Cisproplatin: A Redox-Activatable Cisplatin-Probenecid Pt(IV) Conjugate with Broad NCI-60 Potency that Decouples Antitumor Efficacy from Dose-Limiting Toxicity and Suppresses CIPN.

Cisplatin's clinical utility is limited by severe nephrotoxicity and neurotoxicity. We developed cisproplatin (CPP), a Pt(IV) conjugate combining cisplatin and probenecid in a single, redox-activatable scaffold. CPP exhibits excellent stability under physiological, acidic pH and in serum, yet releases active components under reducing conditions. CPP displays superior potency across the NCI-60 panel, exceeding that of cisplatin. Time-resolved speciation and other physicochemical studies validate a dual mechanism, in which its Pt(IV) state interacts with DNA noncovalently, then releases cisplatin-like Pt(II) species upon reduction, yielding cumulative cytotoxicity. In TNBC cells, CPP outperforms cisplatin and cisplatin/probenecid mixtures, reducing the overall growth and proliferation. In BALB/c mice, CPP exhibited negligible toxicity with low neurotoxicity in CIPN model. Pharmacokinetic analysis showed reduced renal platinum accumulation and prolonged circulation. Together, these data establish CPP as a redox-activatable dual-drug Pt(IV) platform that decouples robust anticancer potency from classical dose-limiting toxicity.