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Photodynamic enhancement of PROTAC prodrug activation in hypoxic tumors

Zhongliang Fu1,2,3, Chunrong Yang2,3, Yuchen Yang2,3

  • 1School of Biomedical Sciences, Hunan University, Changsha 410082, China.

Acta Pharmaceutica Sinica. B
|October 6, 2025
PubMed

Insights

This study introduces a novel prodrug strategy that uses light-activated photodynamic therapy (PDT) to enhance the targeted degradation of cancer cells by proteolysis-targeting chimeras (PROTACs), improving efficacy and reducing toxicity.

Area of Science:

  • Biochemistry
  • Oncology
  • Drug Delivery

Background:

  • Proteolysis-targeting chimeras (PROTACs) offer targeted protein degradation but face challenges with off-target toxicity.
  • Prodrug strategies are being explored to improve PROTAC delivery and specificity.

Purpose of the Study:

  • To develop a light-induced positive feedback system for PROTAC prodrug activation and monitoring.
  • To enhance the antitumor efficacy of PROTACs while mitigating systemic toxicity.

Main Methods:

  • A prodrug (AZO-PRO) was designed with an azo bond that cleaves in hypoxic tumor environments, releasing a PROTAC and a photosensitizer.
  • Photodynamic therapy (PDT) using near-infrared (NIR) laser was employed to exacerbate tumor hypoxia and promote prodrug activation.
  • Fluorescence recovery of the photosensitizer was used to monitor prodrug activation.

Main Results:

  • The azo bond in AZO-PRO selectively cleaved in hypoxic conditions, releasing the active components.
  • PDT enhanced AZO-PRO activation by worsening tumor hypoxia, creating a positive feedback loop.
  • Prodrug activation was successfully monitored via fluorescence signal recovery.

Conclusions:

  • This novel approach enables efficient tracking and activation of PROTAC prodrugs.
  • The combination of PROTACs and PDT enhances antitumor efficacy.
  • The strategy shows promise in mitigating off-target systemic toxicity of PROTACs.
Keywords:
Fluorescence imagingHypoxia-activatedNear-infrared laser irradiationPROTACsPhotodynamic therapyProdrugsProtein degradationTumors

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