Photodynamic therapy(PDT)usually shows limited efficacy in solid tumors since traditional PDT is O_(2)^(-)dependent while solid tumors are inherently hypoxic.In addition,hypoxic tumor cells possess antiapoptotic pathw...Photodynamic therapy(PDT)usually shows limited efficacy in solid tumors since traditional PDT is O_(2)^(-)dependent while solid tumors are inherently hypoxic.In addition,hypoxic tumor cells possess antiapoptotic pathways that resist PDT-induced apoptosis.Therefore,developing photosensitizers(PSs)that show low O_(2)^(-)dependency and can induce nonapoptotic cell death pathways is critically needed.Herein,a series of Ru(II)polypyridine complex-based PSs,RuNMe,RuH,and RuCN,were synthesized,and their applications against hypoxic tumor cells through PDT were investigated.All three complexes showthe ability to generate the superoxide anion radical(·O_(2)^(-)),which is the type I photoreaction and less O_(2)^(-)dependent.RuNMe shows the best PDT performance against MCF-7 cells and three-dimensional multicellular spheroids,due to its higher cellular uptake and more reactive oxygen species generation.More importantly,RuNMe-incubated MCF-7 cells show photoinduced ferroptosis as evidenced by glutathione peroxidase 4 downregulation and lipid peroxide accumulation.This work not only develops a novel ferroptosis-inducing Ru(II)complex with the type I PDT process but also offers an effective strategy to solve tumor hypoxia in PDT.展开更多
基金This work was financially supported by the National Natural Science Foundation of China(grant nos.22122701,21731004,91953201,92153303,21977044,and 21907050)the Natural Science Foundation of Jiangsu Province(grant nos.BK20202004 and BK20190282)the Excellent Research Program of Nanjing University(grant no.ZYJH004).
文摘Photodynamic therapy(PDT)usually shows limited efficacy in solid tumors since traditional PDT is O_(2)^(-)dependent while solid tumors are inherently hypoxic.In addition,hypoxic tumor cells possess antiapoptotic pathways that resist PDT-induced apoptosis.Therefore,developing photosensitizers(PSs)that show low O_(2)^(-)dependency and can induce nonapoptotic cell death pathways is critically needed.Herein,a series of Ru(II)polypyridine complex-based PSs,RuNMe,RuH,and RuCN,were synthesized,and their applications against hypoxic tumor cells through PDT were investigated.All three complexes showthe ability to generate the superoxide anion radical(·O_(2)^(-)),which is the type I photoreaction and less O_(2)^(-)dependent.RuNMe shows the best PDT performance against MCF-7 cells and three-dimensional multicellular spheroids,due to its higher cellular uptake and more reactive oxygen species generation.More importantly,RuNMe-incubated MCF-7 cells show photoinduced ferroptosis as evidenced by glutathione peroxidase 4 downregulation and lipid peroxide accumulation.This work not only develops a novel ferroptosis-inducing Ru(II)complex with the type I PDT process but also offers an effective strategy to solve tumor hypoxia in PDT.
