment groups.”

May combine two claims.

The effects of PTX/C6CP PM (40/3/50) were statistically significant and included 2 of 5 long-term survivors beyond day 60.

“Like in the previous case of combination drug micelles these effects were not only statistically significant but also resulted in 2/5 long-term survivors (beyond day 60).”

May combine two claims.

In PTX/C8CP PM (2/2/10), improved plasma pharmacokinetics was observed for PTX only, not for C8CP.

“In the case of the co-loaded micelles PTX/C8CP PM (2/2/10), containing a relatively more hydrophobic cisplatin derivative C8CP, improved plasma PK was observed for PTX only, but not for C8CP.”

May combine two claims.

For PTX/C6CP PM (2/2/10), plasma half-life, Cmax, and AUCs increased and clearance decreased for both drugs.

“Specifically, there were increases in the plasma half-life, Cmax, AUCs, and decreases in the clearance of both drugs observed for the co-loaded micelles PTX/C6CP PM (2/2/10), containing a relatively less hydrophobic cisplatin derivative, C6CP.”

May combine two claims.

The A2780/CisR tumor was very aggressive and grew rapidly within the first week, with a median animal lifespan of 10.5 days.

“This tumor is very aggressive and rapidly grows within the first week of the study, with the animals median lifespan of 10.5 days (Figure 5a,b).”

May combine two claims.

In the co-drug loaded PM cohorts, 2 of 6 animals in PTX/C6CP (2/2/10) and 3 of 6 in PTX/C8CP (2/2/10) were long-term survivors beyond day 50.

“It also has to be mentioned that in the co-drug loaded PM cohorts, 2 of 6 (PTX/C6CP (2/2/10) PM) and 3 of 6 (PTX/C8CP (2/2/10) PM) long-term survivors (beyond day 50) were observed.”

May combine two claims.

C8CP PM (2/10) appears to have considerably higher plasma and tumor Cmax and AUC than C6CP PM (2/10), while the PK parameters of the respective drugs in PTX/C8CP PM (2/2/10) and PTX/C6CP PM (2/2/10) are similar.

“Indeed, C8CP PM (2/10) appears to have considerably higher Cmax and AUC both in plasma and in tumor when compared with C6CP PM (2/10), while the PK parameters of the respective drugs in PTX/C8CP PM (2/2/10) and PTX/C6CP PM (2/2/10) are similar.”

May combine two claims.

The nanoparticles in the obtained formulations were small, mostly uniform with PDI 0.11 to 0.2, and stable on storage for more than 12 days.

“The nanoparticles in the obtained formulations were small, mostly uniform (PDI 0.11 to 0.2), and stable upon storage for over 12 days.”

May combine two claims.

In PTX/C8CP PM (2/2/10), C8CP plasma half-life slightly decreased (6.54 vs 7.40 h) while PTX half-life increased (5.68 vs 3.67 h).

“In fact, for the co-loaded drug formulation the plasma half-life of C8CP was even slightly decreased when compared to the single drug micelles (t1/2, α 6.54 h vs. 7.40 h), although the half-life of PTX was still increased (t1/2, α 5.68 h vs. 3.67 h).”

May combine two claims.

Although tumor inhibition differences were not significant, the co-loaded PTX/C8CP PM group had a statistically longer lifespan than the corresponding PTX PM and C8CP PM single-drug mixture.

“While the differences in the tumor inhibition between these groups were not significant, the co-loaded PTX/C8CP PM group had a statistically higher lifespan than the respective PTX PM and C8CP PM single drug mixture (Tables S3 and S4).”

May combine two claims.

In the A2780/CisR model, combination drug PMs PTX/C6CP (2/2/10) and PTX/C8CP (2/2/10) produced pronounced tumor growth inhibition and a very significant increase in median lifespan to about 46.5-55.4 days.

“A major improvement in the anti-tumor treatment was observed with both combination drug PMs (PTX/C6CP (2/2/10) PM and PTX/C8CP (2/2/10) PM) which resulted in a pronounced tumor growth inhibition and a very significant increase of the median lifespan to ~46.5–55.4 days.”

May combine two claims.

The micellar system displays a broad range of drug mixing ratios, exceptionally high two-drug loading, and slowed drug release to serum as a result of co-loading.

“This micellar system displays a broad range of drug mixing ratios and exceptionally high two-drug loading as well as the slowed-down release of the drugs to the serum as a result of their co-loading.”

May combine two claims.

The simulation suggests that increasing drug retention in micelles can increase the overall amount of drug in the tumor compartment, but only when micellar and serum-bound drug permeability to tumor are comparable.

“The results of the simulation suggest that an increase of the retention of a drug in the micelle can indeed result in an increase in the overall amount of the drug in the tumor compartment, albeit only in the case when the permeability of the micellar and serum-bound drugs to the tumor are comparable.”

