The main reasons for the limited clinical efficacy of the platinum(II)-based agent cisplatin include drug resistance and significant side effects. Due to their better stability, as well as the possibility to introduce biologically active ligands in their axial positions constructing multifunctional prodrugs, creating platinum(IV) complexes is a tempting strategy for addressing these limitations. Another strategy for developing chemotherapeutics with lower toxicity relies on the ability of nanoparticles to accumulate in greater quantities in tumor tissues through passive targeting. To combine the two approaches, three platinum(IV) conjugates based on a cisplatin scaffold containing in the axial positions derivatives of caffeic and ferulic acid were prepared and loaded into SBA-15 to produce the corresponding mesoporous silica nanoparticles (MSNs). The free platinum(IV) conjugates demonstrated higher or comparable activity with respect to cisplatin against different human breast cancer cell lines, while upon immobilization, superior antiproliferative activity with markedly increased cytotoxicity (more than 1000-fold lower IC₅₀ values) compared to cisplatin was observed. Mechanistic investigations with the most potent conjugate, cisplatin-diacetyl caffeate (1), and the corresponding MSNs (SBA-15|1) in a 4T1 mouse breast cancer cell line showed that these compounds induce apoptotic cell death causing strong caspase activation. In vivo, in BALB/c mice, 1 and SBA-15|1 inhibited the tumor growth while decreasing the necrotic area and lowering the mitotic rate.

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.