on September 21, 2006
Published online before print September 21, 2006, doi: 10.1161/01.ATV.0000245807.65714.0b
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Submitted on May 29, 2006
Accepted on August 28, 2006
cNGR: A Novel Homing Sequence for CD13/APN Targeted Molecular Imaging of Murine Cardiac Angiogenesis In Vivo
Alexandra Buehler *;
From CARIM (A.B., M.A.M.J.Z., B.J.S., T.M.H., B.H.G.J.S.-S., A.B., L.H., J.P.M.C., A.D., M.J.P.), University of Maastricht, Maastricht, The Netherlands; Cardiology (M.B.S., D.P.V.d.K.), University Hospital Utrecht, The Netherlands; Angiogenesis Research Center (E.D.d.M.), Dartmouth Medical School, Hanover, NH.
* To whom correspondence should be addressed. E-mail: abuehler{at}prdbe.jnj.com.
Objective--Previously, the peptide sequence cNGR has been shown to home specifically to CD13/APN (aminopeptidase N) on tumor endothelium. Here, we investigated the feasibility of selective imaging of cardiac angiogenesis using the cNGR-CD13/APN system.
Methods and Results--CD13/APN induction and cNGR homing were studied in the murine myocardial infarction (MI) model. By real-time polymerase chain reaction (PCR) at 7 days after MI, CD13/APN expression was 10- to 20-fold higher in the angiogenic infarct border zone and the MI area than in non-MI areas. In vivo fluorescence microscopy confirmed specific homing of fluorophore-tagged cNGR to the border zone and MI territory at 4 and 7 days after MI with a local advantage of 2.3, but not at 1 or 14 days after MI. Tissue residence half-life was 9.1±0.3 hours, whereas the half-life in plasma was 15.4±3.4 minutes. Pulse chase experiments confirmed reversible binding of cNGR in the infarct area. Fluorescent labeled cNGR conjugates or antibodies were injected in vivo, and their distribution was studied ex vivo by 2-photon laser scanning microscopy (TPLSM). cNGR co-localized exclusively with CD13/APN and the endothelial marker CD31 on vessels.
Conclusions--In cardiac angiogenesis endothelial CD13/APN is upregulated. It can be targeted specifically with cNGR conjugates. In the heart cNGR binds its endothelial target only in angiogenic areas.
Key words: aminopeptidase N • angiogenesis • molecular imaging • NGR • vascular biology
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