• AssumptionThe authors state this as an assumption: A drug's antitumor efficacy is directly proportional to the quantity of that drug that reaches the tumor.
• AssumptionThe authors state this as an assumption: The clearance rate of serum-bound drug is much faster than that of drug in polymeric micelles.
• AssumptionThe authors state this as an assumption: In the three-compartment PK simulation, micelles are stable and do not break down into unimers.

May combine two claims.

In the animal tumor model, formulating both drugs in one micelle improved PK and increased tumor distribution for both drugs.

“The improved PK and increased tumor distribution for both drugs as a result of their formulation in one micelle is demonstrated for the animal tumor model.”

May combine two claims.

Based on the data, stronger drug retention in micelles is associated with greater plasma exposure and greater tumor accumulation of that drug.

“On one hand, based on our data, the stronger the drug is retained in the micelles, the greater the plasma exposure is, and the greater the tumor accumulation of this drug is.”

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

PTX arrests cells in G2/M phase by binding β-tubulin subunits, inhibiting microtubule depolymerization, and causing apoptosis through cell-signaling cascades.

“PTX is a member of taxanes family, which arrest cells in the G2/M phase by binding to the β-tubulin subunits, inhibiting depolymerization of microtubules and cause apoptosis through cell-signaling cascades [3].”

• cites [3] Schiff, 1979, Promotion of microtubule assembly in vitro by taxol, Nature sourceNot checked — no full text of the source

May combine two claims.

High drug loading and concentration of PTX POx micelles have been shown to benefit cancer treatment in animal tumor models by decreasing excipient-related toxicity, widening therapeutic index, and allowing high dose PTX therapy.

“This alone have been shown to be highly beneficial for cancer treatment in animal tumor models by decreasing the excipient-related toxicity, widening the therapeutic index and allowing high dose PTX therapy [15].”

• cites [15] He, 2016, A high capacity polymeric micelle of paclitaxel: implication of high dose drug therapy to safety and in vivo anti-cancer activity, Biomaterials sourceNot checked — no full text of the source

May combine two claims.

The results support PTX and cisplatin co-loaded micelles as a strategy for improved chemotherapy of ovarian and breast cancer and suggest potential for clinical translation.

“Overall, the results provide support for the use of PTX and cisplatin co-loaded micelles as a strategy for improved chemotherapy of ovarian and breast cancer and potential for the clinical translation.”

May combine two claims.

The prodrug with longer alkyl chain (C10CP) was ~30 times more toxic than cisplatin, while C6CP was only ~4 times more toxic.

“Therefore, the prodrug with the longer alkyl chain (C10CP) was ~30 times more toxic compared to cisplatin, while the prodrug with the shorter alkyl chain (C6CP) was only ~4 times more toxic.”

May combine two claims.

Clinical use of cisplatin is complicated by dose-limiting side effects and rapid development of drug resistance.

“Clinical use of cisplatin is complicated by the dose-limiting side effects as well as rapid development of drug resistance [5].”

• cites [5] Siddik, 2003, Cisplatin: mode of cytotoxic action and molecular basis of resistance, Oncogene sourceNot checked — no full text of the source

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

The increase in Pt(II) content may be due to partial reduction of Pt(IV) during rehydration.

“which may be due to partial reduction of the Pt(IV) during the rehydration step in the micelle preparation.”

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

Animals were randomized into groups of five or six mice with approximately the same mean tumor volumes.

“Animals were randomized into groups of five or six mice, each group having approximately same mean tumor volumes of ~ 300 mm3, and then administered via tail vein using q4d x 4 regimen (days 0. 4. 8. 12) with the test articles.”

May combine two claims.

The results suggest that a novel high-capacity polymeric micelle combination regimen of PTX with low-dose cisplatin could be developed and would be superior to high-capacity PTX micelles alone.

“The results suggest a possibility of developing a novel high capacity PM combination drug regimen of PTX combined with low dose of cisplatin, which is superior to high capacity PTX PM micelles alone [15].”

• cites [15] He, 2016, A high capacity polymeric micelle of paclitaxel: implication of high dose drug therapy to safety and in vivo anti-cancer activity, Biomaterials sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The ICP-MS technique used to determine CP prodrugs in PK studies does not distinguish among different forms of platinates.

“Notably, the ICP-MS technique used for determination of CP prodrugs in PK studies does not distinguish between different forms of platinates.”

May combine two claims.

Compared with the POx micelles in this study, prior systems had considerably lower drug loadings and less flexibility in changing drug ratio, which is essential for optimizing synergistic combinations.

“Compared to POx PM in our study, these systems displayed considerably lower drug loadings and less flexibility in changing the drug ratio, which is essential for optimizing synergistic drug combinations.”

May combine two claims.

A decrease in C6CP release rate caused by co-loading with PTX may be responsible for better retention of C6CP in co-loaded micelles in plasma and for improved plasma and tumor PK.

