Reduction-sensitive micelles with sheddable PEG shells self-assembled from a Y-shaped amphiphilic polymer for intracellular doxorubicine release
Reduction-sensitive micelles with sheddable PEG shells self-assembled from a Y-shaped amphiphilic polymer for intracellular doxorubicine release
复制标题
具有可脱落 PEG 壳的还原敏感胶束，由 Y 形两亲性聚合物自组装而成，用于细胞内阿霉素释放
DOI：
10.1016/j.colsurfb.2015.03.040
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发表时间：
2015-05-01
影响因子：
5.8
通讯作者：
Huang, Shi-Wen
中科院分区：
文献类型：
--
作者：
Cui, Can;Yu, Ping;Huang, Shi-Wen
基于Y型两亲性聚合物聚乙二醇-S-S-(PCL)(2)，合成了一种疏水聚酯核与亲水性聚乙二醇壳之间具有二硫键连接的新型可脱壳胶束。然后将胶束用于谷胱甘肽介导的抗癌药物阿霉素(DOX)的细胞内递送到肿瘤细胞中。该聚合物在水溶液中可自组装成平均直径为135 nm的胶束，总载药量为3.6%。在还原剂二硫苏糖醇(DTT)的存在下，这些胶束的亲水性聚乙二醇壳会脱落，从而导致胶束的尺寸发生变化。体外释药研究表明，在DTT存在下，载DOX的mpeg-S-S-(PCL)(2)胶束具有较快的DOX释放速度。结果表明，DOX-S-S-(PCL)(2)胶束对10 mM谷胱甘肽单酯(GSH-OET)处理的HeLa细胞具有较高的细胞毒作用。激光共聚焦扫描显微镜和流式细胞仪分析表明，负载DOX的mpeg-S-S-(PCl)(2)胶束能够有效地内化到HeLa细胞中，并且在GSH-OET处理的细胞中比未处理的细胞更快地释放DOX。细胞内吞作用抑制结果表明，mpeg-S-S-(PCL)(2)胶束主要通过网状蛋白介导的内吞作用进入细胞，少量参与小窝介导的内吞作用。这些结果表明，所提出的Y型还原敏感聚合物在有效的细胞内抗癌药物输送方面具有巨大的潜力。(C)2015爱思唯尔B.V.保留所有权利。
A new type of shell-sheddable micelles with disulfide linkages between the hydrophobic polyester core and hydrophilic poly(ethylene glycol) (PEG) shell was developed based on Y-shaped amphiphilic polymers mPEG-S-S-(PCL)(2). The micelles were then used for the glutathione-mediated intracellular delivery of the anticancer drug doxorubicin (DOX) into tumor cells. The polymer could self-assemble into micelles with an average diameter of 135 nm in aqueous solution and load DOX at a total content of 3.6%. The hydrophilic PEG shell of these micelles could be shed in the presence of reducing agent dithiothreitol (DTT), which resulted in size change of the micelles. In vitro release studies revealed that DOX-loaded mPEG-S-S-(PCL)(2) micelles exhibited faster DOX release in the presence of DTT. MTT assay demonstrated that DOX-loaded mPEG-S-S-(PCL)(2) micelles showed higher cytotoxicity against 10 mM of glutathione monoester (GSH-OEt) pretreated HeLa cells than that of the non-pretreated ones. Confocal laser scanning microscopy and flow cytometry analyses indicated that DOX-loaded mPEG-S-S-(PCL)(2) micelles were efficiently internalized into HeLa cells and exhibited faster DOX release in GSH-OEt-pretreated cells than in cells with no pretreatment. Endocytosis inhibition results proved that mPEG-S-S-(PCL)(2) micelles entered the cells mainly through the clathrin-mediated endocytosis pathway, and caveolae-mediated endocytosis was involved to a small extent. These results indicate the great potential of the proposed Y-shaped reduction-sensitive polymer for application in effective intracellular anticancer drug delivery. (C) 2015 Elsevier B.V. All rights reserved.