Development of Novel Photoactivable Platinum (IV) Prodrugs Based on Click Chemistry

Abstract

Pt(II)-based anticancer agents (e.g. cisplatin, carboplatin, and oxaliplatin) are widely used to treat various forms of cancer. Nevertheless, the efficacy of these drugs are limited in clinical settings due to the drug resistance of cancer and their side effects. To overcome these limitations, researchers have developed octahedral Pt(IV) compounds as prodrugs.Amphiphilic prodrug used to co-deliver cisplatin and doxorubicin have been designed to develop and increase the efficiency of the platinum-based anticancer treatments. This, in turn, improves cellular uptake and inhibits DNA mechanisms; thus, the combination of these agents have demonstrated the high efficacy of anticancer prodrugs. Although, the behavior of conventional Pt (IV) prodrugs are challenging to control, which can limit their efficiency. Therefore, there is a high demand within cancer therapy for the activation of these cytotoxic agents in a controlled manner. We present a new design of near infrared (NIR)-activatable Pt(IV)-based anticancer agents. The photoactivatable Pt(IV) prodrug approach is a promising strategy for engineering novel metallodrugs with high efficacy and low systematic toxicity. The major drawback of reported photoactivatable Pt(IV) prodrugs is that they require high-energy UV-vis light for activation, and such irradiation has very limited tissue penetration capability and is not suitable for phototherapy. NIR activation is highly sought-after for phototherapy, due to deep tissue penetration. In this study, we utilized a copper-free click reaction approach to develop a novel NIR-activatable Pt (IV) prodrug. This Pt (IV) prodrug can be photoactivated by NIR irradiation triggering photoreduction to release the cytotoxic Pt (II); moreover, The Pt (IV) complexes exhibited stability under physiological conditions in the dark and can release the payloads upon irradiation. In addition, upon NIR-irradiation, the complex readily induced DNA damage and triggered cell death in cancer cells, as evidence by flow cytometric analysis and live-cell imaging. Overall, we demonstrated the novel design of controllably activated Pt (IV) prodrugs that shows a sustained drug release upon irradiation, exhibiting cytotoxicity in cancer cells.