“Specifically, a decrease in the release rate of C6CP observed as a result of co-loading of this drug with PTX may be responsible for a relatively better retention of C6CP in the co-loaded micelles in plasma and improvement in the plasma and tumor PK as result of co-loading.”

• AssumptionRests on an assumption: The connection between drug release rate and the pharmacokinetics and tumor distribution of micellar drugs has been relatively little studied.

May combine two claims.

PTX PM have previously been consistently superior to Taxol and Abraxane, so those two clinical nanoformulations were not included in treatment comparisons.

“Since PTX PM have been previously consistently superior to the PTX formulations compared to Taxol and Abraxane (two nanoformulations being used in the clinic) [15] the latters were not included in treatment comparisons.”

• cites [15] He, 2016, A high capacity polymeric micelle of paclitaxel: implication of high dose drug therapy to safety and in vivo anti-cancer activity, Biomaterials sourceNot checked — no full text of the source

May combine two claims.

Some prior co-formulations showed in vitro synergy and in select cases superior in vivo anti-tumor effects, but the reported systems have constraints due to different drug-loading mechanisms.

“Although some of these studies demonstrated a synergistic effect of two drugs in vitro, and in select cases superior anti-tumor effect of co-formulated two drugs compared to single drugs in vivo, the reported systems have constrains due to different mechanisms of drug loading.”

May combine two claims.

The half-life trend results from the assumed lower micelle versus serum clearance rates and appears consistent with experimental data for PTX and C6CP.

“The trend is a result of a lower micelle vs. serum clearance rates assumed and it appears to be consistent with the experimental data in Table 2 and 3 for PTX and C6CP.”

• AssumptionThe authors state this as an assumption: The clearance rate of serum-bound drug is much faster than that of drug in polymeric micelles.

May combine two claims.

Complex equilibria should establish under steady-state conditions, but the existence of such equilibrium in the body should not be assumed automatically because redistribution between micelles and environment may be slow.

“As a result, complex equilibriums should establish in a steady state condition, although an existence of any such equilibrium in the body should not be assumed automatically, because the redistribution of the solutes between the PM and environment could be quite slow [32].”

• cites [32] Kabanov, 2002, Pluronic block copolymers in drug delivery: from micellar nanocontainers to biological response modifiers, Crit. Rev. Ther. Drug Carrier Syst. sourceNot checked — no full text of the source

May combine two claims.

A previous study of Pluronic P85 plasma PK and biodistribution was performed at the critical micelle concentration, with only unimers, and well above it, with both unimers and micelles.

“For example, our previous study of the plasma PK and biodistribution of Pluronic P85 was carried out at the critical micelle concentration (CMC), when only unimers were present, and well above this concentration, when both unimers and micelles were present [33].”

• cites [33] Batrakova, 2004, Distribution kinetics of a micelle-forming block copolymer Pluronic P85, J. Contr. Release sourceNot checked — no full text of the source

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

One possible explanation is that drug molecules transfer to serum proteins and then accumulate in tumors, perhaps in a serum-bound state, along with micelles that can also carry drug to tumor.

“One possible explanation is that the drug molecules are transferred to the serum proteins and then accumulate in the tumors, perhaps, in a serum-bound state, along with the micelles that can also carry the drug to the tumor.”

May combine two claims.

The demonstrated superior efficacy of PTX and cisplatin co-loaded micelles suggests that co-loading is one strategy for improved cancer chemotherapy and that these formulations may hold promise for further translational development.

“The demonstrated superior efficacy of the PTX and cisplatin co-loaded micelles suggests that co-loading of drugs is one strategy for improved chemotherapy of cancer and the researched formulations may hold promise for the further translational development.”

May combine two claims.

The drugs were cleared faster than the micelles, suggesting at least partial release of drugs from micelles to serum proteins.

“That means that the drugs were cleared faster than the micelles and suggests at least partial release of the drugs from the micelles to serum proteins.”

May combine two claims.

Clearance was independent of concentration, indicating renal clearance of unimers but not of micelles, which were above the renal clearance limit.

“It was discovered, that clearance was independent on the concentration, which was indicative of the renal clearance of the unimers but not the micelles (that were above the renal clearance limit).”

• cites [33] Batrakova, 2004, Distribution kinetics of a micelle-forming block copolymer Pluronic P85, J. Contr. Release sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Micelles are dynamic structures and are expected to exchange components with their environment.

“Since micelles are dynamic structures they are expected to exchange their components with the environment.”

May combine two claims.

Block copolymer chains partition between micelles and external solution as unimers, while hydrophobic drugs such as PTX and CP partition between micelles and serum proteins in blood.

“Specifically, the block copolymer chains are partitioned between the micelles and external solution (individually dissolved block copolymer chains or unimers), while the hydrophobic drugs, such as PTX and CP, are partitioned between the micelles and serum proteins present in the blood.”