Molecular Imaging of Angiogenesis

Kyung-Han Lee

doi:10.5124/jkma.2009.52.2.135

J Korean Med Assoc > Volume 52(2); 2009 > Article

Lee: Molecular Imaging of Angiogenesis

Focused Issue of This Month

State-of-the-Art Review on Molecuar Imaging

Journal of the Korean Medical Association

Journal of the Korean Medical Association 2009; 52(2): 135-142.

Published online: February 28, 2009

DOI: http://dx.doi.org/10.5124/jkma.2009.52.2.135

Molecular Imaging of Angiogenesis

Kyung-Han Lee, MD

Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea. khnm.lee@samsung.com

Abstract

Angiogenesis, the process whereby new capillaries are formed by outgrowth from existing microvessels, is required for tumor growth and metastasis, as well as for healing of ischemic injuries. Because angiogenesis is a promising target for molecular therapies, there is a real need to develop molecular imaging methods to monitor angiogenesis activity. Direct imaging of angiogenesis can help define the pathophysiology of angiogenic processes in vivo, and foster personized medicine by identifying patients likely to respond to angiogenesis-targeted drugs and accurately monitor the therapeutic efficacy. Promising imaging targets include integrins, vascular endothelial growth factor (VEGF) receptors, and matrix metalloproteinases. While MRI and optical imaging modalities are also workable, radiolabeled RGD (arginine-glycine-aspartate) probes that target α_vβ₃ integrins overexpressed on activated endothelia are the most extensively investigated and successful angiogenesis imaging technique to date. This technique has repeatedly been validated in preclinical models of cancers and ischemic diseases, and clinical studies are presently ongoing to elucidate the value of RGD positron image tomography (PET) imaging in human patients. Herein, we review the current status of angiogenesis imaging research with special emphasis on integrin-targeted techniques.

Angiogenesis; Molecular imaging; PET; Integrin; VEGF

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Figure 1

Integrin-targeted angiogenesis imaging strategy.

(A) Heterodimeric α_vβ₃ integrin receptors overexpressed on the surface of activated endothelial cells. The extracellular domain of the protein recognizes RGD tripeptide sequences as the binding motif.

(B) General structure of integrin-targeting imaging probes that contain cyclic-RGD residues.

(C, D) Scintigraphic images after injection of a ^99mTc labeled cyclic-RGD probe in (C) a murine tumor model showing clear uptake of a carcinoma and (D) a rat myocardial infarction model showing focal uptake in the cardiac region of ischemia.

Figure 2

Clinical RGD PET images in human patients.

(A) RGD PET/MRI fusion image of a patient with squamous cell carcinoma in the right oral cavity showing intense lesion uptake. The left hand shows transaxial images and the right hand shows corresponding 3D reconstruction images. Adapted by permission from the American Association for Cancer Research: Clin Cancer Res (22), copyright (2007).

(B) MRI, perfusion PET/CT, and RGD PET/CT images of a patient with acute infarction of the apex and apico-anterior myocardial wall. Focal increased uptake of ¹⁸F labeled cyclic-RGD is shown in the area of infarction (right) where perfusion (middle) and systolic function (left) is reduced. Adapted by permission from Oxford University Press: Eur Heart J (30), copyright (2008).

Figure 3

VEGF receptor-targeted angiogenesis imaging.

(A) VEGF probes bind to the extracellular domain of VEGF receptors overexpressed on activated endothelial cells.

(B) Optical images after injection a Cy.5.5 labeled VEGF probe in a mouse with a luciferase-expressing tumor transplant shows tumor delineation by both luminescent and fluorescent signals. Adapted by permission from Macmilla Publishers Ltd: Nat Med (32), copyright (2007).

(C) Transaxial CT and ¹²³I-VEGF images in a patient with primary pancreatic adenocarcimoma showing clear uptake of the malignant lesion. Adapted by permission from Edizioni Minerva Medica: Q J Nucl Med Mol Imaging (34), copyright (2004).