Zhang Xuanmiao, Sun Xun, Li Jilong, Zhang Xiaoning, Gong Tao, Zhang Zhirong
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan, P R China.
Pharmazie. 2011 Jul;66(7):496-505.
This study aimed at developing a novel lipid nanoemulsion formulation of doxorubicin (DOX) which is feasible for scale-up production, exhibits good parenteral acceptability, and further improves the therapeutic index of the drug. Oleic acid was used to form ionic complex with DOX in order to enhance its lipophilicity. The lipid nanoemulsions loaded with doxorubicin-oleic acid complex (DOX-OA-LNs) were prepared using a simple high-pressure homogenization method and fully characterized from physicochemical and in vitro release standpoint. Afterwards, the DOX-OA-LNs and free DOX were compared with respect to their in vitro cellular uptake and cytotoxicity, and their in vivo pharmacokinetics and biodistribution behavior in mice were also investigated. The obtained DOX-OA-LNs could achieve high encapsulation efficiency of 93.7 +/- 1.2% under optimal conditions. The in vitro release behavior displayed biphasic drug release pattern with rapid release at the initial stage and prolonged release afterwards. The DOX-OA-LNs exhibited higher growth inhibitory effect than free DOX by MTT assay. Flow cytometry and confocal microscopy studies showed that the cellular uptake of free DOX and DOX-OA-LNs were comparable. Pharmacokinetics and in vivo distribution studies in mice showed that DOX-OA-LNs demonstrated significantly higher DOX level in blood and longer circulation time than free DOX. Moreover, DOX-OA-LNs significantly decreased DOX concentration in heart, lung and kidney. These results suggested that DOX-OA-LNs could be a promising formulation for the delivery of DOX in tumor chemotherapy.
本研究旨在开发一种新型的阿霉素（DOX）脂质纳米乳剂配方，该配方可用于扩大生产规模，具有良好的肠胃外可接受性，并能进一步提高药物的治疗指数。使用油酸与DOX形成离子复合物以增强其亲脂性。采用简单的高压均质法制备了负载阿霉素-油酸复合物的脂质纳米乳剂（DOX-OA-LNs），并从物理化学和体外释放的角度进行了全面表征。之后，比较了DOX-OA-LNs和游离DOX的体外细胞摄取和细胞毒性，并研究了它们在小鼠体内的药代动力学和生物分布行为。在最佳条件下，所获得的DOX-OA-LNs可实现93.7±1.2%的高包封率。体外释放行为呈现双相药物释放模式，初期快速释放，随后延长释放。通过MTT法测定，DOX-OA-LNs比游离DOX表现出更高的生长抑制作用。流式细胞术和共聚焦显微镜研究表明，游离DOX和DOX-OA-LNs的细胞摄取相当。小鼠体内的药代动力学和分布研究表明，DOX-OA-LNs在血液中的DOX水平显著高于游离DOX，且循环时间更长。此外，DOX-OA-LNs显著降低了心脏、肺和肾脏中的DOX浓度。这些结果表明，DOX-OA-LNs可能是肿瘤化疗中递送DOX的一种有前景的配方。
