Herein,we have designed,synthesized,and characterized two novel coumarin-6-based Ir(Ⅲ)photo-catalysts viz.[Ir(CO_(6))_(2)(dppz)]Cl(Ir1)and[Ir(CO_(6))_(2)(aip)]Cl(Ir2),where CO6=coumarin 6,dppz=dipyrido[3,2-a:2’,3’-...Herein,we have designed,synthesized,and characterized two novel coumarin-6-based Ir(Ⅲ)photo-catalysts viz.[Ir(CO_(6))_(2)(dppz)]Cl(Ir1)and[Ir(CO_(6))_(2)(aip)]Cl(Ir2),where CO6=coumarin 6,dppz=dipyrido[3,2-a:2’,3’-c]phenazine,and aip=2-(anthracen-9-yl)-1H-imidazo[4,5-f][1,10]phenanthroline.Coumarin 6 introduced a green light absorption property.When exposed to green light,complexes Ir1 and Ir2 demonstrated catalytic NADH photo-oxidation with a TOF of ca.840–1000 h^(−1) in PBS,comparable to or higher than the highest achieved TOF with previously reported Ir(Ⅲ)-based photo-catalysts for NADH oxidation.Ir1 and Ir2 also generated^(1)O_(2)on green light irradiation.Both the complexes showed remarkable photo-toxicities against human lung adenocarcinoma cells(A549)and human cervical cancer cells(HeLa)with the IC_(50)and PIs(dark IC_(50)/light IC_(50))in the range of 0.5–1.6μM and>28–71,respectively.Interestingly,these complexes did not show any notable toxicities toward the normal human bronchial epithelial(BEAS-2B)cell line under dark conditions.The selectivity index(SI=light IC_(50)in normal cells/light IC_(50)in cancer cells)of Ir1 and Ir2 for the killing of cancer cells was in the range of 7–19.Moreover,Ir1 and Ir2 also showed good phototoxicity against A549 cancer cells under hypoxic conditions,revealing their potential for hypoxic tumor treatment.The mechanistic investigation of the most potent complex Ir2 in A549 cells revealed that it localized in the mitochondria,generated ROS and oxidized NADH during light exposure,ultimately causing cell apoptosis via mitochondrial depolarization.This strategy of killing cancer cells by combining type-Ⅰ and type-Ⅱ mechanisms,i.e.via NADH oxidation,H2O2,•OH,and 1O2 generation,could provide efficient photo-activated chemotherapy.展开更多
Red light-activatable transition metal complexes have recently emerged as viable materials for use in photodynamic/photochemotherapeutic applications.Ideal photosensitizers or photochemotherapeutic agents are still an...Red light-activatable transition metal complexes have recently emerged as viable materials for use in photodynamic/photochemotherapeutic applications.Ideal photosensitizers or photochemotherapeutic agents are still an elusive goal.Herein,we report the synthesis,characterization and remarkable photodynamic activity of the[LaⅢ(Cur)2(L1)(NO3)](1)-functionalized gold nanocomposite,1-AuNPs,where Cur represents curcumin and L1 represents 5-(1,2-dithiolan-3-yl)-N-(1,10-phenanthroline-5-yl)pentanamide.Functionalization of complex 1 to gold nanoparticles led to a remarkable red shift(λ_(max),755 nm)in the surface plasmon resonance(SPR)band,making the La(Ⅲ)–curcumin-functionalized nanocomposite(1-AuNPs)an ideal photo-sensitizer for use in photodynamic applications.Several photophysical assays confirmed its high efficacy in generating singlet oxygen[ϕ(1O2),0.69]through a type-II photo-process.TD-DFT calculations also predicted the presence of a low-lying triplet excited state and efficient intersystem crossing for the nanoconjugate.The log P values along with the high binding affinity of the 1-AuNPs to serum albumin predicted cellular permeability and transportation through blood.Flowcytometric analysis indicated the selective accumulation and retention of 1-AuNPs in adenocarcinomic human alveolar basal epithelial cells(A549)compared with normal alveolar fibroblast cells(WI-38).Confocal microscopy confirmed the localization of the nanocomposite in mitochondria.The nanoconjugate,1-AuNPs,exhibited remarkable photodynamic activity against adenocarcinomic human alveolar basal epithelial cells(A549)(IC50:25μg mL^(-1) in light;>500μg mL^(-1) in dark)and immortalized human keratinocytes(HaCaT)(IC50:34μg mL^(-1) in light;>500μgmL^(-1) in dark)under red light(600–720 nm,30 J cm^(-2)),with remarkable photo-indices(PI>20).Red light-induced generation of 1O2 by 1-AuNPs in vitro was found to be primarily responsible for the upsetting of the mitochondrial membrane potential(MMP),which led to caspase-3 activated apoptosis in A549 cells via an intrinsic pathway.During apoptosis,the pro-apoptotic BAX protein was upregulated,while the antiapoptotic Bcl-2 protein was downregulated and responsible for apoptosis after the A549 cells were treated with the red light activated nanoconjugate(1-AuNPs).Overall,the La(Ⅲ)–curcumin-functionalized gold nanocomposite is an ideal next generation La(Ⅲ)-based photosensitizer for use in photodynamic applications.展开更多
基金We thank BRNS(54/14/08/2022-BRNS-R),the Government of India,for financial support.
