Novel [3+2+1] Coordinated Iridium (III) Complexes for Hyperefficient Photodynamic Therapy

Abstract

Efficient photosensitizers are crucial for the success of photodynamic therapy (PDT). Herein, we reported two [3+2+1] coordinated organometallic Iridium (III) complexes (labeled as Ir-C1 and Ir-C4). Ir-C1/C4 can generate both type I and type II reactive oxygen species (ROS). In vitro experiments, Ir-C1/C4 show low biotoxicity and high phototoxicity of half-maximal inhibitory concentration values of 14 nM and 33 nM on rectal cancer cell line HCT116, respectively. Western blot analysis revealed that the Ir-C1/C4 activated ferroptosis, apoptosis, and inhibiting autophagy simultaneously. Proteomics analysis demonstrated that the photosensitizers destroyed the endoplasmic reticulum (ER), blocking the signal transmission and material transfer between the ER and other tissues of the cell, especially the ER to Golgi vesicle-mediated transport. Ir-C1/C4 can achieve better antitumor performance than commercial photosensitizer Chlorin e6 and the ferroptosis activator RSL3 at lower concentrations. The low biotoxicity and high phototoxicity make them ideal candidates for PDT. The findings provide new insights into the design of photosensitizers for metal complexes and have significant implications for the development of PDT and related drugs.

Keywords

apoptosis / autophagy / endoplasmic reticulum / ferroptosis / photodynamic therapy

References

[1] J. F. Kelly and M. E. Snell, “Hematoporphyrin Derivative: A Possible Aid in the Diagnosis and Therapy of Carcinoma of the Bladder,” Journal of Urology 115 (1976): 150-151.

[2] U. Chilakamarthi and L. Giribabu, “Photodynamic Therapy: Past, Present and Future,” Chemical Record 17 (2017): 775-802.

[3] F. L. Ma, Q. Jia, Z. W. Deng, et al., “Boosting Luminescence Efficiency of Near-Infrared-II Aggregation-Induced Emission Luminogens via a Mash-Up Strategy of π-Extension and Deuteration for Dual-Model Image-Guided Surgery,” ACS Nano 18 (2024): 9431-9442.

[4] D. E. Dolmans, D. Fukumura, and R. K. Jain, “Photodynamic Therapy for Cancer,” Nature Reviews Cancer 3 (2003): 380-387.

[5] S. Zhang, J. Wang, Z. Wang, et al., “Study of Transient Absorption Spectroscopy of a D-π-A Structure Aggregation-Induced Emission Luminogen and Its Photodynamic Therapy Application,” Journal of Materials Chemistry B 12 (2024): 8349-8356.

[6] J. Cheng, L. Li, D. Jin, et al., “Boosting Ferroptosis Therapy With Iridium Single-Atom Nanocatalyst in Ultralow Metal Content,” Advanced Materials 35 (2023): e2210037.

[7] S. Monro, K. L. Colon, and H. Yin, “Transition Metal Complexes and Photodynamic Therapy From a Tumor-Centered Approach: Challenges, Opportunities, and Highlights From the Development of TLD1433,” Chemical Reviews 119 (2019): 797-828.

[8] G. S. Kulkarni, L. Lilge, M. Nesbitt, R. J. Dumoulin-White, A. Mandel, and M. A. S. Jewett, “A Phase 1b Clinical Study of Intravesical Photodynamic Therapy in Patients With Bacillus Calmette-Guerin-Unresponsive Non-Muscle-Invasive Bladder Cancer,” European Urology Open Science 41 (2022): 105-111.

[9] Z. Liu, S. W. Zhang, M. Zhang, et al., “Highly Efficient Phosphorescent Blue-Emitting [3+2+1] Coordinated Iridium (III) Complex for OLED Application,” Frontiers in Chemistry 9 (2021): 758357.

[10] W. J. Wang, Y. Y. Ling, Y. M. Zhong, Z. Y. Li, C. P. Tan, and Z. W. Mao, “Ferroptosis-Enhanced Cancer Immunity by a Ferrocene-Appended Iridium (III) Diphosphine Complex,” Angewandte Chemie International Edition 61 (2022): e202115247.

[11] L. Ke, F. Wei, L. Xie, et al., “A Biodegradable Iridium (III) Coordination Polymer for Enhanced Two-Photon Photodynamic Therapy Using an Apoptosis-Ferroptosis Hybrid Pathway,” Angewandte Chemie International edition 61 (2022): e202205429.

[12] J. Zhao, Y. Gao, R. Huang, et al., “Design of Near-Infrared-Triggered Metallo-Photosensitizers via a Self-Assembly-Induced Vibronic Decoupling Strategy,” Journal of the American Chemical Society 145 (2023): 11633-11642.

