Targeted vascular delivery of antisense molecules using intravenous microbubbles

Area of Science:

• Vascular Biology and Regenerative Medicine
• Nanotechnology in Medicine
• Gene Therapy Delivery Systems

Background:

• Neointimal hyperplasia is a significant complication following vascular injury and stenting.
• Targeted delivery of therapeutic agents to sites of endothelial damage is crucial for preventing adverse vascular remodeling.
• The c-myc protooncogene plays a role in cellular proliferation contributing to neointimal formation.

Purpose of the Study:

• To evaluate the efficacy of perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles for targeted delivery of antisense to the c-myc protooncogene (anti-c-myc).
• To assess the potential of this system to prevent neointimal hyperplasia following vascular endothelial injury and stenting.

Main Methods:

• Laser scanning microscopy was used to confirm PESDA microbubble adherence to injured aortic endothelium in mice.
• C-myc expression was quantified in pigs following intracoronary injury and treatment with IV anti-c-myc bound to PESDA.
• Neointimal formation was measured in pigs post-stent deployment comparing anti-c-myc alone versus anti-c-myc bound to PESDA.

Main Results:

• PESDA microbubbles selectively adhered to injured aortic endothelium in mice, with binding reduced by complement depletion.
• Systemic administration of anti-c-myc bound to PESDA significantly reduced c-myc expression at the site of coronary endothelial injury.
• A 33% reduction in stenosis and 28% reduction in intimal area were observed in pigs treated with anti-c-myc bound to PESDA post-stenting.

Conclusions:

• Systemic delivery of anti-c-myc bound to PESDA microbubbles is a promising strategy for preventing neointimal hyperplasia.
• This targeted approach offers potential for reducing restenosis within and around implanted coronary stents.