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

当前位置： X-MOL 学术 › Mol. Pharmaceutics › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Codelivery of Paclitaxel and Everolimus at the Optimal Synergistic Ratio: A Promising Solution for the Treatment of Breast Cancer
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-06-04 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00217
Loujin Houdaihed ₁ , James C. Evans ₁ , Christine Allen ₁

Affiliation

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.

中文翻译：

紫杉醇和依维莫司的代码传递以最佳协同比：乳腺癌的有前途的解决方案。

相对于单独使用PTX而言，研究紫杉醇（PTX）和mTOR抑制剂依维莫司（EVER）的组合的临床研究未能显着改善乳腺癌（BC）患者的疗效和毒性。这些令人失望的临床试验结果归因于使用PTX和EVER的组合设计不良的临床前研究，以及两种药物的药代动力学差异显着。在当前的工作中，在六个BC细胞系的面板中检查了PTX和EVER之间潜在的协同作用，这六个BC细胞系的分子亚型和药物敏感性不同。聚合纳米颗粒（NPs）用于以最佳协同比例封装PTX和EVER，以在BC细胞系中实现联合治疗的特异性，共定位递送。PTX和EVER的组合（尤其是在较高剂量的EVER时）在所有评估的BC细胞系中产生了明显的协同作用。确定PTX∶EVER的最佳摩尔比为1∶0.5。通过封装在由聚乙二醇形成的聚合物NP中，以协同比例将组合递送至BC细胞。b-聚（丙交酯-共-乙交酯）（PEG- b-PLGA）共聚物。NP具有小于100 nm的平均直径，并且能够在最佳协同摩尔比下将包封的PTX和EVER在体外保留超过7天。细胞毒性数据表明，在72小时后，MCF-7和SKBR3 BC细胞系中PTX + EVER负载的NPs的细胞毒性明显低于游离药物组合，这表明PTX + EVER负载的NPs保持稳定并保持负载的药物组合。 72小时后的核心。通过流式细胞术评估了SKBR3细胞中FITC标记的NPs的摄取，暴露后24小时后约有41％的细胞显示出可检测的荧光。本研究中用于确定和评估协同PTX的彻底而系统的方法：

更新日期：2018-06-04

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11