Improved Oral Absorption of Doxorubicin by Amphiphilic Copolymer of Lysine-Linked Ditocopherol Polyethylene Glycol 2000 Succinate: In Vitro Characterization and in Vivo Evaluation

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• 作者：Jinling Wang ; Lin Li ; Yuqian Du ; Jin Sun ; Xiaopeng Han ; Cong Luo ; Xiaoyu Ai ; Qi Zhang ; Yongjun Wang ; Qiang Fu ; Zhifu Yang ; Zhonggui He
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：February 2, 2015
• 年：2015
• 卷：12
• 期：2
• 页码：463-473
• 全文大小：582K
• ISSN：1543-8392

文摘

In the previous study, we have synthesized an amphiphilic copolymer of nanostructure-forming material and P-glycoprotein (P-gp) inhibitor, lysine-linked ditocopherol polyethylene glycol 2000 succinate (PLV_2K). The cytotoxicty in vitro and anticancer efficacy in vivo after intravenous administration of DOX-loaded PLV_2K micelles (PLV_2K-DOX) was found more effective than DOX solution (DOX-Sol). However, its performance and mechanism on oral absorption of doxorubicin are not well understood yet. PLV_2K-DOX are spherical micelles with a narrow size distribution of 20.53 卤 2.44 nm. With an in situ intestinal perfusion model, the intestinal absorption potential of PLV_2K-DOX was evaluated in comparison with DOX-Sol. PLV_2K-DOX was specifically absorbed in duodenum and ileum sites of rats after oral administration. The intestinal absorption rate (K_a) of PLV_2K-DOX is 3.19-, 1.61-, and 1.80-fold higher than that of DOX-Sol in duodenum, jejunum, and ileum, respectively. In Caco-2 uptake studies, PLV_2K-DOX micelles significantly improve the internalized amount of DOX by P-gp inhibition of free PLV_2K copolymer and endocytosis of DOX-loaded nanoparticles. Moreover, PLV_2K-DOX micelles improve the membrane permeability of DOX by multiple transcytosis mechanisms, including caveolin-, clathrin-dependent, and caveolin-/clathrin-independent transcytosis in Caco-2 transport studies. However, the transepithelia electrical resistance (TEER) of Caco-2 cellular monolayer is not changed, suggesting no involvement of paracellular transport of PLV_2K-DOX. In vivo pharmacokinetics in rats following oral administration demonstrated that PLV_2K-DOX demonstrates higher AUC (5.6-fold) and longer t_1/2 (1.2-fold) than DOX-Sol. The findings suggest the new PLV_2K micelles might provide an effective nanoplatform for oral delivery of anticancer drugs with poor membrane permeability and low oral bioavailability.