pH-responsive polymer-drug conjugates as multifunctional micelles for cancer-drug delivery
pH-responsive polymer-drug conjugates as multifunctional micelles for cancer-drug delivery
复制标题
pH响应性聚合物药物缀合物作为癌症药物递送的多功能胶束
DOI：
10.1088/0957-4484/25/33/335101
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发表时间：
2014-08-22
期刊：
影响因子：
3.5
通讯作者：
Li, Bang-Jing
中科院分区：
文献类型：
--
作者：
Kang, Yang;Ha, Wei;Li, Bang-Jing
通过亚胺键将4 β-氨基鬼臼毒素（NPOD）与聚乙二醇（PEG）共价连接，制备了一种新型的线性pH敏感型偶联物甲氧基聚乙二醇-4 β-氨基鬼臼毒素（mPEG-NPOD-I）。mPEG-NPOD-I胶束同时作为抗癌药物偶联物和药物载体。作为药物偶联物，mPEG-NPOD-I在5.0和4.0的弱酸性pH下显示出比生理pH 7.4显著更快的NPOD释放。值得注意的是，证实了这种药物缀合物可以有效地将NPOD递送到肿瘤细胞的细胞核，并且对A549、Hela和HepG 2癌细胞产生比亲本NPOD大得多的细胞毒性作用。mPEG-NPOD-I的半数抑制浓度（IC_（50））比NPOD低一个数量级。在体内，mPEG-NPOD-I显著减小了肿瘤的大小，并且生物分布研究表明该药物缀合物可以选择性地在肿瘤组织中蓄积。作为药物载体，mPEG-NPOD-I胶束包封疏水性PTX，载药率为57%，载药量为16%。结果表明，PEG-NPOD-I/PTX具有良好的细胞毒性和pH触发的快速释放特性。我们相信，这些多功能药物共轭胶束具有巨大的潜力，靶向治疗癌症。
We developed a novel linear pH-sensitive conjugate methoxy poly(ethylene glycol)-4 beta-aminopodophyllotoxin (mPEG-NPOD-I) by a covalently linked 4 beta-aminopodophyllotoxin (NPOD) and PEG via imine bond, which was amphiphilic and self-assembled to micelles in an aqueous solution. The mPEG-NPOD-I micelles simultaneously served as an anticancer drug conjugate and as drug carriers. As a drug conjugate, mPEG-NPOD-I showed a significantly faster NPOD release at a mildly acidic pH of 5.0 and 4.0 than a physiological pH of 7.4. Notably, it was confirmed that this drug conjugate could efficiently deliver NPOD to the nuclei of the tumor cells and led to much more cytotoxic effects to A549, Hela, and HepG2 cancer cells than the parent NPOD. The half maximal inhibitory concentration (IC50) of mPEG-NPOD-I was about one order magnitude lower than that of the NPOD. In vivo, mPEG-NPOD-I reduced the size of the tumors significantly, and the biodistribution studies indicated that this drug conjugate could selectively accumulate in tumor tissues. As drug carriers, the mPEG-NPOD-I micelles encapsulated hydrophobic PTX with drug-loading efficiencies of 57% and drug-loading content of 16%. The loaded PTX also showed pH-triggered fast release behavior, and good additive cytotoxicity effect was observed for the PEG-NPOD-I/PTX. We are convinced that these multifunctional drug conjugate micelles have tremendous potential for targeted cancer therapy.