Multifunctional RNA G-Quadruplex Ligand for Integrated Photodynamic Therapy and Oncoprotein Translation Inhibition in...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Immunotherapy

Background:

• RNA G-quadruplexes (rG4s) are emerging targets in cancer therapy.
• Photosensitizers offer a distinct approach by combining molecular targeting and photodynamic activity.
• Developing agents for combined photodynamic therapy and immunomodulation is a key goal in oncology.

Purpose of the Study:

• To design and evaluate TO-ISe, a novel selenium-containing photosensitizer targeting rG4s.
• To investigate the dual-functionality of TO-ISe in photodynamic therapy and immunomodulation.
• To assess the therapeutic efficacy of TO-ISe in preclinical cancer models.

Main Methods:

• Synthesis and characterization of the selenium-containing photosensitizer TO-ISe.
• In vitro assessment of rG4 binding affinity, photodynamic activity, and cytotoxicity.
• Evaluation of TO-ISe's effects on oncogene suppression, cell death pathways, and immune activation.
• In vivo efficacy studies using an orthotopic 4T1 tumor model.

Main Results:

• TO-ISe demonstrated high affinity for rG4s and potent Type I photodynamic activity.
• Selective phototoxicity was observed in cancer cells with significantly lower toxicity in nonmalignant cells.
• Under dark conditions, TO-ISe induced mitochondrial dysfunction, ferroptosis, and apoptosis by suppressing oncogenes.
• Upon irradiation, TO-ISe enhanced antiproliferative effects and activated the cGAS-STING pathway, inducing immunogenic cell death.
• In vivo, TO-ISe with irradiation achieved significant tumor growth inhibition (72.8%) in a 4T1 model.

Conclusions:

• TO-ISe is a potent dual-function agent for photodynamic therapy and immunomodulation.
• Targeting rG4s with TO-ISe offers a promising strategy for cancer treatment.
• The findings support TO-ISe's potential as a novel photodynamic immunotherapeutic agent.