Single-Cell Chemistry of Photoactivatable Platinum Anticancer Complexes.

Elizabeth M Bolitho,Cinzia Imberti,Peter J Sadler,Paul D Quinn,Carlos Sanchez-Cano,Maria Harkiolaki,Huayun Shi

doi:10.1021/jacs.1c08630

Abstract

The Pt(IV) prodrug trans, trans, trans-[Pt(pyridine)2(N3)2(OH)2] (Pt1) and its coumarin derivative trans, trans, trans-[Pt(pyridine)2(N3)2(OH)(coumarin-3-carboxylate)] (Pt2) are promising agents for photoactivated chemotherapy. These complexes are inert in the dark but release Pt(II) species and radicals upon visible light irradiation, resulting in photocytotoxicity toward cancer cells. Here, we have used synchrotron techniques to investigate the in-cell behavior of these prodrugs and visualize, for the first time, changes in cellular morphology and Pt localization upon treatment with and without light irradiation. We show that photoactivation of Pt2 induces remarkable cellular damage with extreme alterations to multiple cellular components, including formation of vacuoles, while also significantly increasing the cellular accumulation of Pt species compared to dark conditions. X-ray absorption near-edge structure (XANES) measurements in cells treated with Pt2 indicate only partial reduction of the prodrug upon irradiation, highlighting that phototoxicity in cancer cells may involve not only Pt(II) photoproducts but also photoexcited Pt(IV) species.

Highlights

The use of light to activate otherwise inert molecules selectively and generate a localized antiproliferative effect is a concept that has been used in cancer treatment for several decades in the form of photodynamic therapy (PDT)
Light-activation mechanisms for metalbased photoactivated chemotherapy (PACT) agents can be tuned through the choice of the metal and its ligand set to affect different photo(bio)chemical pathways through ligand exchange, photodissociation, and photoredox processes.[2]
Pt2 in single PC3 human prostate cancer cells (Figure 2). We have investigated their effects on cancer cell structure, their subcellular localization, and Pt oxidation states, without and with blue light irradiation

Summary

Introduction

The use of light to activate otherwise inert molecules selectively and generate a localized antiproliferative effect is a concept that has been used in cancer treatment for several decades in the form of photodynamic therapy (PDT). One major issue with PDT agents is their dependence on oxygen for antiproliferative activity, through the conversion of ground state 3O2 to excited state 1O2, some recent metal-based photosensitizers have seemingly overcome this problem.[3,7,8] A different type of light-activated therapy, whose mechanism of action does not require oxygen, is photoactivated chemotherapy (PACT), where light is used to modify chemically the structure of a prodrug, releasing active agents intracellularly. Light-activation mechanisms for metalbased PACT agents can be tuned through the choice of the metal and its ligand set to affect different photo(bio)chemical pathways through ligand exchange, photodissociation, and photoredox processes.[2] currently the development of PACT therapies is not as advanced as PDT, there is substantial current preclinical research in the field.[9−11]

Results

Discussion

Conclusion