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One-Step Synthesis of Targeted Acid-Labile Polysaccharide Prodrug for Efficiently Intracellular Drug Delivery
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-01-05 00:00:00 , DOI: 10.1021/acsbiomaterials.7b00856 Di Li 1, 2 , Xiangru Feng 2 , Li Chen 1 , Jianxun Ding 2 , Xuesi Chen 2
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-01-05 00:00:00 , DOI: 10.1021/acsbiomaterials.7b00856 Di Li 1, 2 , Xiangru Feng 2 , Li Chen 1 , Jianxun Ding 2 , Xuesi Chen 2
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The therapeutic potential of the active targeting and acid-sensitive polysaccharide prodrug was investigated. The active targeting of polysaccharide prodrug was based on the specific interaction between cyclo(Arg-Gly-Asp-d-Phe-Lys) peptide (c(RGDfK)) and its receptor αvβ3 integrin overexpressed on the membrane of tumor cells. The cRGD-modified doxorubicin-conjugated hydroxyethyl starch (HES=DOX/cRGD) was synthesized via a one-step Schiff base reaction between oxidized HES, and DOX and c(RGDfK) that achieved an acid-accelerated drug release profile. The targeted polysaccharide prodrug self-assembled into micelle in aqueous environment with a moderate hydrodynamic diameter of 77.1 nm. All data in vitro indicated enhanced cell uptake and elevated cytotoxicity of HES=DOX/cRGD toward human malignant melanoma A375 cells compared with HES=DOX and DOX. Moreover, the smart prodrug also exhibited upregulated accumulation in the tumor, improved antitumor efficacy, and reduced systemic cytotoxicity in vivo. The cRGD-decorated acid-sensitive polysaccharide prodrug was advantageous in both antitumor efficacy and systemic security, showing great prospect in clinical application.
中文翻译：
靶向合成酸的多糖前药的一步合成，可有效地进行细胞内药物递送。
研究了靶向活性和酸敏感性多糖前药的治疗潜力。多糖前药的活性目标的根据，环（精氨酸-甘氨酸- Asp-的之间的特异性相互作用d -Phe-LYS）肽（C（RGDfK））和它的受体α v β 3整联蛋白在肿瘤细胞膜上过表达。通过氧化的HES与DOX和c（RGDfK）之间的一步式Schiff碱反应合成了cRGD修饰的阿霉素共轭羟乙基淀粉（HES = DOX / cRGD），实现了酸加速药物释放曲线。靶向的多糖前药在水性环境中自组装成胶束，中等流体动力学直径为77.1 nm。体外所有数据表明，与HES = DOX和DOX相比，HES = DOX / cRGD对人恶性黑色素瘤A375细胞的细胞摄取增强，细胞毒性增强。此外，聪明的前药还表现出在肿瘤中的上调蓄积，提高了抗肿瘤功效，并降低了体内的全身细胞毒性。
更新日期：2018-01-05
中文翻译：
靶向合成酸的多糖前药的一步合成，可有效地进行细胞内药物递送。
研究了靶向活性和酸敏感性多糖前药的治疗潜力。多糖前药的活性目标的根据，环（精氨酸-甘氨酸- Asp-的之间的特异性相互作用d -Phe-LYS）肽（C（RGDfK））和它的受体α v β 3整联蛋白在肿瘤细胞膜上过表达。通过氧化的HES与DOX和c（RGDfK）之间的一步式Schiff碱反应合成了cRGD修饰的阿霉素共轭羟乙基淀粉（HES = DOX / cRGD），实现了酸加速药物释放曲线。靶向的多糖前药在水性环境中自组装成胶束，中等流体动力学直径为77.1 nm。体外所有数据表明，与HES = DOX和DOX相比，HES = DOX / cRGD对人恶性黑色素瘤A375细胞的细胞摄取增强，细胞毒性增强。此外，聪明的前药还表现出在肿瘤中的上调蓄积，提高了抗肿瘤功效，并降低了体内的全身细胞毒性。
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