2. Academic Validation
  3. Iridium(III) complexes as type I photosensitizers for hypoxic two-photon photodynamic therapy

Iridium(III) complexes as type I photosensitizers for hypoxic two-photon photodynamic therapy

  • J Inorg Biochem. 2025 Nov:272:113006. doi: 10.1016/j.jinorgbio.2025.113006.
Zanru Tan 1,  Jiang Feng 2,  Zixin Tang 1,  Tao Feng 3,  Taihong Liu 4,  Yukun Zhao 5,  Hui Chao 6
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, PR China.
  • 2 Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering, Shanxi Normal University, Xi'an, Shanxi 710119, PR China.
  • 3 Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Bioscience and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: fengt27@163.com.
  • 4 Key Laboratory of Applied Surface and Colloid Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering, Shanxi Normal University, Xi'an, Shanxi 710119, PR China. Electronic address: liuth121@snnu.edu.cn.
  • 5 Department of Dermatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510275, PR China. Electronic address: zhaoyukun7288569@sina.com.
  • 6 MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address: ceschh@mail.sysu.edu.cn.
PMID: 40682924 DOI: 10.1016/j.jinorgbio.2025.113006
Abstract

Photodynamic therapy (PDT), a non-invasive therapeutic modality, has significantly improved skin Cancer treatment in recent years. Nonetheless, the limitations associated with conventional photosensitizers, such as their substantial dependence on oxygen and restricted light penetration, continue to pose considerable challenges for clinical applications. Herein, five Iridium(III) complexes have been developed as type I photosensitizers for two-photon PDT targeting melanoma. These complexes exhibit notable two-photon absorption (TPA) cross-sections (σ2 ≥ 100 GM) and high yields of Reactive Oxygen Species (ROS) under hypoxic conditions, leading to mitochondrial damage and subsequent Apoptosis through ROS generation with low doses of single or two-photon excitation. Notably, Ir4@PEG exhibits an IC50 value of 2.1 μM and a phototoxicity index (PI) of 47 under hypoxic conditions. Cellular assays indicate that Ir4@PEG initially targets and localizes within lysosomes, where the lysosomal membrane is subsequently compromised upon light stimulation, resulting in Ir4 transferring and damaging mitochondria, causing cell Apoptosis. Additionally, Ir4@PEG demonstrates improved tumor penetration, significant ROS production, and marked phototoxicity in hypoxic three-dimensional tumor spheroids. These findings provide new insights into designing oxygen-independent, metal-based two-photon photodynamic therapies against hypoxic melanoma.

Keywords

Hypoxic photodynamic therapy; Iridium; Medicinal inorganic chemistry; Two-photon photosensitizers.

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