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Radiolabeled RGD Uptake and _v Integrin Expression Is Enhanced in Ischemic Murine Hindlimbs

¹ Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
² Department of Chemistry, College of Medicine, Inha University, Inchun, Korea
³ Department of Anatomy, College of Medicine, Inha University, Inchun, Korea

Radiolabeled RGD peptides that target _vß₃ integrin are promising tracers for imaging tumor angiogenesis. Integrins and angiogenesis also play important roles in healing of ischemic lesions. Thus, we investigated the biodistribution of radiolabeled RGD and expression of _v integrin in a mouse model of hindlimb ischemia. Methods: ¹²⁵I-3-Iodo-D-Tyr⁴-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) (¹²⁵I-c(RGD(I)yV)) was synthesized and tested for endothelial binding. Hindlimb ischemia was induced in ICR mice through femoral artery ablation, and perfusion was measured with laser Doppler blood flowmetry. ¹²⁵I-c(RGD(I)yV) biodistribution was evaluated in control animals (n = 7) and ischemic models on day 3, 8, or 14 (n = 6 each). Control experiments were performed using a radiolabeled peptide with a scrambled amino acid sequence (¹²⁵I-GfVGV). Microsections of hindlimb tissue were immunostained for _v integrin expression and stained with alkaline phosphatase to localize vascular endothelial cells. Results: ¹²⁵I-c(RGD(I)yV) retained specific binding to human umbilical vein endothelial cells. Perfusion in ischemic hindlimbs immediately fell to 10% ± 4% of contralateral levels and gradually recovered to 22% ± 11% and 64% ± 9% on days 8 and 14, respectively. ¹²⁵I-c(RGD(I)yV) uptake in ischemic muscles significantly increased from a control level of 0.16 ± 0.05 %ID/g (percentage injected dose per gram of tissue) to 0.85 ± 0.76 %ID/g at day 3, 0.43 ± 0.23 %ID/g at day 8, and 0.43 ± 0.28 %ID/g at day 14 (all P < 0.05). Ischemic muscle-to-lung count ratios had a virtually identical trend: 0.42 ± 0.25 for controls, 2.34 ± 1.70 at day 3 (P < 0.02), 1.46 ± 0.52 at day 8 (P < 0.001), and 1.39 ± 0.94 at day 14 (P < 0.02). In contrast, uptake of the control peptide in ischemic hindlimbs was not different from that of controls. Immunohistochemistry revealed substantially increased _v integrin staining in ischemic hindlimb tissue. Conclusion: Radioiodine RGD uptake is significantly enhanced in ischemic hindlimbs of a mouse model, and is accompanied by an increase in _v integrin expression. Further investigation is thus warranted to illuminate the potential role of radiolabeled RGD for noninvasive monitoring of peripheral ischemic lesions.

Key Words: RGD peptides • integrin • ischemia • angiogenesis

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