Intravascular ultrasound detection and delivery of molecularly targeted microbubbles for gene delivery

Abstract

We have investigated microbubble based targeted delivery and combined intravascular ultrasound (IVUS) imaging as potential therapy to reduce incidence of restenosis following stent placement in atherosclerotic coronary arteries. The goal of these studies was to determine whether IVUS could be used to detect targeted microbubbles and enhance drug/gene delivery through targeting. Fluorescently labeled microbubbles targeted to the inflammatory cell surface marker VCAM-1 were combined with cells under flow to measure adhesion compared to control bubbles. Gene delivery was performed using targeted bubble constructs and 1MHz ultrasound at 200 and 300 kPa - acoustic pressures which can be generated by a modified commercial IVUS catheter. Detection of adherent microbubbles to inflamed cells in culture and flow chambers was measured using a clinical IVUS catheter. VCAM-1 targeted microbubbles enhanced adhesion to inflamed cells up to 100 fold over non-targeted microbubbles. Compared to non-inflamed cells VCAM-1 targeted bubbles exhibited a 7.9 fold increase in adhesion to IL-1beta treated cells. Targeted microbubbles resulted in a 5.5 fold increase in plasmid DNA transfection over non targeted bubbles in conjunction with a focused 1-inch diameter 1MHz transducer and 1.5 fold increase following insonation from a fabricated IVUS transducer at 1.5 MHz. At an equivalent density of 3×10 ⁴ bubbles/mm ² , IVUS image intensity increased 4.3 fold over that of non-bubble-coated surfaces. Rupture of microbubbles from the modified IVUS transducer resulted in a 53% reduction in image intensity. Taken together, these results indicate IVUS may be used to detect targeted microbubbles to inflamed vasculature and subsequently deliver a gene/drug locally.