Chen Yanzuo, Zhang Wei, Huang YuKun, Gao Feng, Sha Xianyi, Lou Kaiyan, Fang Xiaoling
Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China ; Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China ; State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai, People's Republic of China.
Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People's Republic of China ; CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Arlington, VA, USA.
Int J Nanomedicine. 2015 Jun 19;10:4043-57. doi: 10.2147/IJN.S79045. eCollection 2015.
The therapeutic effect of methotrexate (MTX)-conjugated Pluronic-based polymeric mixed micelles (F127/P105-MTX) on the folate receptor-overexpressing tumors treatment was investigated in this study. Due to its high structural similarity to folic acid and the high expression of folate receptor in most solid tumors, MTX serves as not only a cytotoxic agent but also a homing ligand. Cellular uptake and the endocytic mechanism studies of MTX-conjugated mixed micelles were performed in folate receptor-rich KBv and folate receptor-deficient A-549 cancer cells. Additionally, the efficacy and safety studies of F127/P105-MTX in KBv tumor-bearing mice were evaluated. Results indicate that F127/P105-MTX significantly enhanced the cellular uptake in KBv cells as compared to that of conventional non-MTX-conjugated mixed micelles. Moreover, the results showed that F127/P105-MTX can be internalized by both caveolae- and clathrin-mediated endocytosis in energy-dependent and folate receptor-dependent manners. The in vitro and in vivo antitumor efficacies of F127/P105-MTX were significantly enhanced in comparison with MTX-entrapped mixed micelles. Furthermore, no acute toxicities to hematological system and major organs have been observed after intravenous administration during the regimen. Therefore, our results suggest that F127/P105-MTX could be an effective and safe nano-drug delivery system for cancer therapy, especially for the folate receptor-rich cancer treatment.
本研究考察了甲氨蝶呤（MTX）偶联的基于泊洛沙姆的聚合物混合胶束（F127/P105-MTX）对叶酸受体高表达肿瘤的治疗效果。由于MTX与叶酸结构高度相似，且在大多数实体瘤中叶酸受体高表达，MTX不仅作为一种细胞毒性药物，还作为一种归巢配体。在富含叶酸受体的KBv细胞和缺乏叶酸受体的A-549癌细胞中进行了MTX偶联混合胶束的细胞摄取和内吞机制研究。此外，还评估了F127/P105-MTX在荷KBv肿瘤小鼠中的疗效和安全性。结果表明，与传统的未偶联MTX的混合胶束相比，F127/P105-MTX显著增强了KBv细胞的摄取。此外，结果表明，F127/P105-MTX可以通过小窝蛋白介导和网格蛋白介导的内吞作用，以能量依赖和叶酸受体依赖的方式内化。与包裹MTX的混合胶束相比，F127/P105-MTX的体外和体内抗肿瘤疗效显著增强。此外，在给药方案期间静脉给药后，未观察到对血液系统和主要器官的急性毒性。因此，我们的结果表明，F127/P105-MTX可能是一种有效且安全的癌症治疗纳米药物递送系统，尤其适用于富含叶酸受体的癌症治疗。
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