Evaluation of a dimeric-cRGD peptide for targeted PET-CT imaging of peripheral angiogenesis in diabetic mice

Hedhli, Jamila; Slania, Stephanie; Płoska, Agata; Czerwiński, A.; Konopka, Christian J.; Woźniak, Marcin; Banach, Maciej; Dobrucki, Iwona T.; Kalinowski, Leszek; Dobrucki, Lawrence W.

doi:10.1038/s41598-018-23372-9

Cited by 11 publications

(8 citation statements)

References 37 publications

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“…All experiments were performed according to the guiding principles of the American Physiologic Society and approved by the Institutional Animal Care and Use Committee at the University of Illinois at Urbana-Champaign. Hindlimb ischemia was induced in 2-3-month-old male C57BL/6 mice (Jackson Laboratories, USA) using an already established protocol 48 . The mice were anesthetized with 1-3% isoflurane for surgical intervention and imaging.…”

Section: Methodsmentioning

confidence: 99%

Multimodal imaging of the receptor for advanced glycation end-products with molecularly targeted nanoparticles

Konopka¹,

Woźniak²,

Hedhli³

et al. 2018

Theranostics

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The receptor for advanced glycation end-products (RAGE) is central to multiple disease states, including diabetes-related conditions such as peripheral arterial disease (PAD). Despite RAGE's importance in these pathologies, there remains a need for a molecular imaging agent that can accurately assess RAGE levels in vivo. Therefore, we have developed a multimodal nanoparticle-based imaging agent targeted at RAGE with the well-characterized RAGE ligand, carboxymethyllysine (CML)-modified human serum albumin (HSA).Methods: A multimodal tracer (64Cu-Rho-G4-CML) was developed using a generation-4 (G4) polyamidoamine (PAMAM) dendrimer, conjugated with both rhodamine and copper-64 (64Cu) chelator (NOTA) for optical and PET imaging, respectively. First, 64Cu-Rho-G4-CML and its non-targeted analogue (64Cu-Rho-G4-HSA) were evaluated chemically using techniques such as dynamic light scattering (DLS), electron microscopy and nuclear magnetic resonance (NMR). The tracers' binding capabilities were examined at the cellular level and optimized using live and fixed HUVEC cells grown in 5.5-30 mM glucose, followed by in vivo PET-CT imaging, where the probes' kinetics, biodistribution, and RAGE targeting properties were examined in a murine model of hindlimb ischemia. Finally, histological assessment of RAGE levels in both ischemic and non-ischemic tissues was performed.Conclusions: Our RAGE-targeted probe demonstrated an average size of 450 nm, a Kd of 340-390 nM, rapid blood clearance, and a 3.4 times greater PET uptake in ischemic RAGE-expressing hindlimbs than their non-ischemic counterpart. We successfully demonstrated increased RAGE expression in a murine model of hindlimb ischemia and the feasibility for non-invasive examination of cellular, tissue, and whole-body RAGE levels with a molecularly targeted tracer.

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Section: Methodsmentioning

confidence: 99%

Multimodal imaging of the receptor for advanced glycation end-products with molecularly targeted nanoparticles

Konopka¹,

Woźniak²,

Hedhli³

et al. 2018

Theranostics

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“…αVβ3 integrin is minimally expressed in normal quiescent endothelial cells but significantly upregulated during neovascularization. A previous study showed CD31-positive endothelial cells within the capillaries and small arterioles of non-diabetic ischemic hindlimb sections, which correlated with high αVβ3 expression ( Hedhli et al, 2018 ). However, this finding has not been tested in a hindlimb ischemic disease model.…”

Section: Introductionmentioning

confidence: 84%

“…Similar to solid tumors, αVβ3 integrin is highly expressed in nondiabetic ischemic murine hindlimb ( Hedhli et al, 2018 ). Our findings are consistent with previous reports indicating that a low dose of cilengitide promotes angiogenesis in tumor models ( Reynolds et al, 2009 ; Wong et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Antagonizing αvβ3 Integrin Improves Ischemia-Mediated Vascular Normalization and Blood Perfusion by Altering Macrophages

Gao

Shu

et al. 2021

Front. Pharmacol.

