Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction

Abstract

The alphavbeta3-integrin is expressed in angiogenic vessels in response to hypoxia and represents a potential novel target for imaging myocardial angiogenesis. This study evaluated the feasibility of noninvasively tracking hypoxia-induced alphavbeta3-integrin activation within the myocardium as a marker of angiogenesis early after myocardial infarction. Acute myocardial infarction was produced by coronary artery occlusion in rodent and canine studies. A novel (111)In-labeled radiotracer targeted at the alphavbeta3-integrin ((111)In-RP748) was used to localize regions of hypoxia-induced angiogenesis early after infarction. In rodent studies, the specificity of (111)In-RP748 for alphavbeta3-integrin was confirmed with a negative control compound ((111)In-RP790), and regional uptake of these compounds correlated with (201)Tl perfusion and a (99m)Tc-labeled nitroimidazole (BRU59-21), which was used as a quantitative marker of myocardial hypoxia. The ex vivo analysis demonstrated that only (111)In-RP748 was selectively retained in infarcted regions with reduced (201)Tl perfusion and correlated with uptake of BRU59-21. In canine studies, myocardial uptake of (111)In-RP748 was assessed using in vivo single-photon-emission computed tomography (SPECT), ex vivo planar imaging, and gamma well counting of myocardial tissue and correlated with (99m)Tc-labeled 2-methoxy-2-methyl-propyl-isonitrile ((99m)Tc-sestamibi) perfusion. Dual-radiotracer in vivo SPECT imaging of (111)In-RP748 and (99m)Tc-sestamibi provided visualization of (111)In-RP748 uptake within the infarct region, which was confirmed by ex vivo planar imaging of excised myocardial slices. Myocardial (111)In-RP748 retention was associated with histological evidence of alphavbeta3-integrin expression/activation in the infarct region. (111)In-RP748 imaging provides a novel noninvasive approach for evaluation of hypoxia-induced alphavbeta3-integrin activation in myocardium early after infarction and may prove useful for directing and evaluating angiogenic therapies in patients with ischemic heart disease.

Dilated cardiomyopathy alters the expression patterns of CAR and other adenoviral receptors in human heart

“…They are widely expressed by many cell types, including endothelial and smooth muscle cells (Cheresh1987; Janat et al 1992) and are upregulated in hypoxia and angiogenesis (Brooks et al 1994;Kalinowski et al 2008). Our data demonstrate high a v integrin protein expression with strong immunohistochemistry signal in intramyocardial coronary vessels.…”

Integrin-Mediated Drug Delivery in Cancer and Cardiovascular Diseases with Peptide-Functionalized Nanoparticles

“…Imaging of α v β 3 expression in myocardial ischemia have been reported in rats and dogs, using intravenous injection of RPT748, combining a 111 In-complex with a non-peptide α v β 3 ligand [243][244]. In vivo and ex-vivo imaging of myocardial tissue showed that 111 In uptake colocalized with neoangiogenesis in ischemic areas.…”

PET and SPECT in cardiovascular molecular imaging

“…111 InRP748 was also successful in assessing the activation of αvβ3 revieWS integrin in myo cardium early after infarction. 60 Other researchers have reported the use of 99m Tclabeled tracers containing the RGD motif for noninvasive imaging of angiogenesis in various animal models. [61][62][63][64] The 99m Tc labeled peptide, 99m TcNC100692, has a high affinity for the αvβ3 integrins, is metabo lically stable, and has a biodistribution favorable for in vivo imaging purposes.…”