文摘Herein,we have designed,synthesized,and characterized two novel coumarin-6-based Ir(Ⅲ)photo-catalysts viz.[Ir(CO_(6))_(2)(dppz)]Cl(Ir1)and[Ir(CO_(6))_(2)(aip)]Cl(Ir2),where CO6=coumarin 6,dppz=dipyrido[3,2-a:2’,3’-c]phenazine,and aip=2-(anthracen-9-yl)-1H-imidazo[4,5-f][1,10]phenanthroline.Coumarin 6 introduced a green light absorption property.When exposed to green light,complexes Ir1 and Ir2 demonstrated catalytic NADH photo-oxidation with a TOF of ca.840–1000 h^(−1) in PBS,comparable to or higher than the highest achieved TOF with previously reported Ir(Ⅲ)-based photo-catalysts for NADH oxidation.Ir1 and Ir2 also generated^(1)O_(2)on green light irradiation.Both the complexes showed remarkable photo-toxicities against human lung adenocarcinoma cells(A549)and human cervical cancer cells(HeLa)with the IC_(50)and PIs(dark IC_(50)/light IC_(50))in the range of 0.5–1.6μM and>28–71,respectively.Interestingly,these complexes did not show any notable toxicities toward the normal human bronchial epithelial(BEAS-2B)cell line under dark conditions.The selectivity index(SI=light IC_(50)in normal cells/light IC_(50)in cancer cells)of Ir1 and Ir2 for the killing of cancer cells was in the range of 7–19.Moreover,Ir1 and Ir2 also showed good phototoxicity against A549 cancer cells under hypoxic conditions,revealing their potential for hypoxic tumor treatment.The mechanistic investigation of the most potent complex Ir2 in A549 cells revealed that it localized in the mitochondria,generated ROS and oxidized NADH during light exposure,ultimately causing cell apoptosis via mitochondrial depolarization.This strategy of killing cancer cells by combining type-Ⅰ and type-Ⅱ mechanisms,i.e.via NADH oxidation,H2O2,•OH,and 1O2 generation,could provide efficient photo-activated chemotherapy.
基金the Board of Research in Nuclear Science(BRNS),Mumbai(37(2)/14/18/2017-BRNS)for financial support,and NIT Manipur for providing infrastructureWe sincerely thank Prof.Akhil R.Chakravarty,IISc Bangalore,for providing the facility used for cellular studies.We thank the Advanced Material Research Centre,IIT Mandi for recording NMR,ESI-MS,EDX,ICP-OES spectra,and TEM analysis and Miss V.V.Gandhi,BARC for FACS analysis.
文摘Red light-activatable transition metal complexes have recently emerged as viable materials for use in photodynamic/photochemotherapeutic applications.Ideal photosensitizers or photochemotherapeutic agents are still an elusive goal.Herein,we report the synthesis,characterization and remarkable photodynamic activity of the[LaⅢ(Cur)2(L1)(NO3)](1)-functionalized gold nanocomposite,1-AuNPs,where Cur represents curcumin and L1 represents 5-(1,2-dithiolan-3-yl)-N-(1,10-phenanthroline-5-yl)pentanamide.Functionalization of complex 1 to gold nanoparticles led to a remarkable red shift(λ_(max),755 nm)in the surface plasmon resonance(SPR)band,making the La(Ⅲ)–curcumin-functionalized nanocomposite(1-AuNPs)an ideal photo-sensitizer for use in photodynamic applications.Several photophysical assays confirmed its high efficacy in generating singlet oxygen[ϕ(1O2),0.69]through a type-II photo-process.TD-DFT calculations also predicted the presence of a low-lying triplet excited state and efficient intersystem crossing for the nanoconjugate.The log P values along with the high binding affinity of the 1-AuNPs to serum albumin predicted cellular permeability and transportation through blood.Flowcytometric analysis indicated the selective accumulation and retention of 1-AuNPs in adenocarcinomic human alveolar basal epithelial cells(A549)compared with normal alveolar fibroblast cells(WI-38).Confocal microscopy confirmed the localization of the nanocomposite in mitochondria.The nanoconjugate,1-AuNPs,exhibited remarkable photodynamic activity against adenocarcinomic human alveolar basal epithelial cells(A549)(IC50:25μg mL^(-1) in light;>500μg mL^(-1) in dark)and immortalized human keratinocytes(HaCaT)(IC50:34μg mL^(-1) in light;>500μgmL^(-1) in dark)under red light(600–720 nm,30 J cm^(-2)),with remarkable photo-indices(PI>20).Red light-induced generation of 1O2 by 1-AuNPs in vitro was found to be primarily responsible for the upsetting of the mitochondrial membrane potential(MMP),which led to caspase-3 activated apoptosis in A549 cells via an intrinsic pathway.During apoptosis,the pro-apoptotic BAX protein was upregulated,while the antiapoptotic Bcl-2 protein was downregulated and responsible for apoptosis after the A549 cells were treated with the red light activated nanoconjugate(1-AuNPs).Overall,the La(Ⅲ)–curcumin-functionalized gold nanocomposite is an ideal next generation La(Ⅲ)-based photosensitizer for use in photodynamic applications.
