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An Endocellulase-Triggered NO Targeted-Release Enzyme-Prodrug Therapy System and Its Application in Ischemia Injury

Bo He1, Yating Zhang2, Huaping Liu3

  • 1State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.

Advanced Healthcare Materials
|July 8, 2024
PubMed

Insights

This study introduces a novel enzyme-prodrug therapy for controlled nitric oxide (NO) delivery. The system uses a specific enzyme to activate a prodrug, showing promise for treating diseases like ischemia and inflammation.

Area of Science:

  • Biomedical Engineering
  • Drug Delivery Systems
  • Enzyme-Prodrug Therapy

Background:

  • Nitric oxide (NO) is vital for physiological processes, and its controlled delivery is key for treating diseases.
  • Existing enzyme-prodrug therapy (EPT) systems face challenges with nonspecific release and metabolic side effects.
  • Targeted NO release is crucial for effective therapeutic outcomes in various conditions.

Purpose of the Study:

  • To develop a novel, orthogonal EPT system for precise nitric oxide (NO) delivery.
  • To utilize a specific endocellulase (Cel5A-h38) and a novel prodrug (Cel2-NO) for targeted activation.
  • To evaluate the therapeutic efficacy of this system in a preclinical model of hindlimb ischemia.

Main Methods:

  • A novel cellobioside-diazeniumdiolate (Cel2-NO) prodrug was synthesized.
  • An endocellulase (Cel5A-h38) from a rumen bacterium was employed for prodrug activation.
  • Orthogonality was assessed against endogenous enzymes, and in vivo imaging was used to track drug release.
  • Therapeutic effects were evaluated in a mouse hindlimb ischemia model.

Main Results:

  • The Cel2-NO prodrug demonstrated high stability against endogenous enzymes, ensuring specificity.
  • Cel5A-h38 selectively activated the Cel2-NO prodrug without affecting natural substrates.
  • In vivo imaging confirmed targeted drug release.
  • The EPT system significantly reduced ischemic damage, improved ambulation, modulated inflammation, and enhanced tissue repair in the ischemia model.

Conclusions:

  • The developed EPT system offers a highly specific and targeted approach for NO delivery.
  • This novel system overcomes limitations of existing EPTs, showing significant therapeutic potential.
  • The system is broadly applicable for treating cardiovascular diseases, tumors, and inflammation-related disorders through controlled drug delivery.
Keywords:
endocellulaseenzyme‐prodrug therapynitric oxidetargeted delivery

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