ImmunoPET of CD146 in a Murine Hindlimb Ischemia Model

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Abstract
Peripheral Arterial Disease (PAD) is a chronic occlusion of lower-extremity arteries distal to the aortic bifurcation attributable to atherosclerosis. PAD is associated with an elevated risk of morbidity and mortality as well as of deterioration of the quality of life with claudication and chronic leg ischemia being the most frequent complications. Therapeutic angiogenesis is a promising therapeutic strategy that aims to restore the blood flow to the ischemic limb. In this context, assessing the efficacy of pro-angiogenic treatment using a reliable non-invasive imaging technique would greatly benefit the implementation of this therapeutic approach. Herein, we describe the angiogenesis and perfusion recovery characteristics of a mouse model of PAD via in vivo positron emission tomography (PET) imaging of CD146 expression. For that, ischemia was induced by ligation and excision of the right femoral artery of Balb/C mice and confirmed through Laser Doppler imaging. Ischemia-induced angiogenesis was non-invasively monitored and quantified through PET imaging of CD146 expression in the injured leg using a 64Cu-labeled anti-CD146 monoclonal antibody, 64Cu-NOTA-YY146, at postoperative days 3, 10 and 17. The CD146-specific character of 64Cu-NOTA-YY146 was confirmed via a blocking study performed in another cohort at day 10 after surgery. Tracer uptake was correlated with in situ CD146 expression by histological analysis. PET scans results indicated that 64Cu-NOTA-YY146 uptake in the ischemic hindlimb was significantly higher, with a maximum uptake of 14.1 ± 2.0 %ID/g at postoperative day 3, compared to the normal contralateral hindlimb, at all time points (maximum uptake of 2.2 ± 0.2 %ID/g). The pre-injection of a blocking dose resulted in a significantly lower tracer uptake in the operated hindlimb on day 10 after surgery, confirming tracer specificity. CD146/CD31 immunofluorescent co-staining showed excellent correlation between the high uptake of the tracer with in situ CD146 expression levels and a marked co-localization of CD146 and CD31 signals. In conclusion, persistent and specific CD146 uptake of the tracer in the ischemic hindlimb was observed, confirming the feasibility of 64Cu-NOTA-YY146 as an imaging agent to monitor the progression of angiogenesis and recovery in future PAD research.
Funding Information
  • National Cancer Institute (P30CA014520)
  • Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
  • University of Wisconsin-Madison

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