Well-defined polymer-drug conjugate engineered with redox and pH-sensitive release mechanism for efficient delivery of paclitaxel
Well-defined polymer-drug conjugate engineered with redox and pH-sensitive release mechanism for efficient delivery of paclitaxel
复制标题
明确的聚合物-药物缀合物采用氧化还原和 pH 敏感释放机制设计，可有效输送紫杉醇
DOI：
10.1016/j.jconrel.2014.09.009
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发表时间：
2014-11-28
影响因子：
10.8
通讯作者：
Chen, Xuesi
中科院分区：
文献类型：
--
作者：
Lv, Shixian;Tang, Zhaohui;Chen, Xuesi
聚合物-药物偶联物（PDC）的合成是药物传递领域的一个迫切需求。在此，我们开发了一种新型的抗癌PDC，其具有二硫键和酯键的侧基，用于按需递送紫杉醇（PTX），具有氧化还原和pH双重敏感行为。合成了一种简单的聚合物3，3 ′-二硫代二丙酸官能化的聚乙二醇-b-聚赖氨酸（mPEG-b-P（LL-DTPA）），并将PTX直接偶联到mPEG-b-P（LL-DTPA）的羧基上，得到含二硫键的聚合物-PTX偶联物（P（L-SS-PTX））。还制备了另一种结构相似的无二硫键的聚合物-PTX缀合物（P（L-PTX））以验证二硫键的功能。P（L-SS-PTX）胶束在肿瘤相关的还原条件下显示出快速的药物释放。有趣的是，P（L-SS-PTX）胶束中PTX的释放也可以通过增加酸度（pH值约为5）来促进。体外细胞毒性研究表明，与不敏感的P（L-PTX）胶束相比，P（L-SS-PTX）胶束对多种肿瘤细胞的细胞毒性显著增强。对携带B16 F1黑色素瘤的C57 BL/6小鼠的体内研究表明，P（L-SS-PTX）的抗肿瘤活性优于游离PTX和P（L-PTX）。这种双重敏感的前药为抗肿瘤药物的递送提供了一种有用的策略。(C)2014爱思唯尔有限公司版权所有。
The synthesis of polymer-drug conjugate (PDC) capable of convenient preparation and controlled release of therapeutic agents is still an urgent requirement in drug delivery field. Herein, we develop a novel anti-cancer PDC engineered with side groups of disulfide and ester bonds for on-demand delivery of paclitaxel (PTX) with redox and pH dual sensitive behaviors. A simple polymer, 3,3'-dithiodipropionic acid functionalized poly(ethylene glycol)-b-poly(L-lysine) (mPEG-b-P(LL-DTPA)), was synthesized and PTX was directly conjugated to the carboxyl groups of mPEG-b-P(LL-DTPA) to obtain the disulfide-containing polymer-PTX conjugate (P(L-SS-PTX)). Another structural similar polymer-PTX conjugate without disulfide bonds (P(L-PTX)) was also prepared to verify the function of disulfide linkages. The P(L-SS-PTX) micelles showed rapid drug release under tumor-relevant reductive conditions as designed. Interestingly, the PTX release from P(L-SS-PTX) micelles could also be promoted by the increased acidity (pH approximate to 5). In vitro cytotoxicity study showed that the P(L-SS-PTX) micelles exhibited significantly enhanced cytotoxicity against a variety of tumor cells compared to the non-sensitive P(L-PTX) micelles. The in vivo studies on B16F1 melanoma bearing C57BL/6 mice demonstrated the superior antitumor activity of P(L-SS-PTX) over both free PTX and P(L-PTX). This dual-sensitive prodrug provides a useful strategy for anti-tumor drug delivery. (C) 2014 Elsevier B.V. All rights reserved.