Synthesis and evaluation of an injectable everolimus prodrug

Wang, Haibo; Zheng, Xiaohe; Cai, Zhengjiang; Ou, Yu; Zheng, Shan; Zhu, Tianmin

doi:10.1016/j.bmcl.2017.01.069

Cited by 6 publications

(2 citation statements)

References 18 publications

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“…The release of PTX was reduced with the addition of PLGA to the PEG- b -PLGA NPs. This variability in PTX release between formulation A and B was expected as the addition of PLGA has been shown in previous studies to increase the hydrophobicity of the NP core and the compatibility of the hydrophobic drug with the NP core, thereby enhancing the stability of the NPs. − PTX and EVER are hydrophobic drugs with a poor water solubility of 0.3 μg/mL for PTX and 1 μg/mL for EVER. , However, the release of EVER is not altered to the same extent with the addition of PLGA. This could be explained by the fact that EVER may have less compatibility with the PLGA core compared to PTX.…”

Section: Discussionmentioning

confidence: 64%

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Codelivery of Paclitaxel and Everolimus at the Optimal Synergistic Ratio: A Promising Solution for the Treatment of Breast Cancer

2018

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Clinical studies examining the combination of paclitaxel (PTX) and everolimus (EVER), an mTOR inhibitor, have failed to result in significant improvements in efficacy and toxicity in patients with breast cancer (BC), relative to treatment with PTX alone. These disappointing clinical trial results have been attributed to poorly designed preclinical studies using the combination of PTX and EVER as well as the significantly different pharmacokinetic profiles of the two drugs. In the current work, the potential synergy between PTX and EVER was examined in a panel of six BC cell lines that differ in terms of their molecular subtype and drug sensitivity. Polymeric nanoparticles (NPs) were used to encapsulate PTX and EVER at an optimal synergistic ratio to achieve specific, colocalized delivery of the combination therapy in BC cell lines. Combinations of PTX and EVER (especially at relatively high doses of EVER) resulted in pronounced synergy in all BC cell lines evaluated. The optimal molar ratio of PTX:EVER was determined to be 1:0.5. The combination was delivered to BC cells at the synergistic ratio via encapsulation within polymeric NPs formed from the poly(ethylene glycol)- b-poly(lactide- co-glycolide) (PEG- b-PLGA) copolymer. The NPs had an average diameter of less than 100 nm and were capable of in vitro retention of the encapsulated PTX and EVER at the optimal synergistic molar ratio for over 7 days. Cytotoxicity data demonstrated that PTX+EVER-loaded NPs were significantly less cytotoxic than the free drug combination in MCF-7 and SKBR3 BC cell lines following 72 h, suggesting that PTX+EVER-loaded NPs remain stable and retain the drug combination loaded within the core after 72 h. The uptake of FITC-labeled NPs in SKBR3 cells was evaluated by flow cytometry, with approximately 41% of cells demonstrating detectable fluorescence after 24 h of exposure. The thorough and systematic approach used in this study to determine and evaluate a synergistic PTX:EVER ratio in conjunction with a potentially promising delivery vector for the drug combination could offer a future clinical benefit for patients with BC.

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Section: Discussionmentioning

confidence: 64%

“…37−40 PTX and EVER are hydrophobic drugs with a poor water solubility of 0.3 μg/mL for PTX and 1 μg/mL for EVER. 41,42 However, the release of EVER is not altered to the same extent with the addition of PLGA. This could be explained by the fact that EVER may have less compatibility with the PLGA core compared to PTX.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 97%