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

Area of Science:

• Medicinal Chemistry
• Photochemistry
• Materials Science

Background:

• Conventional cisplatin chemotherapy faces challenges due to systemic toxicity.
• Light-activated drug delivery offers a strategy to enhance therapeutic precision.
• Platinum(IV) prodrugs are being explored for controlled drug release.

Purpose of the Study:

• To design and synthesize novel photoactive platinum(IV) prodrugs (Pt-1 and Pt-2) utilizing BODIPY ligands.
• To investigate the light-induced release of cisplatin from these prodrugs.
• To elucidate the mechanism of photoreduction and assess their cytotoxicity.

Main Methods:

• Synthesis of two platinum(IV) prodrugs, Pt-1 and Pt-2, with distinct linker chemistries (carbamate and triazole).
• Evaluation of cisplatin release under blue light irradiation.
• Density Functional Theory (DFT) calculations to understand stability and photoreduction mechanisms.
• In vitro cytotoxicity assays on MCF-7 cells.

Main Results:

• Both Pt-1 and Pt-2 successfully released cisplatin upon blue light exposure without external reductants.
• The dicarboxylated Pt-2 showed enhanced stability in the dark and greater light sensitivity compared to Pt-1.
• DFT and PET estimations indicated photoinduced electron transfer from the BODIPY ligand to the Pt(IV) center as the key release mechanism.
• Prodrugs exhibited negligible dark toxicity but potent cytotoxicity against MCF-7 cells under blue light irradiation.

Conclusions:

• Developed novel light-activated Pt(IV) prodrugs with BODIPY photoactive ligands.
• Demonstrated efficient and controlled cisplatin release triggered by blue light.
• Provided mechanistic insights into the photo-redox processes governing drug release.
• Established the potential of these photoactivatable prodrugs for targeted cancer therapy with reduced side effects.