Strategy for Traceless Codrug Delivery with Platinum(IV) Prodrug Complexes Using Self-Immolative Linkers.

A common challenge in Pt(IV) prodrug design is the limited repertoire of linkers available to connect the Pt(IV) scaffold with the bioactive payload. The commonly employed linkers are either too stable, leading to a linker artifact on the payload upon release, or too unstable, leading to premature release. In this study, we report the synthesis of a new class of Pt(IV) prodrugs using masked self-immolative 4-aminobenzyl linkers for controlled and traceless codrug delivery. Upon reduction of self-immolative Pt(IV) prodrugs, the detached axial ligands undergo decarboxylation and 1,6-elimination for payload release. Introduction of self-immolative linkers conferred good aqueous stability to the Pt(IV) codrug complex. Investigation revealed that efficient 1,6-elimination could be attributed to stabilization of the p-aza-quinone-methide intermediate. In particular, the self-immolative Pt(IV) prodrugs with cinnamate and coumarin derivatives were more potent than the coadministration of cisplatin with an unconjugated cinnamate or coumarin payload in vitro.

A Cisplatin-Selective Fluorescent Probe for Real-Time Monitoring of Mitochondrial Platinum Accumulation in Living Cells.

Mitochondria have emerged as important targets for cisplatin in cancer therapy. Apart from cisplatin, anticancer Pt complexes based on similar scaffolds have also been developed to target mitochondria. Yet cellular processing of cisplatin or these mitochondria-targeting Pt analogues remained unexplored, largely due to a lack of tools capable of probing these Pt drugs within an intracellular environment. We developed the first mitochondria-targeted fluorescent probe for real-time monitoring of Pt accumulation in mitochondria. We applied the probe to investigate mitochondria as cellular targets for Pt drug complexes and uncovered two distinct pathways whereby these Pt complexes could be delivered to mitochondria after cell entry.

Design and investigation of photoactivatable platinum(iv) prodrug complexes of cisplatin.

Platinum(iv) carboxylate scaffolds have garnered considerable research interest because they can be engineered to function as prodrugs of clinical platinum(ii) anticancer drugs. These platinum(iv) prodrug complexes are stable and tunable, and activated by reduction to release their cytotoxic platinum(ii) cargo. Here we propose new platinum(iv) prodrug complexes designed to release cisplatin via photoreduction upon UV irradiation. The central strategy is to utilise aryl carboxylate ligands on the axial positions of that platinum(iv) scaffold that confer significant UV absorption and would stabilise carboxyl radical formation, thus favouring homolytic Pt-O bond cleavage. We isolated and identified aryl carboxyl radicals via spin-trapping and showed that the photoreduced platinum species mirror cisplatin reactivity toward DNA bases, thereby validating the efficacy of this approach.