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Background: αVβ3 integrin has been implicated in the physiological processes and pathophysiology of important angiogenesis-related disorders; however, the preclinical and clinical data on integrin αVβ3 antagonists have not demonstrated improved outcomes. Our goal was to test the hypothesis that inhibition of αVβ3 integrin improves blood flow in a mouse hindlimb ischemia model.Methods: In this study, we examined the effect of cilengitide, an αVβ3/αVβ5 integrin-specific RGD-mimetic cyclic peptide, on blood perfusion and angiogenesis after hindlimb ischemia. Blood flow was measured using Laser Doppler Scanner. Vascular density, and macrophages infiltration were examined by immunofluorescence. Macrophage polarization was measured by quantitative real time PCR.Results: We found that low-dose, not high-dose, cilengitide increased blood flow perfusion, capillary formation, and pericyte coverage, accompanied by an accumulation of macrophages and increased expression of the chemokine (C-C motif) ligand 2 (CCL2) in ischemic muscles. Macrophage depletion using clodronate liposomes resulted in a reduction in low-dose cilengitide-induced blood flow perfusion, macrophage accumulation, pericyte coverage, and CCL2 expression. Finally, in vitro assays showed that low-dose, not high-dose, cilengitide increased macrophage migration.Conclusion: These studies identified a novel role of the inhibition of αVβ3 integrin in modulating ischemia-induced angiogenesis, possibly through effects on macrophage infiltration and polarization, and revealed αVβ3 integrin inhibition to be a promising therapeutic strategy for peripheral artery disease.

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“…The accumulation of [ 18 18]-Galacto-RGD within the infarcted area peaked seven days post MI, correlated strongly with newly formed vessels and it could be blocked by a competitive inhibitor, which suggests the successful imaging of angiogenesis in the process of myocardial healing [ 27 ]. Various independent research groups were able to validate the concept of α v β 3 -integrin imaging—with both SPECT and PET tracers—as a surrogate marker for angiogenesis in the healing process of ischemically damaged myocardium [ 13 , 28 , 29 ] and skeletal muscle [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

[68Ga]-NODAGA-RGD Positron Emission Tomography (PET) for Assessment of Post Myocardial Infarction Angiogenesis as a Predictor for Left Ventricular Remodeling in Mice after Cardiac Stem Cell Therapy

Lang

Döring

Gäbel

et al. 2020

Cells

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Angiogenesis plays a central role in the healing process following acute myocardial infarction. The PET tracer [68Ga]-NODAGA-RGD, which is a ligand for the αvβ3 integrin, has been investigated for imaging angiogenesis in the process of healing myocardium in both animal and clinical studies. It’s value as a prognostic marker of functional outcome remains unclear. Therefore, the aim of this work was to establish [68Ga]-NODAGA-RGD for imaging angiogenesis in the murine infarct model and evaluate the tracer as a predictor for cardiac remodeling in the context of cardiac stem cell therapy. [68Ga]-NODAGA-RGD PET performed seven days after left anterior descending coronary artery (LAD) occlusion in 129S6 mice showed intense tracer accumulation within the infarct region. The specificity was shown in a sub-group of animals by application of the competitive inhibitor cilengitide prior to tracer injection in a subgroup of animals. Myocardial infarction (MI) significantly reduced cardiac function and resulted in pronounced left ventricular remodeling after three weeks, as measured by cardiac MRI in a separate group. Cardiac induced cells (CiC) that were derived from mESC injected intramyocardially in the therapy group significantly improved left ventricular ejection fraction (LVEF). Surprisingly, CiC transplantation resulted in significantly lower tracer accumulation seven days after MI induction. Accordingly, we successfully established the PET tracer [68Ga]-NODAGA-RGD for the assessment of αvβ3 integrin expression in the healing process after MI in the mouse model. Yet, our results indicate that the mere extent of angiogenesis following MI does not serve as a sufficient prognostic marker for functional outcome.

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Evaluation of a dimeric-cRGD peptide for targeted PET-CT imaging of peripheral angiogenesis in diabetic mice

Cited by 11 publications

References 37 publications

Multimodal imaging of the receptor for advanced glycation end-products with molecularly targeted nanoparticles

Multimodal imaging of the receptor for advanced glycation end-products with molecularly targeted nanoparticles

Antagonizing αvβ3 Integrin Improves Ischemia-Mediated Vascular Normalization and Blood Perfusion by Altering Macrophages

[68Ga]-NODAGA-RGD Positron Emission Tomography (PET) for Assessment of Post Myocardial Infarction Angiogenesis as a Predictor for Left Ventricular Remodeling in Mice after Cardiac Stem Cell Therapy

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