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A Deep-Red-Absorbing Osmium(II) Complex as a Photosensitizer for Photodynamic Therapy Inducing Immunogenic Cell Death
Yiyi Zhang1, Pierre Mesdom1, Eduardo Izquierdo-García1,2
1Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory For Inorganic Chemical Biology, Paris, France.
Abstract:
Immunogenic cell death (ICD), which converts tumor cells into their own vaccine, plays a pivotal role in the development of novel anticancer therapies. Here, a small series of osmium(II) polypyridyl complexes was synthesized, and their biological activity in the dark and upon light irradiation against various cancer cell lines was studied. The compound Os2 (bearing two 4,7-diphenyl-1,10-phenanthrolines and one substituted bipyridine ligand) was discovered to be the most effective photosensitizer (PS) for photodynamic therapy (PDT) of this series through the photogeneration of 1O2 and •OH. In addition, Os2 was found to exhibit promising toxicity upon deep-red irradiation under both normoxia and hypoxia. These observations indicate that this PS is working through a mixture of Type-I and Type-II mechanisms. More interestingly, upon 740 nm irradiation, Os2 can stimulate a strong ICD response on CT26 and MCA205 cells both in vitro and in vivo. A comprehensive immune analysis showed that mice vaccinated with Os2-treated CT26-luc cells boosted the systemic specific adaptive immune responses, including the activation of CD8+ T cells and reprogramming of macrophages, leading to effective inhibition of tumor growth. Os2 is, to the best of our knowledge, the first photoactive osmium-based complex inducing ICD.
Insights
A novel osmium complex, Os2, acts as a potent photosensitizer for photodynamic therapy, effectively inducing immunogenic cell death (ICD) in cancer cells. This discovery offers a new strategy for cancer vaccines by stimulating adaptive immune responses.
Area of Science:
- Materials Science
- Chemical Biology
- Immunology
Background:
- Immunogenic cell death (ICD) is crucial for developing novel anticancer therapies by converting tumor cells into vaccines.
- Osmium(II) polypyridyl complexes are being explored for their therapeutic potential in cancer treatment.
Purpose of the Study:
- To synthesize and evaluate osmium(II) polypyridyl complexes as photosensitizers for cancer therapy.
- To investigate the mechanism of action, including photodynamic therapy (PDT) and immunogenic cell death (ICD) induction.
- To assess the in vitro and in vivo efficacy of the most promising compound.
Main Methods:
- Synthesis of a series of osmium(II) polypyridyl complexes.
- Evaluation of dark toxicity and phototoxicity against various cancer cell lines.
- Mechanism studies involving reactive oxygen species (ROS) generation (Type-I and Type-II pathways).
- In vitro and in vivo assessment of ICD induction and anti-tumor effects using CT26 and MCA205 cell lines.
- Comprehensive immune analysis in mice, including T cell activation and macrophage reprogramming.
Main Results:
- The compound Os2 demonstrated significant phototoxicity via photogeneration of 1O2 and •OH, acting through Type-I and Type-II mechanisms.
- Os2 effectively induced immunogenic cell death (ICD) in CT26 and MCA205 cells upon 740 nm irradiation, both in vitro and in vivo.
- Mice treated with Os2-modified CT26-luc cells showed enhanced systemic adaptive immune responses, including CD8+ T cell activation and macrophage reprogramming.
- Significant inhibition of tumor growth was observed in vivo.
Conclusions:
- Os2 is identified as a highly effective photosensitizer for photodynamic therapy and a potent inducer of immunogenic cell death.
- Os2 represents the first photoactive osmium-based complex capable of inducing ICD, offering a novel platform for cancer immunotherapy.
- The study highlights the potential of Os2 in developing new cancer vaccines and therapies by harnessing the immune system against tumors.
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