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EXPERIMENTAL STUDIES

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

Debabrata Mukherjee, MD^*, James Wong, MD, PhD^*, Brian Griffin, MD^*, Stephen G. Ellis, MD^*, Thomas Porter, MD, Subha Sen, PhD^* and James D. Thomas, MD, FACC^*

^* Cardiovascular Imaging Center, Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
Department of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

Manuscript received February 19, 1999; revised manuscript received November 18, 1999, accepted January 12, 2000.

Reprint requests and correspondence: Dr. James D. Thomas, Department of Cardiology, Desk F15, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195.
thomasj{at}cesmtp.ccf.org

OBJECTIVES

In this study, the feasibility of delivering and enhancing the uptake of vascular endothelial growth factor (VEGF) into the intact endothelium by using ultrasound (US) facilitation was determined.

BACKGROUND

A limitation of tissue-targeted drug delivery is the need for direct arterial cannulation. We postulate a mechanism by which agents injected intravenously may be targeted to a tissue using US and ultrasonic contrast agents.

METHODS

We used a rat model to test the ability of US and an ultrasonic contrast agent perflurocarbon exposed sonicated dextrose albumin (PESDA) to increase uptake of VEGF in the myocardium. Continuous wave Doppler US (0.6 W/cm² at 1 MHz for 15 min) was applied to the chest wall overlying the myocardium during intravenous injection with either VEGF (100 µg/kg) alone or a combination of VEGF and PESDA (0.1%). Control rats had VEGF infused without US or PESDA. The VEGF uptake was measured quantitatively in the heart, lung, liver and kidneys by enzyme-linked immunosorbent assay (ng/g of tissue) 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 revealed deposition of VEGF in the endothelium of small intramyocardial arterioles.

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 uptake 10-fold to 13-fold.

Abbreviations and Acronyms   CABG = coronary artery bypass grafting   ELISA = enzyme-linked immunosorbent assay   FITC = fluorescein isothiocyanate   KHB = Krebs-Henseleit bicarbonate   PBS = phosphate buffered saline   PCNA = proliferating cells   PESDA = perfluorocarbon-exposed sonicated dextrose albumin   PTCA = percutaneous transluminal coronary angioplasty   rhVEGF = recombinant human VEGF   US = ultrasound   VEGF = vascular endothelial growth factor   vWF = von Willibrand factor

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