Liu Jinjian, Deng Hongzhang, Liu Qiang, Chu Liping, Zhang Yumin, Yang Cuihong, Zhao Xuefei, Huang Pingsheng, Deng Liandong, Dong Anjie, Liu Jianfeng
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, P.R. China.
Nanoscale. 2015 Mar 14;7(10):4451-60. doi: 10.1039/c4nr07435a.
The key to developing more nanocarriers for the delivery of drugs in clinical applications is to consider the route of the carrier from the administration site to the target tissue and to look for a simple design to complete this whole journey. We synthesized the amphiphilic copolymer cRGDfK-poly(ethylene glycol)-b-poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate) (cRGD-PETM) to construct multifunctional micelles. These micelles combined enhanced drug-loading efficiency with tumor-targeting properties, visual detection and controllable intracellular drug release, resulting in an improved chemotherapeutic effect in vivo. Doxorubicin (DOX) was encapsulated within the cRGD-PETM micelles as a model drug (termed as cRGD-PETM/DOX Ms). The size and morphology of the micelles were characterized systematically. As a result of the hydrophobic interaction and the π-π conjugation between the DOX molecules and the PTTMA copolymers, the cRGD-PETM/DOX Ms showed an excellent drug-loading capacity. The results of in vitro drug-release studies indicated that the cumulative release of DOX from cRGD-PETM/DOX Ms at pH 5.0 was twice that at pH 7.4. The results of fluorescent microscopic analysis showed that the cRGD-PETM/DOX Ms could be internalized by 4T1 and HepG2 cells via receptor-mediated endocytosis with rapid intracellular drug release, which resulted in increased cytotoxicity compared with free DOX. Ex vivo imaging studies showed that the cRGD-PETM/DOX Ms improved the accumulation and retention of the drug in tumor tissues. Studies of the in vivo anticancer effects showed that the cRGD-PETM/DOX Ms had a significantly higher therapeutic efficacy with lower side-effects than free DOX and PETM/DOX Ms. These results show that the multifunctional cRGD-PETM/DOX Ms have great potential as vehicles for the delivery of hydrophobic anticancer drugs.
开发更多用于临床药物递送的纳米载体的关键在于，要考虑载体从给药部位到靶组织的途径，并寻找一种简单的设计来完成这一整个过程。我们合成了两亲性共聚物cRGDfK-聚乙二醇-b-聚（2,4,6-三甲氧基亚苄基-1,1,1-三（羟甲基）乙烷甲基丙烯酸酯）（cRGD-PETM）以构建多功能胶束。这些胶束结合了增强的载药效率、肿瘤靶向特性、可视化检测和可控的细胞内药物释放，从而在体内产生了改善的化疗效果。将阿霉素（DOX）作为模型药物包裹在cRGD-PETM胶束中（称为cRGD-PETM/DOX Ms）。系统地表征了胶束的大小和形态。由于DOX分子与PTTMA共聚物之间的疏水相互作用和π-π共轭，cRGD-PETM/DOX Ms表现出优异的载药能力。体外药物释放研究结果表明，DOX从cRGD-PETM/DOX Ms在pH 5.0时的累积释放量是在pH 7.4时的两倍。荧光显微镜分析结果表明，cRGD-PETM/DOX Ms可通过受体介导的内吞作用被4T1和HepG2细胞内化，并实现细胞内药物的快速释放，与游离DOX相比，这导致细胞毒性增加。体外成像研究表明，cRGD-PETM/DOX Ms提高了药物在肿瘤组织中的蓄积和滞留。体内抗癌作用研究表明，cRGD-PETM/DOX Ms比游离DOX和PETM/DOX Ms具有显著更高的治疗效果且副作用更低。这些结果表明，多功能cRGD-PETM/DOX Ms作为疏水性抗癌药物递送载体具有巨大潜力。
