Ten-fold augmentation of endothelial uptake of vascular endothelial growthfactor with ultrasound after systemic administration

OBJECTIVES In this study, the feasibility of delivering and enhancing the u ptake of vascular endothelial growth factor (VEGF) into the intact endothel ium by using ultrasound (US) facilitation was determined. BACKGROUND A limitation of tissue-targeted drug delivery is the need for di rect arterial cannulation. We postulate a mechanism by which agents injecte d intravenously may be targeted to a tissue using US and ultrasonic contras t agents. METHODS We used a rat model to test the ability of US and an ultrasonic con trast agent perflurocarbon exposed sonicated dextrose albumin (PESDA) to in crease uptake of VEGF in the myocardium. Continuous wave Doppler US (0.6 W/ cm(2) at 1 MHz for 15 min) was applied to the chest wall overlying the myoc ardium during intravenous injection with either VEGF (100 mu g/kg) alone or a combination of VEGF and PESDA (0.1%). Control rats had VEGF infused with out US or PESDA. The VEGF uptake was measured quantitatively in the heart, lung, liver and kidneys by enzyme-linked immunosorbent assay (ng/g of tissu e) and morphologically by fluorescence microscopy. RESULTS There was an eight-fold increase in VEGF uptake in the heart by US alone (16.86 +/- 1.56 vs. 2.11 +/- 0.953 ng/g of tissue, p < 0.0001) and a 13-fold increase with US + PESDA (26.78 +/- 2.88 vs. 2.11 +/- 0.953 ng/g of tissue, p < 0.0001) compared with control rats. Fluorescence microscopy re vealed deposition of VEGF in the endothelium of small intramyocardial arter ioles. CONCLUSIONS These results show a marked increase in endothelial VEGF uptake with US and US + PESDA. Thus, US may be used to augment endothelial VEGF u ptake 10-fold to 13-fold. (C) 2000 by the American College of Cardiology.