Hybrid Platinum(IV)-Naproxen Nanostructured Drugs Reprogram Melanoma Cells and Overpower Cisplatin

The concept of hybrid drugs that integrate cytotoxic and anti-inflammatory activity, enabling the simultaneous delivery of a chemotherapeutic agent and a non-steroidal anti-inflammatory drug (NSAID) into the tumor microenvironment (TME), was created with the aim of blocking the mitogenic signals that lead to tumor renewal. Here, we provide for the first time a detailed insight into the mechanism of action of a platinum(IV) complex based on the cisplatin (CP) scaffold bearing two deprotonated NSAID ligands (naproxenate (Npx)) in axial position ([CP(Npx)₂]), free and immobilized in nanostructured silica SBA-15 (SBA-15|[CP(Npx)₂]), in a melanoma model. The conjugate in free or loaded form diminished the viability of cancer cells more potently than CP, with an exceptional preference for the malignant phenotype. Type I and II programed cell death, senescence, and terminal differentiation of the surviving cell fraction were the basic mechanisms of action by which the new hybrid molecule achieved its effect in vitro. In the mouse melanoma model, the application of the therapeutic agents led to a reduction in tumor volume, extinguishing of intratumoral inflammation, and an overall better toxicity profile compared to CP. Overall, this approach improved the efficacy of chemotherapy by removing obstacles that cause chronic inflammation in the TME.