Development of a Light-Triggered Biotin-Bioorthogonal System for Targeted Anti-Tumor Therapy.

Area of Science:

• Biomedical Engineering
• Chemical Biology
• Drug Delivery Systems

Background:

• Conventional bioorthogonal reactions, like tetrazine (TZ) and trans-cyclooctene (TCO) coupling, often lack precise control, limiting their application in drug delivery.
• Uncontrolled bioorthogonal reactions can lead to suboptimal drug release and potential off-target toxicity.

Purpose of the Study:

• To design and validate a novel light-triggered bioorthogonal system for spatiotemporal control over drug delivery.
• To improve the efficacy and reduce the toxicity of chemotherapy drugs, specifically DOX, through a controlled release mechanism.

Main Methods:

• Development of a light-sensitive bioorthogonal system involving T-1B, T-2B, and TCO-conjugated molecules.
• Utilizing blue LED irradiation to trigger the release of T-2B from T-1B.
• Conjugating TCO with imaging probes (TCO-Cy5.5) and a prodrug (TCO-DOX) for simultaneous bioimaging and chemotherapy.

Main Results:

• Blue LED irradiation (2 min, 20 W) efficiently released T-2B from T-1B.
• TCO-DOX demonstrated enhanced cell permeability and higher intracellular concentrations in vitro and in vivo.
• DOX-mediated chemoimmunotherapy showed tumor-specific accumulation, potent inhibition of cell proliferation, and enhanced anti-tumor immune response in cellular and animal models.

Conclusions:

• The developed light-triggered bioorthogonal system offers precise spatiotemporal control for drug delivery.
• This strategy effectively overcomes the efficacy and toxicity limitations associated with conventional DOX-mediated chemoimmunotherapy.
• The system presents a feasible and effective therapeutic regimen for cancer treatment, improving drug targeting and anti-tumor immunity.