Synthesis, Mechanistic Study, and Biological Evaluation of Visible Light-activatable Platinum(IV) Anticancer Prodrugs

Project: Research

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Description

Platinum-based anticancer drugs including cisplatin, carboplatin, and oxaliplatin are the first-line clinical treatment against a variety of solid tumors such as testicular, cervical, head and neck, ovarian, and colorectal. These drugs have minimum selectivity against tumors, however, which can lead to severe toxic side effects. Much effort has been devoted to the development of next-generation platinum drugs with an enhanced therapeutic window but with low toxicity. In this proposed project, we aim to obtain a novel series of platinum(IV) prodrugs that can be activated by visible light to overcome the issues of conventional platinum complexes. We make full use of the advantages of octahedral platinum(IV) moiety based on clinically used platinum drugs and offer the drugs photoactivation properties, especially by visible light. Our initial study showed that an oxaliplatin-based platinum(IV) prodrug is remarkably stable in the dark even in the presence of a reducing agent and that the prodrug is quickly photoactivated to release oxaliplatin. This platinum(IV) prodrug is significantly active against platinum-resistant human ovarian cancer cells with cytotoxicity enhanced up to three orders of magnitude over that of oxaliplatin. These data form the basis for the further development of photoactivatable Pt(IV) prodrugs. The complexes will be designed, synthesized, and well characterized. Their photophysical and photochemical properties will be scrutinized, and their photoactivation mechanism will be examined. In vitro biological activity including phototoxicity and the intracellular action mechanism will be tested, and in vivo toxicity and antitumor activity will be revealed. The proposed project will generate a couple of leading prodrugs with high stability and a localized cytotoxic effect, and these prodrugs are expected to have increased selectivity and lowered toxicity. The project will also foster the creation of a new toolkit in the area of medicinal inorganic chemistry for both chemical and biological applications.

Detail(s)

Project number9042697
Grant typeGRF
StatusFinished
Effective start/end date1/09/182/08/22