High amounts of glutathione in tumour cells are able to decrease the effectiveness of cancer treatments by capturing the therapeutically necessary reactive oxygen species during the photodynamic therapy(PDT)process.In...High amounts of glutathione in tumour cells are able to decrease the effectiveness of cancer treatments by capturing the therapeutically necessary reactive oxygen species during the photodynamic therapy(PDT)process.In addition,many photosensitizers for PDT are limited by the light tissue penetration depth,which hinders the application of these compounds to treat deep seated or large tumors.To overcome the aforementioned drawbacks,herein,the use of a mitochondrial-targeting iridium_((III))prodrug Ir-B(OH)2 which is responsive to the tumour microenvironment(H_(2)O_(2)rich)and able to release two-photon photosensitizers(Ir-OH)for PDT and methylquinone as a glutathione scavenger for disrupting the mitochondrial redox homeostasis is presented.Based on the reduction of glutathione,the cancerous cells were more vulnerable to oxidative stress caused by two-photon photodynamic therapy.Upon twophoton laser irradiation(730 nm),a strong and amplified phototoxic effect towards human gastric adenocarcinoma(AGS)cellular and animal models was observed.展开更多
Mounting evidence suggests that impairment of mitochondrial DNA(mtDNA),an important element in the response of mitochondrial biological function but more susceptible to damage than nuclear DNA(nDNA),can activate the p...Mounting evidence suggests that impairment of mitochondrial DNA(mtDNA),an important element in the response of mitochondrial biological function but more susceptible to damage than nuclear DNA(nDNA),can activate the progress of cell death.Herein,an iridium(Ⅲ)moiety was introduced to a terpyridyl platinum(Ⅱ)derivative,and the designed compound,Ir-Pt,has achieved mitochondrial accumulation by a rate of up to 76%as determined by ICP-MS.The anticancer activity and mechanism of action have been investigated.The MTT assay indicated that Ir-Pt exhibited strong antitumor activity towards cisplatinresistant cancer cells(A549R).Additionally,the designed complex severely damaged mtDNA,sequentially disrupted the mitochondrial function,and resulted in a loss of mitochondrial membrane potential(MMP)and depletion of ATP.Furthermore,cell death occurred as a consequence of necrosis induced by Ir-Pt,characterized by the release of LDH,over-expression of the RIP3 protein and lack of activation of the typical apoptotic signal in caspase 3/7.All of these results suggested that the mtDNA-targeting Ir-Pt is a potential antitumor agent that overcomes cisplatin-resistance in cancer cells.展开更多
Intracellular calcium levels are closely related to cell survival.The disruption of the calcium buffering capacity or an overload of the calcium levels enhances the susceptibility of cells towards external stimuli suc...Intracellular calcium levels are closely related to cell survival.The disruption of the calcium buffering capacity or an overload of the calcium levels enhances the susceptibility of cells towards external stimuli such as reactive oxygen species.Capitalizing on this,herein,a pH-responsive calcium carbonate nano-platform loaded with Ir(Ⅲ)complexes(IrCOOH-CaCO_(3)@PEG)for combined calcium overload and two-photon photodynamic therapy is proposed.Notably,the introduction of the carboxyl group is a core factor to improve the loading content of Ir(Ⅲ)complexes.Upon cellular uptake into cancerous cells,the nanomaterial was found to selectively accumulate in the lysosomes where the acidic environment caused the decomposition of the nanomaterial,releasing the Ir(Ⅲ)complexes and an excess of calcium ions.The combination of calcium overload and the generation of reactive oxygen species upon irradiation by the Ir(Ⅲ)complexes generated a high cytotoxic effect.The loaded nanoplatform demonstrated a strong tumor growth inhibition effect in a breast cancer tumor-bearing mouse model upon exposure to deeply pene-trating two-photon irradiation at 750 nm.We strongly believe that the Ir(Ⅲ)complex containing nanoplat-form approach we proposed could be a versatile method,and this approach of combining calcium over-load therapy and photodynamic therapy holds great potential for cancer therapy.展开更多
基金supported by the National Natural Science Foundation of China(No.21525105 and 21778079)the Fundamental Research Funds for the Central Universities of China(No.20lgjc01)supported by Dr Zhubing He from Shenzhen Key Laboratory of Full Spectral Solar Electricity Generation(FSSEG).
