Metal-based Complexes For Cancer Phototherapy

Photodynamic therapy(PDT)is a non-invasive and effective method for tumor treatment,which can directly affect cancer cells and induce cell death through necrosis or apoptosis.PDT is based on the use of a PS which can accumulate at the tumr site and be excited with the suitable wavelength light.Metal-based photosensitizers have attracted great interest in PDT because of their rich excited state behaviors and structural diversity.Herein,aiming to overcome the drawbacks of the photosensitizers mentioned above,two types of metal-based photosensitizers with different mode of actions were designed and synthesized.1.Light-activated ruthenium(?)-bicalutamide prodrugs for prostate cancerPolypyridyl ruthenium(?)complexes have shown potential phototherapy application due to their unique biological properties.In this paper,three polypyridyl ruthenium(?)complexes 1-3 have been designed for photoactivated chemotherapy.The clinically approved anticancer drug bicalutamide were caged by the ruthenium(?)center through the nitrile group to tumor.Docking studies showed that ruthenium(?)fragments can effectively prevent the binding of complexes 1-3 to AR(androgen receptor).Once irradiation with blue light(465 nm),complexes 1-3 can release bicalutamide and anticancer Ru(?)fragments,which possesses dual-action of AR binding and DNA interaction simultaneously.In vitro cytotoxicity study on these complexes further confirmed that complexes 1-3 exhibited considerable cytotoxicity upon irradiation with blue light,while complex 3 can be activated at 660 nm,which greatly increases the scope of complex 3 in deeper tissues.Theoretical calculations showed that the lowest singlet excitation energy of complex 3 is lower than that of complexes 1-2.Overall,the synthesized complexes can be activated by light and result in the dissociation of the ligand,which is an effective therapeutic agent to achieve enhanced drug efficacy and reduced side effects and toxicity.2.Iridium(?)complex–derived polymeric micelles with NIR excitation for tumor therapy.Cyclometalated iridium(?)complexes have been reported as PSs to meet many essential requirements and offer many advantages for PDT.Herein,an iridium(?)-based photosensitizer 4 with a long-lived intraligand(³IL)excited state has been designed and synthesized,which shows significantly enhanced singlet oxygen(¹O₂)generation efficiency(?45 folds)relative to that of the model iridium(?)complex 5under 460 nm irradiation.In order to achieve deep tissue penetration,complex 4 was further covalently bonded to the upconversion nanoparticles(UCNPs).Besides,1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole(YC-1),an effective HIF-1?inhibitor,was physically adsorbed into the hydrophobic layer at the surface of UCNPs.After near-infrared(NIR)radiation,complex 4-mediated toxic ¹O₂ was generated for PDT,whose efficient conversion of oxygen to ¹O₂ during the PDT would exacerbate the hypoxic condition of tumor tissue and lead to the upregulation of HIF-1?for the following HIF-1 targeting tumor therapy.The treatment platform shows good anti-cancer performance in both in vitro and in vivo anti-tumor activity tests in a hypoxic environment.This study highlights the potential for applying a nanoplatform consisting of long-lived iridium-based photosensitizers and HIF-1?inhibitors in tumor treatments,which converts PDT-induced tumor hypoxia to a therapy advantage,thus opening up ideas to overcome the hypoxia in PDT therapy.