Nonemissive Iridium(III) Solvent Complex as a Self-Reporting Photosensitizer for Monitoring Phototherapeutic Efficacy in a 'Signal On' Mode

Analytical Chemistry Chemistry Medicinal Chemistry Oncology Medicine Biochemistry Life Sciences
Iridium(III) solvent complex Self-reporting photosensitizer Phototherapeutic efficacy Signal on Immunogenic cell death

Iridium(III) Solvent Complex as a Self-Reporting Photosensitizer for Monitoring Phototherapeutic Efficacy

Academic Background

Cancer is one of the leading causes of global mortality, significantly impacting patients’ quality of life. In recent years, photodynamic therapy (PDT) has garnered considerable attention as a promising technology for cancer treatment due to its non-invasive nature, high specificity, controllability, and high spatiotemporal precision. PDT works by using photosensitizers (PSs) to generate highly cytotoxic reactive oxygen species (ROS) upon light irradiation, thereby inducing cancer cell death. However, conventional photosensitizers typically exhibit “always-on” fluorescence signals, making it challenging to monitor therapeutic efficacy in real-time during the PDT process. Therefore, the development of new photosensitizers with both effective photodynamic therapy performance and self-reporting capabilities has become a focal point of current research.

This study aims to address this issue by designing and synthesizing two non-emissive iridium(III) solvent complexes, exploring their potential in PDT, and enabling real-time monitoring of phototherapeutic efficacy.

Source of the Paper

This paper was co-authored by Manping Qian, Ke Wang, Peng Yang, Yu Liu, Meng Li, Chengxiao Zhang, and Honglan Qi from the Key Laboratory of Analytical Chemistry for Life Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University. The paper was published on August 1, 2024, in the journal Chemical & Biomedical Imaging, titled Nonemissive Iridium(III) Solvent Complex as a Self-Reporting Photosensitizer for Monitoring Phototherapeutic Efficacy in a “Signal On” Mode.

Research Process and Results

1. Design and Synthesis of Photosensitizers

The research team designed and synthesized two non-emissive iridium(III) solvent complexes: [(dfppy)2Ir(dmso)]Cl (Ir-DMSO) and [(dfppy)2Ir(acn)]Cl (Ir-ACN). Here, dfppy stands for 2,4-difluorophenylpyridine, dmso for dimethyl sulfoxide, and acn for acetonitrile. These complexes were synthesized through a two-step reaction, first forming the chloro-bridged iridium(III) dimer [(dfppy)2Ir(μ-Cl)]2 (Ir1), which was then reacted with dmso or acn to produce the target compounds.

2. Photophysical and Biological Properties

The team conducted a detailed study of the photophysical properties of Ir-DMSO and Ir-ACN. The results showed that both complexes exhibit strong absorption bands in the 230-340 nm range and weak absorption bands in the 340-470 nm range. Their molar extinction coefficients were 6.84×10^4 M^-1 cm^-1 (Ir-DMSO) and 5.53×10^4 M^-1 cm^-1 (Ir-ACN), higher than many reported photosensitizers. Additionally, both complexes showed weak photoluminescence (PL) emission with quantum yields below 0.01%.

In cytotoxicity experiments, the IC50 values of Ir-DMSO and Ir-ACN in the dark were 118.8 μM and 81.3 μM, respectively, while under light irradiation (20 mW/cm^2, 10 minutes), the IC50 values dropped to 7.7 μM and 6.4 μM. Due to its lower dark toxicity, Ir-DMSO was selected for further PDT studies.

3. Study of Self-Reporting Function

Under light irradiation, Ir-DMSO not only killed cancer cells but also self-reported cell death through enhanced PL emission. Colocalization experiments revealed that Ir-DMSO primarily accumulated in the endoplasmic reticulum and mitochondria. Upon light exposure, Ir-DMSO generated ROS and enabled real-time monitoring of phototherapeutic efficacy through specific coordination reactions with histidine (His) or His-containing proteins.

4. Investigation of Immunogenic Cell Death

The team further investigated the mode of cell death induced by Ir-DMSO during PDT and found that it could trigger immunogenic cell death (ICD). Hallmarks of ICD include ROS generation, upregulation of surface-exposed calreticulin (CRT), secretion of high-mobility group box 1 (HMGB1), and adenosine triphosphate (ATP). These results indicate that Ir-DMSO not only exhibits photodynamic therapeutic effects but also activates immune responses through ICD.

5. Validation of Self-Feedback Mechanism

Through experiments, the team validated the self-feedback mechanism of Ir-DMSO. Under light irradiation, the enhanced PL signal of Ir-DMSO synchronized with the cell death process, demonstrating its ability to monitor phototherapeutic efficacy in real-time. Additionally, the team found that the PL signal enhancement of Ir-DMSO primarily resulted from interactions with intracellular histidine or His-containing proteins.

Conclusion and Significance

This study successfully designed and synthesized two non-emissive iridium(III) solvent complexes, with Ir-DMSO demonstrating excellent photodynamic therapeutic effects and self-reporting capabilities. Under light irradiation, Ir-DMSO not only generated ROS to induce cell death but also enabled real-time monitoring of therapeutic efficacy through PL signal enhancement. Furthermore, the study revealed the mechanism of Ir-DMSO-induced immunogenic cell death, providing a new strategy for precise PDT.

Research Highlights

  1. Novel Photosensitizer Design: By introducing organic solvents as auxiliary ligands, iridium(III) solvent complexes with self-reporting capabilities were synthesized.
  2. Real-Time Monitoring of Phototherapeutic Efficacy: Ir-DMSO enabled real-time monitoring of cell death through PL signal enhancement under light irradiation, without the need for additional signal probes.
  3. Immunogenic Cell Death: The study uncovered the ICD mechanism induced by Ir-DMSO, offering new insights into immune therapy in PDT.

Future Prospects

Although Ir-DMSO shows great potential in PDT, its strong blue-light absorption limits its application in deep tissues. Future research will focus on developing near-infrared self-reporting photosensitizers based on iridium(III) complexes to further enhance the clinical application value of PDT.

This research provides new insights into the precise treatment of photodynamic therapy, showcasing the immense potential of self-reporting photosensitizers in cancer treatment. By enabling real-time monitoring of phototherapeutic efficacy, researchers can better control the treatment process, reducing the risks of overtreatment or delayed treatment.