pH and Reduction Dual-Sensitive Copolymeric Micelles for Intracellular Doxorubicin Delivery
pH and Reduction Dual-Sensitive Copolymeric Micelles for Intracellular Doxorubicin Delivery
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DOI：
10.1021/bm200804j
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发表时间：
2011-10-01
影响因子：
6.2
通讯作者：
Xing, Malcolm M. Q.
中科院分区：
文献类型：
--
作者：
Chen, Jun;Qiu, Xiaozhong;Xing, Malcolm M. Q.
本研究针对肿瘤组织中低pH、高还原环境的特点，开发了一种新型的pH和还原双敏感胶束，用于抗癌药物阿霉素（DOX）的释放。这些亚100 nm胶束在生理条件下呈现核-壳结构，但响应于酸性和还原性刺激而快速释放负载的药物。以2，2 ′-二硫代二乙醇二丙烯酸酯、4，4 ′-三亚甲基联哌啶和甲氧基-PEG-NH_2为原料，通过Michael加成聚合反应合成了一种聚（β-氨基酯）重复单元中含有二硫键的新型共聚物。DOX在弱酸性环境（pH 6.5）中比在pH 7.4或在更高浓度（5 mM）的还原剂（DTT）存在下从胶束中释放得更快。释放在A中更有效。在两种刺激（pH 6.5和5 mM DTT）的情况下。MTT法显示，在较高浓度下，载药胶束对HepG 2肿瘤细胞的杀伤作用明显高于阿霉素，而空白胶束对肿瘤细胞的杀伤作用很低。共聚焦显微镜观察表明，该胶束能迅速内化，有效地将药物送入细胞核，抑制细胞生长。这些结果表明，该共聚物是一种新型有效的pH和还原双重响应纳米载体，可增强对癌细胞的药效。
This study develops novel pH and reduction dual-sensitive micelles for the anticancer drug doxorubicin (DOX) delivery owing to the fact that the tumor tissues show low pH and high reduction environment. These sub-100 nm micelles present a core - shell structure under physiological conditions, but quickly release the loaded drugs responding to acidic and reductive stimuli. With disulfide bonds in each repeat unit of poly(beta-amino ester)s, the novel copolymer was synthesized via Michael addition polymerization from 2,2'-dithio-diethanol diacrylate, 4,4'-trimethylene.dipiperidine, and methoxy-PEG- NH2. DOX released faster from micelles in a weakly acidic environment (pH 6.5) than at PH 7.4 or in the presence of a higher concentration (5 mM) of reducing agent (DTT). The release is even more effective in a. scenario of both stimuli (pH 6.5 and 5 mM DTT). MTT assay showed that the DOX-loaded micelles had a higher cytotoxicity for HepG2 tumor cells than DOX at higher concentrations, and that blank micelles had a very low cytotoxicity to the tumor cells. Confocal microscopy observation showed that the micelles can be quickly internalized, effectively deliver the drugs into nuclei, and inhibit cell growth. These results present the copolymer as a novel and effective pH and reduction dual-responsive nanocarrier to enhance drug efficacy for cancer cells.