Published online before print September 21, 2006, doi: 10.1161/01.ATV.0000245807.65714.0b
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© 2006 American Heart Association, Inc.
Vascular Biology |
cNGR: A Novel Homing Sequence for CD13/APN Targeted Molecular Imaging of Murine Cardiac Angiogenesis In Vivo
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.
Correspondence to Alexandra Buehler, Johnson & Johnson, Janssen pharmaceutica n.v., Turnhoutseweg 30, B-2340 Beerse, Belgium. 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.
In murine myocardial infarcts we show that the cell surface marker CD13/APN (aminopeptidase N) is selectively upregulated on angiogenic endothelium. Using in vivo fluorescence imaging and ex vivo 2-photon scanning electron microscopy, we show that angiogenic CD13/APN can be targeted and imaged specifically with the synthetic targeting peptide cNGR.
Key Words: aminopeptidase N • angiogenesis • molecular imaging • NGR • vascular biology
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