Light-Responsive Pt(IV) Prodrugs with Controlled Photoactivation and Low Dark Toxicity

Abstract

Light-induced release of cisplatin from Pt(IV) prodrugs represents a promising approach for precise control over the antiproliferative activity of Pt-based chemotherapeutic drugs. This method has the potential to overcome crucial drawbacks of conventional cisplatin therapy, such as high general toxicity toward healthy organs and tissues. Herein, we report two Pt(IV) prodrugs with BODIPY-based photoactive ligands <b>Pt-1</b> and <b>Pt-2</b>, which were designed using carbamate and triazole linkers, respectively. Both prodrugs demonstrated the ability to release cisplatin under blue light irradiation without the requirement of an external reducing agent. Dicarboxylated <b>Pt-2</b> prodrug turned out to be more stable in the dark and more sensitive to light than its monocarbamate <b>Pt-1</b> counterpart; these observations were explained using DFT calculations. The investigation of the photoreduction mechanism of <b>Pt-1</b> and <b>Pt-2</b> prodrugs using DFT modeling and Δ<i>G</i>⁰ PET estimation suggests that the photoinduced electron transfer from the singlet excited state of the BODIPY axial ligand to the Pt(IV) center is the key step in the light-induced release of cisplatin from the complexes. Cytotoxicity studies demonstrated that both prodrugs were nontoxic in the dark and toxic to MCF-7 cells under low-dose irradiation with blue light, and the observed effect was solely due to the cisplatin release from the Pt(IV) prodrugs. Our research presents an elegant synthetic approach to light-activated Pt(IV) prodrugs and presents findings that may contribute to the future rational design of photoactivatable Pt(IV) prodrugs.