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Dimeric camptothecin-loaded RGD-modified targeted cationic polypeptide-based micelles with high drug loading capacity and redox-responsive drug release capability
Biomaterials Science ( IF 5.8 ) Pub Date : 2017-10-23 00:00:00 , DOI: 10.1039/c7bm00791d Zhaopei Guo 1, 2, 3, 4, 5 , Xingzhi Zhou 1, 2, 3, 4, 5 , Mengze Xu 1, 2, 3, 4, 5 , Huayu Tian 5, 6, 7, 8, 9 , Xuesi Chen 5, 6, 7, 8, 9 , Meiwan Chen 1, 2, 3, 4, 5
Biomaterials Science ( IF 5.8 ) Pub Date : 2017-10-23 00:00:00 , DOI: 10.1039/c7bm00791d Zhaopei Guo 1, 2, 3, 4, 5 , Xingzhi Zhou 1, 2, 3, 4, 5 , Mengze Xu 1, 2, 3, 4, 5 , Huayu Tian 5, 6, 7, 8, 9 , Xuesi Chen 5, 6, 7, 8, 9 , Meiwan Chen 1, 2, 3, 4, 5
Affiliation
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Camptothecin (CPT) is a broad spectrum anticancer drug, but its application is limited due to the poor water solubility, lactone ring instability, and low drug loading potential. In this study, biocompatible cationic polypeptide-based micelles were developed to deliver dimeric CPT (DCPT) with the aim of overcoming the above-mentioned obstacles and achieving favorable therapeutic effects. Cationic polypeptide poly-lysine-block-poly-leucine (PLys-b-PLeu) was fabricated via the ring-opening polymerization of N-ε-carbobenzoxy-L-lysine (ε-Lys(Z)) and L-leucine (Leu) and further grafted with polyethylene glycol (PEG) and an arginine-glycine-aspartic acid (RGD) peptide. DCPT was synthesized by reacting CPT and 2-hydroxyethyl disulfide, and micelles were prepared using a dialysis method. The obtained DCPT-loaded RGD-PEG-g-poly-L-lysine-b-poly-L-leucine (DRPPP) micelles showed a high encapsulation efficiency of 89.7% and a high drug loading capacity of 46.1%. In addition, the DRPPP micelles remained stable under physiological conditions (PBS at a pH of 7.4) but showed rapid release when triggered by a reductive environment (PBS at a pH of 7.4 with 10 mM dithiothreitol). Compared to micelles without RGD decoration, the DRPPP micelles exhibited an increased cellular uptake through RGD targeting and were internalized into cells via caveolae-mediated endocytosis and macropinocytosis. Furthermore, the DRPPP micelles exerted an enhanced cytotoxicity against MDA-MB-231 cells compared to MCF-7 cells, which expressed less αvβ3 receptors. Besides, the DRPPP micelles induced cell apoptosis and caused a decrease of mitochondrial membrane potential. These results indicate that dimeric camptothecin-loaded cationic polypeptide-based micelle is a promising strategy for cancer therapy.
中文翻译：
装载有喜树碱的二聚体，经RGD修饰的靶向阳离子多肽基胶束，具有高载药量和氧化还原反应性药物释放能力
喜树碱（CPT）是一种广谱抗癌药物，但由于水溶性差，内酯环不稳定性和低载药量，其应用受到了限制。在这项研究中，基于生物相容性阳离子多肽的胶束被开发用于递送二聚体CPT（DCPT），以克服上述障碍并获得良好的治疗效果。阳离子多肽聚赖氨酸嵌段-聚亮氨酸（PLys- b -PLeu）制作通过的开环聚合Ñ -ε-carbobenzoxy-大号-赖氨酸（ε-赖氨酸（Z））和大号-亮氨酸（Leu），并进一步接枝聚乙二醇（PEG）和精氨酸-甘氨酸-天冬氨酸（RGD）肽。通过使CPT和2-羟乙基二硫化物反应来合成DCPT，并使用透析方法制备胶束。获得的DCPT负载的RGD-PEG- g -poly- L-赖氨酸-b -poly- L-亮氨酸（DRPPP）胶束显示出89.7％的高包封率和46.1％的高载药量。此外，DRPPP胶束在生理条件下（pH值为7.4的PBS）保持稳定，但在还原性环境（pH 7.4的PBS中含10 mM二硫苏糖醇）触发时显示出快速释放。与没有RGD装饰的胶束相比，DRPPP胶束通过RGD靶向显示出更高的细胞摄取，并通过小窝介导的内吞作用和巨胞饮作用被内化到细胞中。此外，DRPPP胶束施加针对MDA-MB-231细胞相比MCF-7细胞，其表达更少的α增强的细胞毒性v β 3受体。此外，DRPPP胶束诱导细胞凋亡并导致线粒体膜电位降低。这些结果表明二聚喜树碱加载的阳离子多肽基胶束是一种有前途的癌症治疗策略。
更新日期：2017-11-22
中文翻译：
装载有喜树碱的二聚体，经RGD修饰的靶向阳离子多肽基胶束，具有高载药量和氧化还原反应性药物释放能力
喜树碱（CPT）是一种广谱抗癌药物，但由于水溶性差，内酯环不稳定性和低载药量，其应用受到了限制。在这项研究中，基于生物相容性阳离子多肽的胶束被开发用于递送二聚体CPT（DCPT），以克服上述障碍并获得良好的治疗效果。阳离子多肽聚赖氨酸嵌段-聚亮氨酸（PLys- b -PLeu）制作通过的开环聚合Ñ -ε-carbobenzoxy-大号-赖氨酸（ε-赖氨酸（Z））和大号-亮氨酸（Leu），并进一步接枝聚乙二醇（PEG）和精氨酸-甘氨酸-天冬氨酸（RGD）肽。通过使CPT和2-羟乙基二硫化物反应来合成DCPT，并使用透析方法制备胶束。获得的DCPT负载的RGD-PEG- g -poly- L-赖氨酸-b -poly- L-亮氨酸（DRPPP）胶束显示出89.7％的高包封率和46.1％的高载药量。此外，DRPPP胶束在生理条件下（pH值为7.4的PBS）保持稳定，但在还原性环境（pH 7.4的PBS中含10 mM二硫苏糖醇）触发时显示出快速释放。与没有RGD装饰的胶束相比，DRPPP胶束通过RGD靶向显示出更高的细胞摄取，并通过小窝介导的内吞作用和巨胞饮作用被内化到细胞中。此外，DRPPP胶束施加针对MDA-MB-231细胞相比MCF-7细胞，其表达更少的α增强的细胞毒性v β 3受体。此外，DRPPP胶束诱导细胞凋亡并导致线粒体膜电位降低。这些结果表明二聚喜树碱加载的阳离子多肽基胶束是一种有前途的癌症治疗策略。
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