A Cathepsin B-Triggered CO-Releasing Molecule with a Non-Toxic Metal Core for Targeted Tumor Delivery

Area of Science:

• Biomedical Engineering
• Cancer Therapeutics
• Drug Delivery Systems

Background:

• Carbon monoxide (CO) exhibits therapeutic potential, particularly in cancer treatment.
• Current CO-releasing molecules (CORMs) face limitations in clinical translation due to stability, toxicity, and targeting issues.

Purpose of the Study:

• To synthesize and characterize a novel enzyme-triggered CO-releasing molecule (ET-CORM) for antibody conjugation.
• To enable site-specific and targeted delivery of CO to cancer cells.

Main Methods:

• Developed an ET-CORM based on a biocompatible iron core, releasing CO upon cathepsin B (CatB) cleavage.
• Utilized a bioorthogonal handle for efficient, site-specific conjugation of ET-CORM to trastuzumab antibodies.
• Characterized the ET-CORM-antibody conjugate (ET-CORM-Ab) for drug-to-antibody ratio (DAR) and CO loading.

Main Results:

• Successfully synthesized and characterized the ET-CORM-Ab conjugate with a DAR of 6.8 (approx. 20 CO molecules per conjugate).
• Demonstrated selective intracellular CO delivery to HER2-overexpressing and CatB-expressing cancer cells in vitro.
• Validated the enzyme-triggered release mechanism activated by the tumor-associated protease CatB.

Conclusions:

• This study presents a metal-based CORM-antibody conjugate activated by a tumor-associated enzymatic trigger.
• The developed ET-CORM-Ab conjugate offers a promising platform for targeted CO delivery in cancer therapy.
• Opens new avenues for investigating CO-mediated effects and advancing CO-based cancer treatments.