Biomedical Polymers Laboratory and Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, People's Republic of China.
Biomacromolecules. 2010 Apr 12;11(4):848-54. doi: 10.1021/bm1001069.
Reduction-responsive biodegradable micelles were developed from disulfide-linked dextran-b-poly(epsilon-caprolactone) diblock copolymer (Dex-SS-PCL) and applied for triggered release of doxorubicin (DOX) in vitro and inside cells. Dex-SS-PCL was readily synthesized by thiol-disulfide exchange reaction between dextran orthopyridyl disulfide (Dex-SS-py, 6000 Da) and mercapto PCL (PCL-SH, 3100 Da). Dynamic light scattering (DLS) measurements showed that Dex-SS-PCL yielded micelles with an average size of about 60 nm and a low polydispersity index (PDI 0.1-0.2) in PB (50 mM, pH 7.4). Interestingly, these micelles formed large aggregates rapidly in response to 10 mM dithiothreitol (DTT), most likely due to shedding of the dextran shells through reductive cleavage of the intermediate disulfide bonds. DOX could be efficiently loaded into the micelles with a drug loading efficiency of about 70%. Notably, the in vitro release studies revealed that Dex-SS-PCL micelles released DOX quantitatively in 10 h under a reductive environment, mimicking that of the intracellular compartments such as cytosol and the cell nucleus, whereas only about 27% DOX was released from reduction insensitive Dex-PCL micelles in 11.5 h under otherwise the same conditions and about 20% DOX released from Dex-SS-PCL micelles in 20 h under the nonreductive conditions. The cell experiments using fluorescence microscopy and confocal laser scanning microscopy (CLSM) showed clearly that DOX was rapidly released to the cytoplasm as well as to the cell nucleus. MTT studies revealed a markedly enhanced drug efficacy of DOX-loaded Dex-SS-PCL micelles as compared to DOX-loaded reduction-insensitive Dex-PCL micelles. These reduction-responsive biodegradable micelles have appeared highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy.
基于二硫键连接的葡聚糖-b-聚己内酯两亲性嵌段共聚物（Dex-SS-PCL）制备了响应型降解胶束，并用于体外和细胞内阿霉素（DOX）的触发释放。Dex-SS-PCL 通过葡聚糖邻吡啶二硫（Dex-SS-py，6000 Da）和巯基-聚己内酯（PCL-SH，3100 Da）之间的硫醇-二硫交换反应很容易合成。动态光散射（DLS）测量结果表明，Dex-SS-PCL 在 PB（50 mM，pH 7.4）中形成平均粒径约为 60nm、低多分散指数（PDI 0.1-0.2）的胶束。有趣的是，这些胶束在 10mM 二硫苏糖醇（DTT）的作用下迅速形成大的聚集物，这很可能是由于中间二硫键的还原断裂导致葡聚糖壳的脱落。DOX 可以被有效地包封到胶束中，载药效率约为 70%。值得注意的是，体外释放研究表明，在还原环境下，Dex-SS-PCL 胶束在 10 小时内定量释放 DOX，模拟了细胞内区室（如细胞质和细胞核）的情况，而在相同条件下，还原不敏感的 Dex-PCL 胶束在 11.5 小时内仅释放约 27%的 DOX，在非还原条件下，Dex-SS-PCL 胶束释放约 20%的 DOX。荧光显微镜和共聚焦激光扫描显微镜（CLSM）的细胞实验清楚地表明，DOX 迅速释放到细胞质和细胞核。MTT 研究表明，与负载还原不敏感的 Dex-PCL 胶束的 DOX 相比，负载 DOX 的 Dex-SS-PCL 胶束的药物疗效明显增强。这些响应型可生物降解胶束有望成为癌症治疗中靶向细胞内递送疏水性化疗药物的理想选择。
