Camptothecin (CPT) is a broad spectrum anticancer drug, but its application is limited by 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 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, 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 10mM dithiothreitol). Compared to micelles without RGD decoration, DRPPP micelles exhibited increased cellular uptake through RGD targeting and were internalized into cells via caveolae-mediated endocytosis and macropinocytosis. Furthermore, DRPPP micelles exerted enhanced cytotoxicity against MDA-MB-231 cells compared to MCF-7 cells, which expressed less αvβ3 receptors. Besides, DRPPP induced cell apoptosis and caused decrease of mitochondrial membrane potential. These results indicate that dimeric camptothecin-loaded cationic polypeptide-based micelles are a promising strategy for cancer therapy.

中文翻译：

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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，但其应用受到水溶性差，内酯环不稳定性和低载药量的限制。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），以克服上述障碍并实现良好的治疗效果。阳离子多肽聚赖氨酸嵌段聚亮氨酸（PLys-b-PLeu）是通过N-ε-碳苯甲氧基-L-赖氨酸（ε-Lys（Z））和L-亮氨酸（Leu ），然后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。获得的负载DCPT的RGD-PEG-g-聚-L-赖氨酸-b-聚-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和10mM二硫苏糖醇）触发下显示出快速释放。与没有RGD装饰的胶束相比，DRPPP胶束通过RGD靶向显示出增加的细胞摄取，并通过小窝介导的内吞作用和巨胞吞作用被内化到细胞中。此外，与表达较少的αvβ3受体的MCF-7细胞相比，DRPPP胶束对MDA-MB-231细胞具有增强的细胞毒性。此外，DRPPP诱导细胞凋亡并导致线粒体膜电位降低。