State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Int J Pharm. 2014 Dec 10;476(1-2):185-98. doi: 10.1016/j.ijpharm.2014.09.017. Epub 2014 Sep 16.
Tanshinone IIA (TAN) has few clinical applications for anti-cancer therapy mainly due to its high lipophicity, low cellular uptake, and poor bioavailability. To improve the anti-cancer effect and bioavailability of TAN, we developed a mixed micelle system constituted with D-α-tocopheryl polyethylene glycol succinate-graft-poly(D,L-lactide-co-glycolide) (TPGS-g-PLGA) copolymer and Pluronic F68. TAN was encapsulated in the TPGS-g-PLGA/Pluronic F68 mixed micelles by using the thin film hydration technology optimized by the central composite design/response surface method (CCD/RSM). TAN-loaded mixed micelles were highly stable in the presence or absence of bovine serum albumin (BSA) and achieved sustained drug release in vitro. Compared with free TAN, TAN mixed micelles had higher cytotoxicity and pro-apoptotic effects against human hepatocellular carcinoma HepG2 cells. The significant enhancement on pro-apoptosis by TAN micelles was evidenced by increased chromosome condensation, mitochondria membrane potential loss, cell apoptosis, and cleavages of caspase-3 and PARP. Furthermore, pharmacokinetic studies revealed that TAN mixed micelles significantly prolonged the circulation time and improved bioavailability of TAN in rats. These results demonstrated that TAN-loaded TPGS-g-PLGA/F68 mixed micelles are an effective strategy to deliver TAN for cancer therapy.
丹参酮 IIA（TAN）在癌症治疗中的临床应用较少，主要是由于其高亲脂性、低细胞摄取率和差的生物利用度。为了提高 TAN 的抗癌效果和生物利用度，我们开发了一种由 D-α-生育酚聚乙二醇琥珀酸酯-g-聚（D，L-丙交酯-co-乙交酯）（TPGS-g-PLGA）共聚物和泊洛沙姆 F68 组成的混合胶束系统。采用中心复合设计/响应面法（CCD/RSM）优化的薄膜水化技术，将 TAN 包封在 TPGS-g-PLGA/泊洛沙姆 F68 混合胶束中。TAN 载药混合胶束在存在或不存在牛血清白蛋白（BSA）的情况下均高度稳定，并在体外实现了药物的持续释放。与游离 TAN 相比，TAN 混合胶束对人肝癌 HepG2 细胞具有更高的细胞毒性和促凋亡作用。TAN 胶束对促凋亡作用的显著增强通过染色体浓缩、线粒体膜电位丧失、细胞凋亡和 caspase-3 和 PARP 的裂解得到证实。此外，药代动力学研究表明，TAN 混合胶束显著延长了 TAN 在大鼠体内的循环时间并提高了其生物利用度。这些结果表明，载 TAN 的 TPGS-g-PLGA/F68 混合胶束是一种有效的 TAN 给药策略，可用于癌症治疗。
