Type I Rhodamine-Sensitized Iridium(III) Complex Photosensitizers Activate Pyroptosis for Hypoxic Photodynamic...

Area of Science:

• Photodynamic immunotherapy
• Cancer research
• Materials science

Background:

• Photodynamic immunotherapy (PDI) efficacy is limited by tumor hypoxia and immune suppression.
• Developing hypoxia-tolerant type I photosensitizers (PSs) that induce pyroptosis is crucial for improving PDI.
• Understanding the structure-property relationship of type I PSs is essential for rational design.

Purpose of the Study:

• To synthesize and characterize novel cyclometalated Ir(III) complexes as type I PSs.
• To investigate the structure-property relationship and enhance intramolecular photoinduced electron transfer (IPET).
• To evaluate the efficacy of these PSs in generating reactive oxygen species and inducing pyroptosis under hypoxic conditions for PDI.

Main Methods:

• Synthesis of a series of cyclometalated Ir(III) complexes (Ir1-Ir5) with acetylacetone-functionalized rhodamine ligands using a donor-acceptor (D-A) strategy.
• Evaluation of superoxide radical generation efficiency under low-power white light.
• Assessment of phototoxicity and pyroptosis induction in CT26 cells under hypoxic conditions.
• In vitro and in vivo studies to confirm tumor ablation and immune response.

Main Results:

• The synthesized Ir(III) complexes (Ir1-Ir5) demonstrated significantly improved superoxide radical generation (20-fold higher than methylene blue).
• Complex Ir3 showed exceptional phototoxicity under hypoxia (IC50 = 0.46 μM) due to enhanced radical production.
• Ir3 successfully activated pyroptosis in CT26 cells, triggering a strong immune response and effective tumor ablation in vivo.

Conclusions:

• Modification of anchoring groups enhances intramolecular electron transfer, enabling the switch from type II to type I photosensitizers.
• The developed type I PSs are hypoxia-tolerant and can effectively induce pyroptosis, overcoming limitations in PDI.
• This study provides a promising strategy for developing hypoxia-resistant PDI agents for cancer therapy.