Published Online
on June 23, 2003

A more recent version of this article appeared on July 8, 2003

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Submitted on January 13, 2003
Revised on March 14, 2003
Accepted on March 26, 2003

Targeted In Vivo Labeling of Receptors for Vascular Endothelial Growth Factor. Approach to Identification of Ischemic Tissue

Erxiong Lu MD, William R. Wagner PhD, Ute Schellenberger PhD, Judith A. Abraham PhD, Alexander L. Klibanov PhD, Steven R. Woulfe PhD, Melissa M. Csikari BS, David Fischer BS, George F. Schreiner MD, Gary H. Brandenburger PhD, and Flordeliza S. Villanueva MD^*

From the University of Pittsburgh (E.L., W.R.W., M.M.C., D.F., F.S.V.), Cardiovascular Institute and Department of Bioengineering, Pittsburgh, Pa; Scios Inc (U.S., J.A.A., G.F.S.), Sunnyvale, Calif; and Mallinckrodt Inc (A.L.K., S.R.W., G.H.B.), St Louis, Mo.

^* To whom correspondence should be addressed. E-mail: villanuevafs{at}msx.upmc.edu.

Background--A method for identifying tissue experiencing hypoxic stress due to atherosclerotic vascular disease would be clinically useful. Vascular endothelial growth factor-121 (VEGF₁₂₁) is an angiogenic protein secreted in response to hypoxia that binds to VEGF receptors overexpressed by ischemic microvasculature. We tested the hypothesis that VEGF receptors could serve as markers for ischemic tissue and hence provide a target for imaging such tissue with radiolabeled human VEGF₁₂₁.

Methods and Results--A rabbit model of unilateral hindlimb ischemia was created by femoral artery excision (n=14). Control rabbits (n=5) underwent identical surgery without femoral excision. On postoperative day 10, rabbits were intravenously administered 100 µCi of ¹¹¹In-labeled recombinant human VEGF₁₂₁, and biodistribution studies and planar imaging were conducted at 3, 24, and 48 hours. On postmortem gamma counting, there was greater accumulation of ¹¹¹In-labeled VEGF₁₂₁ in ischemic than in control tissue (P<0.02). Differential uptake of isotope by ischemic muscle was not seen in rabbits injected with ¹²⁵I-labeled human serum albumin (n=6). Radioactivity imaged in hindlimb regions of interest was significantly higher in ischemic muscle than in sham-operated and contralateral nonoperated hindlimb at 3 hours (P<0.02). Immunohistochemical staining confirmed upregulation of VEGF receptors in ischemic skeletal muscle.

Conclusions--Identification of the ischemic state via targeted radiolabeling of hypoxia-induced angiogenic receptors is possible. This approach could be useful for monitoring the efficacy of revascularization strategies such as therapeutic angiogenesis.

Key words: angiogenesis • hypoxia • imaging • isotopes • receptors

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