Light-Activatable Nitric Oxide Release via Intramolecular Electron Transfer for Tumor Pyroptosis Induction

Area of Science:

• Biomedical Engineering
• Photodynamic Therapy
• Cancer Research

Background:

• Developing long-wavelength-activated nitric oxide (NO) donors is crucial for deep tissue penetration and reduced phototoxicity in phototherapy.
• Current methods face challenges in precise photo-controlled NO release.

Purpose of the Study:

• To report a novel deep-red light-triggered NO-releasing molecule (DBTBT-NO) for enhanced cancer therapy.
• To investigate a new photoexcitation-mediated electron transfer mechanism for peroxynitrite generation.

Main Methods:

• Synthesized and characterized DBTBT-NO, a benzisothiadiazole-based N-nitrosaniline derivative.
• Utilized deep-red light activation to induce photoinduced intramolecular charge separation and NO release.
• Investigated the reaction of NO with superoxide anions to form peroxynitrite within mitochondria.

Main Results:

• DBTBT-NO efficiently releases NO and generates abundant peroxynitrite upon deep-red light irradiation (15 J/cm², 0.4 µm).
• The generated peroxynitrite effectively induces tumor cell pyroptosis, inhibiting tumor growth and metastasis in vivo.
• Demonstrated excellent biosafety of the DBTBT-NO treatment in preclinical models.

Conclusions:

• This study presents a novel mechanism for generating peroxynitrite via long-wavelength photolysis of benzisothiadiazole-based N-nitrosanilines.
• DBTBT-NO serves as a promising unimolecular peroxynitrite photoinitiator for photoimmunotherapy.
• The findings facilitate simplified and improved phototherapy strategies for cancer treatment.