[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

Abstract

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.

Preliminary Clinical Application of RGD-Containing Peptides as PET Radiotracers for Imaging Tumors

“…RGD-based imaging of myocardial infarction observed consistent findings from studies of rats, specific RGD tracer accumulation uptake increased in vivo corresponding to infarcted and peri-infarct myocardial regions, and decreased after reperfusion (167)(168)(169)(170). Tracer uptakes were expected to be used to monitor the process of myocardial repair (171)(172)(173). Makowski et al confirmed the feasibility of 18 F-Galacto-RGD to monitor vascular remodeling during evolving MI in human studies; tracer uptake was significantly correlated with infarct size and impairment of myocardial blood flow (174).…”

“…RGD-based imaging of myocardial infarction observed consistent findings from studies of rats, specific RGD tracer accumulation uptake increased in vivo corresponding to infarcted and peri-infarct myocardial regions, and decreased after reperfusion ( 167 – 170 ). Tracer uptakes were expected to be used to monitor the process of myocardial repair ( 171 – 173 ). Makowski et al.…”

Radiometallation and photo-triggered release of ready-to-inject radiopharmaceuticals from the solid phase

“…To date, two 68 Ga-based PET tracers have reached FDA approval and utilize 68 Ga provided predominantly from the generator; the comparably large elution volumes require fractionation and concentration of the eluted activity using ion-exchange chromatography to ascertain high molar activity (MA) radiolabeling in solution. 44,45 Following radiolabeling, the product is further puried with solid phase extraction to remove unbound 68 Ga. These steps are both time consuming and can lead to additional loss of radioactivity during separation and transfer.…”

Recent Advances in Cardiovascular Diseases Research Using Animal Models and PET Radioisotope Tracers

“…Lang et al had previously demonstrated the effectiveness of their cardiac induced cells (CiC) transplant in promoting angiogenesis [56]. They decided to test the effectiveness of the [ 68 Ga]-NODAGA-RGD in a mouse model of myocardial infarction.…”