Is platinum the new gold? Re-evaluating platinum's enduring role and future potential in the era of novel ovarian cancer therapies

Platinum (Pt)-based chemotherapy has served for decades as the foundation of ovarian cancer therapy. Yet, its gains are always undermined by severe toxic side effects and drug resistance. Although a new generation of therapy - including anti-angiogenic drugs, PARP inhibitors, ADCs, and immune checkpoint inhibitors- has emerged, issues of costs and patient stratification have limited their use as first line treatment. Hence, platinum-based drugs won't be easily surpassed by newer modalities in the immediate future, providing a window of opportunities to make them work more efficiently. This review re-evaluates the future of platinum therapies by exploring key strategies to counteract resistance mediated by intracellular mechanisms and the complex tumour microenvironment. One approach includes converting non-specific and reactive FDA-approved Pt(II) agents into the next-generation Pt(IV) prodrugs, which are stable, single/dual/multi-action or stimuli-triggered agents that become activated only inside target cells, releasing their original Pt(II) counterparts and two additional axial ligands. A second approach includes the development of advanced nanoscale delivery systems to enhance the amount of chemotherapeutic reaching the tumour site while minimizing off target effects. These nanotechnology platforms span from liposomes to virus-like particles and can be engineered to bypass biological obstacles while avoiding premature elimination from the body, even though they are associated with immunogenic reactions. By uniting advances in platinum chemistry with the precision offered by modern nanotechnology, a new therapeutic paradigm emerges-one that can enhance efficacy, reduce systemic toxicity, and offer a more accessible alternative to costly biologics, thereby securing a renewed and enduring role for platinum in ovarian cancer treatment.