¹³¹I Induced In Vivo Proteolysis by Photoswitchable azoPROTAC Reinforces Internal Radiotherapy

Area of Science:

• Radiochemistry
• Pharmacology
• Oncology

Background:

• Photopharmacology offers spatiotemporal control of drug activity using light-sensitive molecules.
• Current limitations include UV light's poor tissue penetration, hindering in vivo applications.
• Radioisotopes offer a potential alternative trigger for photoswitchable drugs.

Purpose of the Study:

• To investigate the use of iodine-131 (¹³¹I) as a trigger for photoswitchable drugs.
• To evaluate the efficacy of ¹³¹I-triggered azoPROTAC in protein degradation and cancer therapy.
• To explore the potential of radioisotope-triggered photopharmacology for deep-tissue applications.

Main Methods:

• Synthesized and utilized an azobenzene-containing Proteolysis Targeting Chimera (azoPROTAC).
• Assessed ¹³¹I-induced trans-cis photoisomerization and protein degradation (BRD4, c-Myc) in 4T1 cells.
• Evaluated in vivo tumor growth inhibition, radiotherapy enhancement, and immunological effects in a 4T1 tumor-bearing mouse model.

Main Results:

• ¹³¹I successfully triggered azoPROTAC isomerization, leading to BRD4 and c-Myc degradation comparable to light irradiation.
• Co-administration of ¹³¹I and azoPROTAC inhibited tumor growth in mice.
• Enhanced radiotherapy and anti-tumor immunological effects were observed with the combined treatment.

Conclusions:

• Radioisotope-triggered photopharmacology is feasible and effective in a preclinical mouse model.
• ¹³¹I can serve as a viable trigger for photoswitchable drugs, overcoming UV light penetration limitations.
• This approach holds promise for advancing photopharmacology in deep tissues and improving cancer therapy.