Hui Jiang, Qiaoshan Lie, Fa Wang, Shufei Li, Jinrong Yang, Wanhe Wang,* Taihong Liu,* Johannes Karges,* and Hui Chao*. J. Med. Chem., 2026. https://doi.org/10.1021/acs.jmedchem.6c02622

A collaborative team from Jinan University, Sun Yat-Sen University, Shaanxi Normal University, and Ruhr University Bochum has reported a lysosome-targeted dinuclear iridium(III) photosensitizer, Ir₂-pbt-877, in the Journal of Medicinal Chemistry. The complex combines near-infrared two-photon activation with type-I reactive oxygen species generation under hypoxia and links organelle stress to ferroptosis and antitumor immune activation.

By combining π-conjugation extension with dinuclearization, the researchers identified Ir₂-pbt-877 as a lead compound with a singlet-oxygen quantum yield of 0.81, a maximum two-photon absorption cross section at 810 nm, and low dark cytotoxicity. Under hypoxia, singlet-oxygen generation was suppressed, whereas superoxide generation remained detectable, supporting a hypoxia-tolerant type-I photodynamic pathway.

In cisplatin-resistant A549R lung cancer cells, photoactivation induced lysosomal membrane permeabilization, cathepsin B release, calcium dysregulation, mitochondrial depolarization, and PINK1-associated mitophagy. These changes were accompanied by GSH depletion, reduced GPX4 expression, Fe(II) accumulation, and enhanced lipid peroxidation. Inhibitor-rescue experiments supported a functional connection between mitophagy and ferroptosis, together with the release or exposure of immunogenic danger signals.

In a sequential contralateral CMT167 rechallenge model in mice, the PEG-based nanoformulation Ir₂-pbt-877@PEG, combined with local two-photon irradiation, suppressed primary tumor growth and delayed the growth of a non-irradiated contralateral tumor implanted seven days after treatment. Increased dendritic-cell maturation and CD8⁺ T-cell infiltration, together with fewer regulatory T cells, supported systemic antitumor immune activation. These preclinical findings provide a basis for developing hypoxia-tolerant metal-based photosensitizers that connect photodynamic therapy with ferroptosis-associated immune responses.

Figure 1. Molecular design and proposed action mechanism of the lysosome-targeted dinuclear iridium(III) photosensitizer Ir2-Pbt-877

First Author: Jiang Hui, doctoral candidate, Jinan University and Sun Yat-Sen University

Correspondence Authors: Prof. Wang Wanhe, Jinan University; Prof. Liu Taihong, Shaanxi Normal University; Prof. Johannes Karges, Ruhr University Bochum; Prof. Chao Hui, Jinan University and Sun Yat-Sen University

Full Text Link: https://doi.org/10.1021/acs.jmedchem.6c02622