A podophyllotoxin-loaded nanostructured lipid carrier markedly suppresses tumor growth in mice by inducing DNA damage and activating the mitochondrial apoptotic pathway

Abstract The application of many anticancer agents is limited by poor bioavailability, low tumor-targeting efficiency, and systemic toxicity. Although Podophyllotoxin (PPT) possesses potent anti-tumor activity, its clinical utility is constrained by these drawbacks. Nanostructured lipid carriers (NLCs) represent a promising strategy to overcome such limitations. Therefore, this study aimed to improve the anticancer efficacy of PPT through encapsulation in a newly synthesized NLC formulation. Ehrlich Solid Carcinoma (ESC)-bearing mice were treated with free PPT or PPT-loaded NLC (PPT-NLC) at doses of 1, 1.5, and 2 mg/kg for fourteen days. Tumor growth, histopathological alterations, oxidative stress biomarkers, DNA damage, and the expression of genes and proteins associated with apoptosis and redox regulation were evaluated using biochemical assays, qRT-PCR, comet assay, and immunohistochemistry. Treatment with PPT and PPT-NLC significantly suppressed tumor growth, resulting in a 51.9–82.8% reduction in tumor size, with PPT-NLC exhibiting greater efficacy than free PPT. Tumor suppression was accompanied by reduced Bcl-2 protein expression and increased Cas-3 protein expression, and markedly increased DNA damage. Treatments also restored SOD, GST, and catalase activities in muscle, liver, and kidney tissues to levels approaching those of normal mice. At the molecular level, PPT and PPT-NLC significantly upregulated Bax, Cas-3, cytochrome c, and P53, while downregulating Bcl-2, NF-κB, Nrf-2, and HO-1, and upregulating Keap-1 in ESC tissues in a dose-dependent manner. Overall, PPT-NLC demonstrated superior antitumor efficacy compared with free PPT through enhancing DNA damage, activating the mitochondria-mediated apoptosis, suppressing tumor-associated redox-survival signaling, and restoring redox homeostasis. These findings highlight the potential of NLC-mediated delivery as a promising strategy for enhancing the therapeutic performance of PPT in cancer treatment.