d-伪-Tocopherol Polyethylene Glycol Succinate-Based Redox-Sensitive Paclitaxel Prodrug for Overcoming Multidrug Resistance in Cancer Cells

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• 作者：Yuling Bao ; Yuanyuan Guo ; Xiangting Zhuang ; Dan Li ; Bolin Cheng ; Songwei Tan ; Zhiping Zhang
• 刊名：Molecular Pharmaceutics
• 出版年：2014
• 出版时间：September 2, 2014
• 年：2014
• 卷：11
• 期：9
• 页码：3196-3209
• 全文大小：834K
• ISSN：1543-8392

文摘

To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-伪-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of 鈭?40 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC₅₀ of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration鈥搕ime curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.

Keywords:

prodrug; redox-sensitive; TPGS; Paclitaxel; multidrug resistance