Targeted In Vivo Labeling of Receptors for Vascular Endothelial Growth Factor

Abstract

Background— A method for identifying tissue experiencing hypoxic stress due to atherosclerotic vascular disease would be clinically useful. Vascular endothelial growth factor-121 (VEGF 121 ) 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 VEGF 121 . 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 111 In-labeled recombinant human VEGF 121 , and biodistribution studies and planar imaging were conducted at 3, 24, and 48 hours. On postmortem gamma counting, there was greater accumulation of 111 In-labeled VEGF 121 in ischemic than in control tissue ( P <0.02). Differential uptake of isotope by ischemic muscle was not seen in rabbits injected with 125 I-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.

How molecular imaging is speeding up antiangiogenic drug development

“…Recombinant human VEGF 121 has been labeled with 111 In for identification of ischemic tissue in a rabbit model, where unilateral hind limb ischemia was created by femoral artery excision (18). However, virtually no difference was observed between the ischemic hind limb and the contralateral hind limb.…”

“…It was found that antibody distribution and clearance were quite heterogeneous not only between patients but also between individual tumors of the same patient, suggesting that intra-patient dose escalation approaches or more precisely defined patient cohorts would be preferred in the design of phase I studies with antiangiogenic antibodies such as HuMV833. 18 F for PET imaging applications as good tumor-to-background ratio was achieved as early as 1 to 2 hours after injection.…”

“…Monomeric RGD peptide c(RGDyV) was first labeled with 125 I by Haubner et al (48). A glycopeptide based on c(RGDfK) was later labeled with 18 F via a 2-[ 18 F]fluoropropionate prosthetic group, and the resulting [ 18 F]galacto-RGD exhibited integrin a v h 3 -specific tumor uptake in integrin-positive M21 melanoma xenograft model (49). Initial clinical trials in healthy volunteers and a limited number of cancer patients revealed that this tracer can be safely given to patients and is able to delineate certain lesions that are integrin positive ( Fig.…”

“…We have labeled a series of RGD peptides with 18 F for PET imaging, using PEGylation and polyvalency to improve the tumor-targeting efficacy and pharmacokinetics (51 -56). Fig.…”

“…In addition to 18 F, 64 Cu-labeled RGD peptides are also of considerable interest. Copper-64 is an attractive radionuclide for both PET imaging and targeted radiotherapy of cancer.…”