[13] L. Zhang and D. Ding, “Recent Advances of Transition Ir (III) Complexes as Photosensitizers for Improved Photodynamic Therapy,” View 2 (2021): 20200179.

[14] T. Nie, W. Zou, Z. Meng, et al., “Bioactive Iridium Nanoclusters With Glutathione Depletion Ability for Enhanced Sonodynamic-Triggered Ferroptosis-Like Cancer Cell Death,” Advanced Materials 34 (2022): e2206286.

[15] K. W. Lee, Y. Gao, W. C. Wei, et al., “Anti-Quenching NIR-II J-Aggregates of Benzo[c]Thiophene Fluorophore for Highly Efficient Bioimaging and Phototheranostics,” Advanced Materials 35 (2023): e2211632.

[16] M. G. Colombo, A. Hauser, and H. U. Gudel, “Evidence for Strong Mixing Between the Lc and Mlct Excited-States in Bis(2-Phenylpyridinato-C2,N') (2,2'-Bipyridine)Iridium (III),” Inorganic Chemistry 32 (1993): 3088-3092.

[17] K. A. King and R. J. Watts, “Dual Emission From an Ortho-Metalated Ir (III) Complex,” Journal of the American Chemical Society 109 (1987): 1589-1590.

[18] Z. Gu, C. Flemington, T. Chittenden, and G. P. Zambetti, “ei24, a p53 Response Gene Involved in Growth Suppression and Apoptosis,” Molecular and Cellular Biology 20 (2000): 233-241.

[19] J. Hagenbuchner, M. J. Ausserlechner, V. Porto, et al., “The Anti-Apoptotic Protein BCL2L1/Bcl-xL Is Neutralized by Pro-Apoptotic PMAIP1/Noxa in Neuroblastoma, Thereby Determining Bortezomib Sensitivity Independent of Prosurvival MCL1 Expression,” Journal of Biological Chemistry 285 (2010): 6904-6912.

[20] Y. Tian, J. Lu, X. Q. Hao, et al., “FTH1 Inhibits Ferroptosis Through Ferritinophagy in the 6-OHDA Model of Parkinson's Disease,” Neurotherapeutics 17 (2020): 1796-1812.

[21] E. L. Eskelinen, “Roles of LAMP-1 and LAMP-2 in Lysosome Biogenesis and Autophagy,” Molecular Aspects of Medicine 27 (2006): 495-502.

[22] A. Karagiota, G. Chachami, and E. Paraskeva, “Lipid Metabolism in Cancer: The Role of Acylglycerolphosphate Acyltransferases (AGPATs),” Cancers 14 (2022): 228.

[23] M. Song, L. Pang, M. Zhang, Y. Qu, K. V. Laster, and Z. Dong, “Cdc2-Like Kinases: Structure, Biological Function, and Therapeutic Targets for Diseases,” Signal Transduction and Targeted Therapy 8 (2023): 148.

[24] M. D. Herrero-Martin, M. Pineda, P. Briones, et al., “A New Pathologic Mitochondrial DNA Mutation in the Cytochrome Oxidase Subunit I (MT-CO1),” Human Mutation 29 (2008): E112-E122.

[25] C. D. Green and L. K. Olson, “Modulation of Palmitate-Induced Endoplasmic Reticulum Stress and Apoptosis in Pancreatic Beta-Cells by Stearoyl-CoA Desaturase and Elovl6,” American Journal of Physiology. Endocrinology and Metabolism 300 (2011): E640-E649.

[26] J. S. Choi, H. Y. Shin, K. S. Kwon, et al., “Effects of Oxypeucedanin on Global Gene Expression and MAPK Signaling Pathway in Mouse Neuroblastoma Neuro-2A Cells,” Planta Medica 77 (2011): 1512-1518.

[27] Q. G. Tao, J. Fujimoto, T. Y. Men, et al., “Identification of the Retinoic Acid-Inducible Gprc5a as a New Lung Tumor Suppressor Gene,” NCI Journal of the National Cancer Institute 99 (2007): 1668-1682.

[28] S. Gery, N. Komatsu, L. Baldjyan, A. Yu, D. Koo, and H. P. Koeffler, “The Circadian Gene Per1 Plays an Important Role in Cell Growth and DNA Damage Control in Human Cancer Cells,” Molecular Cell 22 (2006): 375-382.

[29] S. Raichur, S. T. Wang, P. W. Chan, et al., “CerS2 Haploinsufficiency Inhibits Beta-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance,” Cell metabolism 20 (2014): 687-695.

RIGHTS & PERMISSIONS

2025 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.