pH-Sensitive Docetaxel-Loaded d-伪-Tocopheryl Polyethylene Glycol Succinate鈥揚oly(尾-amino ester) Copolymer Nanoparticles for Overcoming Multidrug Resistance

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• 作者：Shuang Zhao ; Songwei Tan ; Yuanyuan Guo ; Jing Huang ; Min Chu ; Hudan Liu ; Zhiping Zhang
• 刊名：Biomacromolecules
• 出版年：2013
• 出版时间：August 12, 2013
• 年：2013
• 卷：14
• 期：8
• 页码：2636-2646
• 全文大小：743K
• 年卷期：v.14,no.8(August 12, 2013)
• ISSN：1526-4602

文摘

Multidrug resistance (MDR) is one of the major obstacles to successful chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is an important factor responsible for MDR. Herein, a novel copolymer, d-伪-tocopheryl polyethylene glycol 1000-block-poly(尾-amino ester) (TPGS-b-PBAE, TP), was synthesized for overcoming multidrug resistance by the synergistic effect of the pH-sensitive behavior of PBAE and P-gp inhibiting activity of TPGS. Docetaxel (DTX) was chosen as the model drug. The resulting DTX-loaded nanoparticles were stable at pH 7.4, while they dissociated in a weakly acidic environment (pH 5.5) and released the incorporated DTX quickly. The DTX-loaded TP nanoparticles increased the cell cytotoxicity against both drug-sensitive human ovarian A2780 and drug-resistant A2780/T cells. The IC₅₀ of DTX-loaded TP against A2780/T cells was 100-fold lower than that of commercial DTX. This was associated with enhanced DTX-induced apoptosis and cell arrest in the G2/M phase. Furthermore, P-gp inhibition assays, including enhancement of the fluorescence intensity of rhodamine 123 and reduction of the intracellular ATP levels, confirmed the P-gp inhibition nature of the TP copolymer. The use of the TP copolymer is a new approach to improve the therapeutic effect of anticancer drugs in MDR tumors.