文摘High amounts of glutathione in tumour cells are able to decrease the effectiveness of cancer treatments by capturing the therapeutically necessary reactive oxygen species during the photodynamic therapy(PDT)process.In addition,many photosensitizers for PDT are limited by the light tissue penetration depth,which hinders the application of these compounds to treat deep seated or large tumors.To overcome the aforementioned drawbacks,herein,the use of a mitochondrial-targeting iridium_((III))prodrug Ir-B(OH)2 which is responsive to the tumour microenvironment(H_(2)O_(2)rich)and able to release two-photon photosensitizers(Ir-OH)for PDT and methylquinone as a glutathione scavenger for disrupting the mitochondrial redox homeostasis is presented.Based on the reduction of glutathione,the cancerous cells were more vulnerable to oxidative stress caused by two-photon photodynamic therapy.Upon twophoton laser irradiation(730 nm),a strong and amplified phototoxic effect towards human gastric adenocarcinoma(AGS)cellular and animal models was observed.
基金supported by the National Science Foundation of China(No.21525105,21778079,and 21907112)the Ministry of Education of China(No.IRT-17R111)+1 种基金the China Postdoctoral Science Foundation(No.2019M653143)the Fundamental Research Funds for the Central Universities(No.19lgpy130).
文摘Mounting evidence suggests that impairment of mitochondrial DNA(mtDNA),an important element in the response of mitochondrial biological function but more susceptible to damage than nuclear DNA(nDNA),can activate the progress of cell death.Herein,an iridium(Ⅲ)moiety was introduced to a terpyridyl platinum(Ⅱ)derivative,and the designed compound,Ir-Pt,has achieved mitochondrial accumulation by a rate of up to 76%as determined by ICP-MS.The anticancer activity and mechanism of action have been investigated.The MTT assay indicated that Ir-Pt exhibited strong antitumor activity towards cisplatinresistant cancer cells(A549R).Additionally,the designed complex severely damaged mtDNA,sequentially disrupted the mitochondrial function,and resulted in a loss of mitochondrial membrane potential(MMP)and depletion of ATP.Furthermore,cell death occurred as a consequence of necrosis induced by Ir-Pt,characterized by the release of LDH,over-expression of the RIP3 protein and lack of activation of the typical apoptotic signal in caspase 3/7.All of these results suggested that the mtDNA-targeting Ir-Pt is a potential antitumor agent that overcomes cisplatin-resistance in cancer cells.
基金supported by the National Natural Science Foundation of China(No.22120102002)the Science and Technology Innovation Program of Hunan Province of China(No.2021RC5028).
文摘Intracellular calcium levels are closely related to cell survival.The disruption of the calcium buffering capacity or an overload of the calcium levels enhances the susceptibility of cells towards external stimuli such as reactive oxygen species.Capitalizing on this,herein,a pH-responsive calcium carbonate nano-platform loaded with Ir(Ⅲ)complexes(IrCOOH-CaCO_(3)@PEG)for combined calcium overload and two-photon photodynamic therapy is proposed.Notably,the introduction of the carboxyl group is a core factor to improve the loading content of Ir(Ⅲ)complexes.Upon cellular uptake into cancerous cells,the nanomaterial was found to selectively accumulate in the lysosomes where the acidic environment caused the decomposition of the nanomaterial,releasing the Ir(Ⅲ)complexes and an excess of calcium ions.The combination of calcium overload and the generation of reactive oxygen species upon irradiation by the Ir(Ⅲ)complexes generated a high cytotoxic effect.The loaded nanoplatform demonstrated a strong tumor growth inhibition effect in a breast cancer tumor-bearing mouse model upon exposure to deeply pene-trating two-photon irradiation at 750 nm.We strongly believe that the Ir(Ⅲ)complex containing nanoplat-form approach we proposed could be a versatile method,and this approach of combining calcium over-load therapy and photodynamic therapy holds great potential for cancer therapy.
