Multitargeting prodrugs that release oxaliplatin, doxorubicin and gemcitabine are potent inhibitors of tumor growth and effective inducers of immunogenic cell death.

A multitargeting prodrug (2) that releases in cancer cells gemcitabine, oxaliplatin, and doxorubicin in their active form is a potent cytotoxic agent with nM IC50s; is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32% compared to the non-treated, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co-administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed 80% tumor reduction in a re-challenge study compared to 73% induced by doxorubicin.