Is GSH Chelated Pt Molecule Inactive in Anti‐Cancer Treatment? A Case Study of Pt₆GS₄

Abstract Platinum (Pt) drugs are widely used in anti‐cancer treatment although many reports advocated that tumor cells could inactivate Pt drugs via glutathione‐Pt (GSH‐Pt) adducts formation. To date, GSH chelated Pt molecules have not been assessed in cancer treatment because GSH‐Pt adducts are not capable of killing cancer cells, which is widely accepted and well followed. In this report, endogenous biothiol is utilized to precisely synthesize a GSH chelated Pt molecule (Pt₆GS₄). This Pt₆GS₄ molecule can be well taken up by aggressive triple negative breast cancer (TNBC) cells. Subsequently, its metabolites could enter nuclei to interact with DNA, finally the DNA‐Pt complex triggers TNBC cell apoptosis via the p53 pathway. Impressively, high efficacy for anti‐cancer treatment is achieved by Pt₆GS₄ both in vitro and in vivo when compared with traditional first‐line carboplatin in the same dosage. Compared with carboplatin, Pt₆GS₄ keeps tumor bearing mice alive for a longer time and is non‐toxic for the liver and kidneys. This work opens a route to explore polynuclear Pt compound with accurate architecture for enhancing therapeutic effects and reducing systemic toxicity.