Co-Delivery of Paclitaxel by a Capsaicin Prodrug Micelle Facilitating for Combination Therapy on Breast Cancer.,Molecular Pharmaceutics

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Co-Delivery of Paclitaxel by a Capsaicin Prodrug Micelle Facilitating for Combination Therapy on Breast Cancer.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-06-28 , DOI: 10.1021/acs.molpharmaceut.9b00209
Yang Lan ₁ , Yue Sun ₁ , Tong Yang ₁ , Xueqin Ma _{1,

2} , Mei Cao ₃ , Lu Liu ₁ , Shuangyu Yu ₁ , Aichen Cao ₁ , Yanhua Liu _{1,

2}

Affiliation

Poor anticancer ability, serious adverse reaction, and drug resistance against paclitaxel (PTX) have limited its clinical applications. When a mouse breast carcinoma cell line (4T1) was treated with both PTX and capsaicin (CAP), there was a synergistic anti-proliferative effect demonstrated with a combination index of 0.28. Therefore, a novel polyethylene glycol-derivatized CAP (PEG-Fmoc-CAP2) polymeric prodrug micellar carrier was developed and further encapsulated with PTX for antitumor combination treatment. The PEG-Fmoc-CAP2 polymeric micelles co-delivered with PTX achieved a 62.3% fraction of apoptotic cells in comparison to 45.4% fraction of apoptotic cells to that upon treatment with PTX alone. Comparable CAP amounts were found in the cell lysate treatment with PEG-Fmoc-CAP2-conjugated micelles to that of free CAP-treated 4T1 cells after 12 h treatment. Pharmacokinetic and biodistribution studies showed that the micelles possessed much longer circulation time in blood and preferential tumor tissue accumulation compared to the Taxol solution. Importantly, PTX/CAP-loaded micelles exhibited superior in vivo antitumor activity on the inhibition rate of tumor growth than other treatments (70.5% tumor growth reduction in PTX/CAP micelle-treated mice vs 57.8, 43.3, and 23.8% of tumor growth inhibition rate in PTX/PEG-Fmoc-OA2 micelles, Taxol, and PEG-Fmoc-CAP2 micelle-treated mice, respectively). Thus, the dual-functional PEG-Fmoc-CAP2 polymeric prodrug micelles are a promising co-delivery nanosystem for achieving synergistic antitumor efficacy of PTX and CAP.

中文翻译：

辣椒素前药胶束共同递送紫杉醇，促进乳腺癌的联合治疗。

抗癌能力差，严重的不良反应以及对紫杉醇（PTX）的耐药性限制了其临床应用。当用PTX和辣椒素（CAP）共同处理小鼠乳腺癌细胞系（4T1）时，组合指数为0.28，证明具有协同的抗增殖作用。因此，开发了新型的聚乙二醇衍生的CAP（PEG-Fmoc-CAP2）聚合前药胶束载体，并进一步用PTX封装以用于抗肿瘤联合治疗。与单独使用PTX处理相比，与PTX共递送的PEG-Fmoc-CAP2聚合物胶束实现了62.3％的凋亡细胞比例，而凋亡细胞的比例为45.4％。在用PEG-Fmoc-CAP2缀合的胶束处理细胞裂解液后，在处理12 h后发现与游离CAP处理的4T1细胞可比的CAP量。药代动力学和生物分布研究表明，与紫杉醇溶液相比，胶束具有更长的血液循环时间和优先的肿瘤组织积累。重要的是，载有PTX / CAP的胶束对肿瘤生长的抑制率优于其他治疗方法（PTX / CAP胶束处理的小鼠的肿瘤生长减少率达70.5％，而肿瘤生长抑制率分别为57.8、43.3和23.8％（分别在PTX / PEG-Fmoc-OA2胶束，紫杉醇和PEG-Fmoc-CAP2胶束处理的小鼠中的速率）。因此，

更新日期：2019-06-14

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