Sun Huanli, Guo Bingnan, Cheng Ru, Meng Fenghua, Liu Haiyan, Zhong Zhiyuan
Biomedical Polymers Laboratory, Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Ren-Ai Road 199, Suzhou 215123, PR China.
Biomaterials. 2009 Oct;30(31):6358-66. doi: 10.1016/j.biomaterials.2009.07.051. Epub 2009 Aug 8.
Biodegradable micelles with sheddable poly(ethylene glycol) shells were developed based on disulfide-linked poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-SS-PCL) diblock copolymer and applied for rapid intracellular release of doxorubicin (DOX). PEG-SS-PCL was prepared with controlled block lengths via exchange reaction between PEG orthopyridyl disulfide and mercapto PCL. The micelles formed from PEG-SS-PCL, though sufficiently stable in water, were prone to fast aggregation in the presence of 10mm dithiothreitol (DTT), due to shedding of the PEG shells through reductive cleavage of the intermediate disulfide bonds. Interestingly, the in vitro release studies revealed that these shell-sheddable micelles released DOX quantitatively within 12h under a reductive environment analogous to that of the intracellular compartments such as cytosol and the cell nucleus. In contrast, minimal drug release (<20%) was observed within 24h for the reduction insensitive PEG-PCL micelles under the same conditions as well as for PEG-SS-PCL micelles under the non-reductive conditions. Remarkably, cell experiments showed that these shell-sheddable micelles accomplished much faster release of DOX inside cells and higher anticancer efficacy as compared to the reduction insensitive control. These shell-sheddable biodegradable micelles are highly promising for the efficient intracellular delivery of various lipophilic anticancer drugs to achieve improved cancer therapy.
基于二硫键连接的聚（乙二醇）-b-聚（ε-己内酯）（PEG-SS-PCL）二嵌段共聚物，开发了具有可脱落聚（乙二醇）壳的可生物降解胶束，并将其应用于阿霉素（DOX）的快速细胞内释放。通过PEG邻吡啶基二硫醚与巯基PCL之间的交换反应，制备了具有可控嵌段长度的PEG-SS-PCL。由PEG-SS-PCL形成的胶束虽然在水中足够稳定，但在10mM二硫苏糖醇（DTT）存在下容易快速聚集，这是由于PEG壳通过中间二硫键的还原裂解而脱落。有趣的是，体外释放研究表明，这些可脱壳胶束在类似于细胞溶质和细胞核等细胞内区室的还原环境下，在12小时内定量释放DOX。相比之下，在相同条件下，对还原不敏感的PEG-PCL胶束以及在非还原条件下的PEG-SS-PCL胶束在24小时内观察到的药物释放量最小（<20%）。值得注意的是，细胞实验表明，与还原不敏感的对照相比，这些可脱壳胶束在细胞内实现了更快的DOX释放和更高的抗癌疗效。这些可脱壳的可生物降解胶束在高效细胞内递送各种亲脂性抗癌药物以实现改善的癌症治疗方面具有很大的前景。
