Novel half-sandwich iridium(Ⅲ) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolones (IrPCp,IrPSf,IrPLm,IrPNr) were studied as possible anticancer chemotherapeutics and showed higher potency tha...Novel half-sandwich iridium(Ⅲ) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolones (IrPCp,IrPSf,IrPLm,IrPNr) were studied as possible anticancer chemotherapeutics and showed higher potency than other well-known metal-based agents i.e.,Pt(Ⅱ) drugs.All compounds were characterized by elemental analysis,selected spectroscopic methods (i.e.,absorption and fluorescence spectroscopy,NMR),ESI-MS spectrometry,X-ray diffraction,and electrochemical techniques.The studied complexes exhibited promising cytotoxicity in vitro with IC_(50) values significantly lower than that of the reference drug – cisplatin.The insight into the mode of action revealed the uniform distribution of the Ir(Ⅲ) complexes in both the nucleus and cytoplasm (Pearson’s co-localization coefficient of 0.63).Precise cytometric analysis provided clear evidence for the predominance of apoptosis in the induced cell death.The activation of caspase-3/7 along with the decrease of mitochondrial membrane potential also confirmed the apoptotic cell death.The investigated Ir(Ⅲ) complexes may induce changes in the cell cycle leading to G_(2)/M phase arrest.ROS generation as a plausible pathway responsible for the cytotoxicity was confirmed by determination of redox potentials enabling efficient ROS production.Furthermore,Pluronic P-123 micelles loaded with selected Ir(Ⅲ) complexes were proposed to overcome low solubility and to minimize serious systemic side effects by administering the complex in a controlled manner.The resulting nanoformulations (IrPCp_M,IrPNr_M) facilitated efficient drug accumulation for human lung adenocarcinoma and human prostate carcinoma (A549 and DU-145 cell lines),as demonstrated by confocal microscopy and ICP-MS analysis.In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated.展开更多
基金support of the Polish National Science Centre(Grant 2016/23/D/ST5/00269).
文摘Novel half-sandwich iridium(Ⅲ) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolones (IrPCp,IrPSf,IrPLm,IrPNr) were studied as possible anticancer chemotherapeutics and showed higher potency than other well-known metal-based agents i.e.,Pt(Ⅱ) drugs.All compounds were characterized by elemental analysis,selected spectroscopic methods (i.e.,absorption and fluorescence spectroscopy,NMR),ESI-MS spectrometry,X-ray diffraction,and electrochemical techniques.The studied complexes exhibited promising cytotoxicity in vitro with IC_(50) values significantly lower than that of the reference drug – cisplatin.The insight into the mode of action revealed the uniform distribution of the Ir(Ⅲ) complexes in both the nucleus and cytoplasm (Pearson’s co-localization coefficient of 0.63).Precise cytometric analysis provided clear evidence for the predominance of apoptosis in the induced cell death.The activation of caspase-3/7 along with the decrease of mitochondrial membrane potential also confirmed the apoptotic cell death.The investigated Ir(Ⅲ) complexes may induce changes in the cell cycle leading to G_(2)/M phase arrest.ROS generation as a plausible pathway responsible for the cytotoxicity was confirmed by determination of redox potentials enabling efficient ROS production.Furthermore,Pluronic P-123 micelles loaded with selected Ir(Ⅲ) complexes were proposed to overcome low solubility and to minimize serious systemic side effects by administering the complex in a controlled manner.The resulting nanoformulations (IrPCp_M,IrPNr_M) facilitated efficient drug accumulation for human lung adenocarcinoma and human prostate carcinoma (A549 and DU-145 cell lines),as demonstrated by confocal microscopy and ICP-MS analysis.In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated.
