title: Improved oral absorption of doxorubicin by amphiphilic copolymer of lysine-linked ditocopherol polyethylene glycol 2000 succinate: in vitro characterization and in vivo evaluation.
abstract: 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 (PLV2K). The cytotoxicty in vitro and anticancer efficacy in vivo after intravenous administration of DOX-loaded PLV2K micelles (PLV2K-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. PLV2K-DOX are spherical micelles with a narrow size distribution of 20.53 ± 2.44 nm. With an in situ intestinal perfusion model, the intestinal absorption potential of PLV2K-DOX was evaluated in comparison with DOX-Sol. PLV2K-DOX was specifically absorbed in duodenum and ileum sites of rats after oral administration. The intestinal absorption rate (Ka) of PLV2K-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, PLV2K-DOX micelles significantly improve the internalized amount of DOX by P-gp inhibition of free PLV2K copolymer and endocytosis of DOX-loaded nanoparticles. Moreover, PLV2K-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 PLV2K-DOX. In vivo pharmacokinetics in rats following oral administration demonstrated that PLV2K-DOX demonstrates higher AUC (5.6-fold) and longer t1/2 (1.2-fold) than DOX-Sol. The findings suggest the new PLV2K micelles might provide an effective nanoplatform for oral delivery of anticancer drugs with poor membrane permeability and low oral bioavailability.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, and ‡Municipal Key Laboratory of Biopharmaceutics, Shenyang Pharmaceutical University , Wenhua Road, Shenyang 110016, China.
authors.forename: Jinling
authors.initials: J
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Du
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Han
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Ai
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Yang
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D018938:Caco-2 Cells; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine / Q000737:chemistry*; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D024505:Tocopherols / Q000737:chemistry*
chemical_list: D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin; C000595210:polyethylene glycol 2000; D008239:Lysine; D024505:Tocopherols
keywords: P-glycoprotein; amphiphilic copolymer; doxorubicin; micelles; oral absorption; vitamin E succinate