Amphiphilic carboxymethyl chitosan-quercetin conjugate with P-gp inhibitory properties for oral delivery of paclitaxel

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• 作者：Xiaoying Wang^a ; ^b ; Yihang Chen^a ; Fatima Zohra Dahmani^a ; Lifang Yin^a ; Jianping Zhou^a ; ^{zhoujpcpu@163.com" class="auth_mail} ; Jing Yao^a ; ^{yaoj3@163.com" class="auth_mail}
• 关键词：Polymeric micelles ; Oral delivery ; Carboxymethyl chitosan ; Quercetin ; Paclitaxel ; Enhanced absorption
• 刊名：Biomaterials
• 出版年：August 2014
• 年：2014
• 卷：35
• 期：26
• 页码：7654-7665
• 全文大小：2646 K

文摘

An amphiphilic carboxymethyl chitosan-quercetin (CQ) conjugate was designed and synthesized for oral delivery of paclitaxel (PTX) to improve its oral bioavailability by increasing its water solubility and bypassing the P-gp drug efflux pumps. CQ conjugate had low critical micelle concentration (55.14 渭g/mL), and could self assemble in aqueous condition to form polymeric micelles (PMs). PTX-loaded CQ PMs displayed a particle size of 185.8 ± 4.6 nm and polydispersity index (PDI) of 0.134 ± 0.056. The drug-loading content (DL) and entrapment efficiency (EE) were 33.62 ± 1.34% and 85.63 ± 1.26%, respectively. Moreover, PTX-loaded CQ PMs displayed similar sustained-release profile in simulated gastrointestinal fluids (pH 1.2/pH 6.8) and PBS (pH 7.4). In situ intestinal absorption experiment showed that PTX-loaded CQ PMs significantly improved the effective permeability of PTX as compared to verapamil (P < 0.01). Likewise, PTX-loaded CQ PMs significantly enhanced the oral bioavailability of PTX, resulting in strong antitumor efficacy against tumor xenograft models with better safety profile as compared to Taxol^® and Taxol^® with verapamil. Overall, the results implicate that CQ PMs are promising vehicles for the oral delivery of water-insoluble anticancer drugs.