Antineoplastic Enzyme as Drug Carrier with Activatable Catalytic Activity for Efficient Combined Therapy

Area of Science:

• Biomaterials Science
• Nanotechnology
• Drug Delivery

Background:

• Traditional glucose oxidase (GOx) delivery faces challenges with carrier leakage and enzyme exposure.
• Inhibiting GOx's catalytic activity in circulation is crucial for safe systemic administration.
• Developing self-carrier systems for enzymes like GOx is a promising therapeutic strategy.

Purpose of the Study:

• To develop glucose oxidase (GOx) as a self-carrier for targeted drug delivery.
• To investigate the self-assembly of GOx with hydrophobic molecules into stable nanoparticles (NPs).
• To evaluate the acidity-triggered release and reactivation of GOx within the tumor microenvironment.

Main Methods:

• Self-assembly of GOx with hydrophobic drugs (sorafenib, paclitaxel, cyanin derivatives) into uniform nanoparticles.
• Assessment of GOx catalytic activity inhibition within NPs due to hydrophobic pocket binding.
• Evaluation of GOx activity recovery in acidic tumor microenvironments.
• In vivo studies on 4T1 breast tumor models using combined therapies.

Main Results:

• GOx successfully self-assembled with hydrophobic molecules into stable, uniform nanoparticles.
• Nanoparticle formation significantly inhibited GOx catalytic activity in vitro.
• Acidity in the tumor microenvironment triggered GOx dissociation and largely recovered enzyme activity.
• Combined starvation, ferroptosis, photothermal, and chemotherapy using GOx-NPs effectively inhibited tumor growth in vivo.

Conclusions:

• GOx can function as a self-carrier, forming stable nanoparticles with hydrophobic drugs.
• The "OFF-to-ON" acidity-triggered enzyme activity switch ensures safe intravenous administration.
• This novel approach offers a potent strategy for combined cancer therapy, including starvation and ferroptosis induction.