Repurposed Axitinib delivered via lipid-extruded PEGylated liposomes: 2D/3D breast cancer cell evaluation and in-vivo pharmacokinetics

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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 IC50 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. In-vivo 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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