Innovative Approach to Pt(IV) Complexes: Addressing the Limitations of Traditional Chemotherapy Through Targeted...

Platinum-based chemotherapy remains a cornerstone of cancer treatment. However, classical Pt(II) drugs, including cisplatin, carboplatin, and oxaliplatin, show significant limitations. They induce systemic toxicity, show poor tumor-targeting capability, and give rise to drug resistance. These issues result in treatment failure in 20-90% of patients with certain solid tumors. Pt(IV) complexes are a next-generation prodrug platform to address these challenges. Their octahedral configuration and improved stability in biological fluids are largely superior to those of Pt(II) drugs. This reduces reactions with non-target tissues and mitigates systemic toxicity. Pt(IV) prodrugs remain largely inactive until they enter cells, where they are mainly reduced by elevated glutathione (GSH) levels prevalent in the tumor microenvironment. This mechanism releases the active Pt(II) form that eradicates cancer cells, enabling drug activation mainly within tumors. The structure of Pt(IV) complexes also permits flexible design, allowing attachment of targeting moieties, such as folate, biotin, or peptides, as well as antibodies or components, that direct the drug to mitochondria or the nucleus. This enables multiple strategies for combating cancer. Designs encompass GSH-responsive release and active targeting to specific cellular compartments, while also integrating with other treatment modalities, such as immunotherapy, phototherapy, and radiotherapy. In preclinical studies, these approaches have shown increased drug accumulation in tumors, improved uptake by resistant cells, reversal of platinum resistance, and reduced damage to kidneys and nerves. Although Pt(IV) complexes still encounter challenges in synthesis and scale-up, their flexible design provides a platform for platinum chemotherapy that is safer, more selective, and capable of targeting cancer through multiple avenues.