Zhao Haizheng, Yung Lin Yue Lanry
Department of Chemical and Biomolecular Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore.
Int J Pharm. 2008 Feb 12;349(1-2):256-68. doi: 10.1016/j.ijpharm.2007.07.040. Epub 2007 Aug 6.
Folate or folic acid has been employed as a targeting moiety of various anticancer agents to increase their cellular uptake within target cells since folate receptors are vastly overexpressed in several human tumors. In this study, a biodegradable polymer poly(d,l-lactide-co-glycolide)-poly(ethylene glycol)-folate (PLGA-PEG-FOL) was used to form micelles for encapsulating anticancer drug doxorubicin (DOX). The drug loading content, encapsulation efficiency and in vitro release were characterized. To evaluate the targeting ability of the folate conjugated micelles, the cytotoxicity and cellular uptake of DOX-loaded micelles on three cancer cell lines with different amount of folate receptors (KB, MATB III, C6) and normal fibroblast cells (CCL-110) were compared. The cytotoxicity of PLGA-PEG-FOL micelles to cancer cells was found to be much higher than that of normal fibroblast cells, demonstrating that the folate conjugated micelles has the ability to selectively target to cancer cells. For normal cells, the cellular uptake of PLGA-PEG-FOL micelles was similar to PLGA-PEG micelles without folate conjugation, and was substantially lower than that of cancer cells. In addition, the cell cycle analysis showed that the apoptotic percentage of normal fibroblasts was substantially lower compared with the cancer cells after exposing to DOX-loaded PLGA-PEG-FOL micelles. An optimal folate amount of approximately 40-65% on the micelles was found to be able to kill cancer cells but, at the same time, to have very low effect to normal cells.
由于叶酸受体在多种人类肿瘤中大量过表达，叶酸或叶酸已被用作各种抗癌药物的靶向部分，以增加它们在靶细胞内的细胞摄取。在本研究中，一种可生物降解的聚合物聚（d，l-丙交酯-共-乙交酯）-聚（乙二醇）-叶酸（PLGA-PEG-FOL）被用于形成胶束以包裹抗癌药物阿霉素（DOX）。对药物负载量、包封率和体外释放进行了表征。为了评估叶酸共轭胶束的靶向能力，比较了负载DOX的胶束对三种具有不同叶酸受体量的癌细胞系（KB、MATB III、C6）和正常成纤维细胞（CCL-110）的细胞毒性和细胞摄取。发现PLGA-PEG-FOL胶束对癌细胞的细胞毒性远高于正常成纤维细胞，表明叶酸共轭胶束具有选择性靶向癌细胞的能力。对于正常细胞，PLGA-PEG-FOL胶束的细胞摄取与未共轭叶酸的PLGA-PEG胶束相似，且显著低于癌细胞。此外，细胞周期分析表明，暴露于负载DOX的PLGA-PEG-FOL胶束后，正常成纤维细胞的凋亡百分比与癌细胞相比显著更低。发现胶束上约40-65%的最佳叶酸量能够杀死癌细胞，但同时对正常细胞的影响非常小。
