Ruthenium(II) polypyridyl complexes as mitochondria-targeted two-photon photodynamic anticancer agents.
Clinical acceptance of photodynamic therapy is currently hindered by poor depth efficacy and inefficient activation of the cell death machinery in cancer cells during treatment. To address these issues, photoactivation using two-photon absorption (TPA) is currently being examined. Mitochondria-targeted therapy represents a promising approach to target tumors selectively and may overcome the resistance in current anticancer therapies. Herein, four ruthenium(II) polypyridyl complexes (RuL1-RuL4) have been designed and developed to act as mitochondria-targeted two-photon photodynamic anticancer agents. These complexes exhibit very high singlet oxygen quantum yields in methanol (0.74-0.81), significant TPA cross sections (124-198 GM), remarkable mitochondrial accumulation, and deep penetration depth. Thus, RuL1-RuL4 were utilized as one-photon and two-photon absorbing photosensitizers in both monolayer cells and 3D multicellular spheroids (MCSs). These Ru(II) complexes were almost nontoxic towards cells and 3D MCSs in the dark and generate sufficient singlet oxygen under one- and two-photon irradiation to trigger cell death. Remarkably, RuL4 exhibited an IC50 value as low as 9.6 μM in one-photon PDT (λirr = 450 nm, 12 J cm(-2)) and 1.9 μM in two-photon PDT (λirr = 830 nm, 800 J cm(-2)) of 3D MCSs; moreover, RuL4 is an order of magnitude more toxic than cisplatin in the latter test system. The combination of mitochondria-targeting and two-photon activation provides a valuable paradigm to develop ruthenium(II) complexes for PDT applications.
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Jiangping
J
Liu
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Yu
Y
Chen
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Guanying
G
Li
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Pingyu
P
Zhang
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Chengzhi
C
Jin
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Leli
L
Zeng
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China.
Liangnian
L
Ji
MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, PR China. Electronic address: ceschh@mail.sysu.edu.cn.
Hui
H
Chao
D000970:Antineoplastic Agents / Q000737:chemistry*; D002470:Cell Survival; D002945:Cisplatin / Q000737:chemistry; D056831:Coordination Complexes / Q000737:chemistry*; D004307:Dose-Response Relationship, Radiation; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D000432:Methanol / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D010778:Photochemotherapy / Q000379:methods*; D017785:Photons; D017319:Photosensitizing Agents / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*; D026082:Singlet Oxygen / Q000737:chemistry; D018874:Spheroids, Cellular / Q000187:drug effects
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004337:Drug Carriers; D017319:Photosensitizing Agents; D026082:Singlet Oxygen; D012428:Ruthenium; D002945:Cisplatin; D000432:Methanol
3D multicellular spheroids; Mitochondria; Photodynamic therapy; Ruthenium(II) complex; Two-photon