Catalytic olefin metathesis in blood

Area of Science:

• Bioconjugate Chemistry
• Catalysis
• Drug Delivery

Background:

• Direct in vivo drug synthesis offers targeted disease treatment with reduced side effects.
• Transition-metal catalysis is promising for in vivo drug synthesis but faces deactivation by blood components.
• Developing robust catalysts that function effectively in biological environments remains a challenge.

Purpose of the Study:

• To develop a stable artificial metalloenzyme (ArM) capable of catalyzing drug synthesis directly in blood.
• To demonstrate the efficacy of ArM-mediated olefin metathesis for in vivo synthesis of molecular scaffolds and an antitumor drug.
• To evaluate the therapeutic potential of ArM in inhibiting tumor growth in vivo.

Main Methods:

• Design and synthesis of a robust albumin-based artificial metalloenzyme (ArM).
• Evaluation of ArM stability and catalytic activity in blood, including olefin cross-metathesis.
• Functionalization of ArM with cyclic-Arg-Gly-Asp (cRGD) peptide for targeted delivery.
• Assessment of in vivo antitumor efficacy in mouse models.

Main Results:

• The albumin-based ArM demonstrated high stability, retaining activity after 24 hours in blood.
• Achieved the first example of catalytic olefin cross-metathesis directly in blood.
• Functionalized ArM efficiently synthesized an antitumor drug in vivo.
• cRGD-ArM significantly inhibited tumor growth in mice at lower dosages.

Conclusions:

• Albumin-based ArMs provide a robust platform for in vivo drug synthesis via transition-metal catalysis in blood.
• This approach enables targeted therapeutic drug construction in vivo, offering a potential strategy for side-effect-free therapies.
• The developed ArM system holds promise for advancing cancer treatment and other diseases requiring localized drug action.