Anti-tumor activity of silymarin nanoliposomes in combination with iron: In vitro and in vivo study

Combination therapy represents a promising strategy in cancer management by reducing chemotherapy resistance and associated side effects. Silymarin (SLM) has been extensively investigated due to its potent antioxidant properties and demonstrated efficacy against cancer cells. Under certain conditions however, polyphenolic compounds may also exhibit prooxidant activity by elevating intracellular reactive oxygen species (ROS), which can harm the target cells. In this study, we hypothesized that the simultaneous administration of iron (Fe) could alter the antioxidant characteristic of SLM nanoliposomes (SLM Lip) to a prooxidant state. Hence, we first developed a SLM Lip preparation using lipid film method, and then investigated the anti-oxidant properties as well as the cytotoxicity of the liposomal preparation. We also explored the efficacy of concomitant administration of iron sucrose and SML Lip on the tumor growth and survival of mice bearing tumors. We observed that exposing cells to iron, and consecutive treatment with SLM Lip (Fe + SLM Lip) could induce greater toxicity to 4 T1 breast cancer cells compared to SLM Lip. Further, Fe + SLM Lip combination demonstrated a time-dependent effect on reducing the catalase activity compared to SLM Lip, while iron treatment did not alter cell toxicity and catalase activity. In a mouse breast cancer model, the therapeutic efficacy of Fe + SLM Lip was superior compared to SLM Lip, and the treated animals survived longer. The histopathological findings did not reveal a significant damage to the major organs, whereas the most significant tumor necrosis was evident with Fe + SLM Lip treatment. The outcomes of the present investigation unequivocally underscored the prospective use of Fe + SLM combination in the context of cancer therapy, which warrants further scrutiny.