Overcoming Cisplatin Resistance in 3D Oral Squamous Cell Carcinoma Models via Nanoparticle-Mediated Pt(IV) Drug Delivery

Advanced oral squamous cell carcinoma (OSCC) patients with cisplatin-refractory tumors face a poor prognosis and limited therapeutic options. Cisplatin-based systemic chemotherapy has long been the gold standard despite producing unmanageable adverse side effects and toxicity. Compared to Pt(II)-based analogs, octahedral Pt(IV)-based compounds have demonstrated remarkable potential as antitumor prodrugs. Pt(VI) derivates are chemically inert remaining intact until internalized within cells, demonstrating higher tolerability and selectivity towards cancer cells. In this study we compare antitumoral response implementing primary patient-derived 2D and 3D OSCC in vitro models treated with both cisplatin and a novel Pt(IV) compound. We also test the delivery and efficacy of these anticancer drugs via novel encapsulation of this Pt(IV) prodrug in the framework of mesoporous silica nanoparticles (Pt(IV)-cov@MSN). Our results show a significant improvement of delivery and cytotoxicity of Pt(IV)-cov@MSN in both cisplatin-responsive and cisplatin-resistant primary patient-derived in vitro models. We also show how Pt(IV)-cov@MSN elicits p53-dependent apoptotic cell death superior to that obtained with cisplatin treatment in OSCCs. These findings highlight 3D-primary models as key tools for drug and nanocarrier testing, as well as potential targeted and selective delivery strategies for novel chemotherapeutic agents.