Photodynamic enhancement of PROTAC prodrug activation in hypoxic tumors.
10.1016/j.apsb.2025.07.020
- Author:
Zhongliang FU
1
;
Chunrong YANG
2
;
Yuchen YANG
2
;
Meichen PAN
1
;
Hongwei HOU
2
;
Jinghong LI
1
Author Information
1. School of Biomedical Sciences, Hunan University, Changsha 410082, China.
2. Beijing Life Science Academy, Beijing 102209, China.
- Publication Type:Journal Article
- Keywords:
Fluorescence imaging;
Hypoxia-activated;
Near-infrared laser irradiation;
PROTACs;
Photodynamic therapy;
Prodrugs;
Protein degradation;
Tumors
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4945-4960
- CountryChina
- Language:English
-
Abstract:
Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic strategy for targeted protein degradation. However, the clinical application of PROTACs may be hindered by off-target toxicity resulting from non-tissue-specific protein degradation and ingenious prodrug strategies may open new avenues to addressing this concern. Herein, we propose a light-induced positive feedback strategy to use photodynamic therapy (PDT) to improve the activation efficiency of PROTAC prodrugs, monitor PROTAC release, and combine PROTAC to induce tumor cell apoptosis. In the hypoxic tumor microenvironment, the azo bond in AZO-PRO selectively cleaves, triggering the release of the potent protein degrader PRO and the multifunctional photosensitizer. Once activated, the fluoresce signal of the photosensitizer dramatically recovers, allowing monitoring of prodrug activation. Additionally, upon irradicating the tumor site using near-infrared (NIR) laser, PDT exacerbates tumor hypoxia, further promoting AZO-PRO activation. Our work introduces a novel approach to efficiently track and activate PROTAC prodrugs, enhance their antitumor efficacy, and mitigate off-target systemic toxicity.
