通过脂质挤出聚乙二醇化脂质体递送老药新用的阿昔替尼：二维/三维乳腺癌细胞评价及体内药代动力学研究

摘要(中文译文)

聚乙二醇化脂质体纳米载体已成为一种有前景的药物递送平台，可改善难溶性抗癌药物的药代动力学性能和全身循环。本研究制备了载阿昔替尼的聚乙二醇化脂质体（F11-PEGliposome），并评估其治疗乳腺癌的潜力。采用Box-Behnken设计优化制备脂质体，随后通过脂质挤出法进行挤出，获得囊泡粒径为158.6±2.4 nm、PDI为0.12±0.01、zeta电位为-1.2±0.5、包封率为79.9±1.8%。在二维细胞培养研究中，F11-PEGliposome显示出增强的抗癌活性，IC值分别比游离阿昔替尼低1.7倍和2.13倍。细胞摄取、ROS生成、JC-1线粒体膜电位和AO/EB染色实验显示其内化增强并诱导凋亡。在三维球体模型中，F11-PEGliposome表现出对肿瘤的深度穿透、显著的生长抑制、增加的ROS产生以及明显的凋亡性细胞死亡。药代动力学和生物分布研究显示其循环时间延长、生物利用度提高、半衰期延长。组织病理学评价及血清AST、ALT、肌酐和BUN水平降低表明肝毒性和肾毒性减轻。Western blot分析显示cleaved caspase-3和cleaved PARP1呈剂量依赖性增加，支持凋亡的结论。

Abstract

PEGylated liposomal nanocarriers have emerged as a promising drug delivery platform for improving the pharmacokinetic performance and systemic circulation of poorly water-soluble anticancer drugs. In this study, Axitinib-loaded PEGylated liposomes (F11-PEGliposome) were prepared and evaluated for the potential treatment of breast cancer. Liposomes were prepared by optimization with a Box-Behnken design and subsequently extruded using lipid extrusion to obtain a vesicle size of 158.6 ± 2.4 nm, PDI of 0.12 ± 0.01, zeta potential of -1.2 ± 0.5, and entrapment efficiency of 79.9 ± 1.8%. In 2D cell culture studies, F11-PEGliposome showed enhanced anticancer activity with IC values of 1.7- and 2.13-fold lower than free Axitinib. Cellular uptake, ROS generation, JC-1 mitochondrial membrane potential, and AO/EB staining assays exhibited enhanced internalization and apoptosis induction. In 3D spheroid models, F11-PEGliposome exhibited deep penetration in the tumor, significant growth inhibition, increased ROS production, and pronounced apoptotic cell death. pharmacokinetic and biodistribution studies showed extended circulation, enhanced bioavailability, and prolonged half-life. Reduced hepatic and renal toxicity was evident as shown by histopathological evaluation and decreased serum AST, ALT, creatinine, and BUN levels. Western blot analysis revealed dose-dependent increases of cleaved caspase-3 and cleaved PARP1, supporting the conclusion of apoptosis.

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