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Self-Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug-Enzyme

Shanshan Jiang1,2, Bhaskar Gurram1,3, Junfei Zhu1

  • 1Marshall Laboratory of Biomedical Engineering, International Cancer Center, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 21, 2024
PubMed

Insights

A novel prodrug assembly (NTP@GOx) uses glucose oxidase (GOx) to release multiple cancer drugs. This system enhances drug release in the tumor microenvironment (TME) for improved antitumor therapy.

Area of Science:

  • Biomedical Engineering
  • Materials Science
  • Oncology

Background:

  • Endogenous stimuli-responsive prodrugs offer targeted cancer therapy with reduced toxicity.
  • Reactive oxygen species (ROS) alone are insufficient for complete drug release in the tumor microenvironment (TME).

Purpose of the Study:

  • To develop a self-boosting, enzyme-assembled prodrug system for programmable release of multiple therapeutic agents.
  • To enhance drug delivery and efficacy in antitumor therapy by overcoming limitations of ROS-triggered release.

Main Methods:

  • A heterodimeric prodrug (NBS-TK-PTX, NTP) was designed, incorporating a ROS-sensitive thioketal (TK) linker and binding to glucose oxidase (GOx).
  • The NTP@GOx assembly was engineered for inhibited GOx activity, which is recovered upon partial dissociation in the acidic TME.
  • GOx-catalyzed hydrogen peroxide generation triggered TK linker cleavage and drug release, alongside further assembly dissociation.

Main Results:

  • The NTP@GOx assembly demonstrated a self-boosting, multi-step release mechanism in response to TME conditions.
  • GOx activity was initially inhibited by NTP and subsequently recovered and amplified in the TME.
  • The system successfully released paclitaxel (PTX) for chemotherapy and NBS for photodynamic therapy.

Conclusions:

  • The developed ROS-activatable heterodimeric prodrug assembly (NTP@GOx) enables programmable, self-boosting release of multiple anticancer agents.
  • This approach shows significant potential for multimodal synergistic cancer therapy by enhancing drug delivery and efficacy.
Keywords:
antitumor therapyglucose oxidaseheterodimeric prodrugreactive oxygen speciesself‐boosted programmable release

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