title: (64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque.
abstract: The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [(18)F]FBA-LyP-1 was low (0.31 ± 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with (64)Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE(-/-)) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-(64)Cu than the (ARAL)4-dendrimer-(64)Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-(64)Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-(64)Cu (0.22 ± 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in vivo PET imaging of plaque and that LyP-1 could be further exploited for the delivery of therapeutics with multivalent carriers or nanoparticles.
authors.affiliation: Department of Biomedical Engineering, University of California , Davis, California 95616, United States.
authors.forename: Jai Woong
authors.initials: JW
authors.lastname: Seo
authors.forename: Hyounggee
authors.initials: H
authors.lastname: Baek
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.forename: Jiro
authors.initials: J
authors.lastname: Kusunose
authors.forename: Juliana
authors.initials: J
authors.lastname: Hamzah
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000000981:diagnostic imaging*; D003301:Copper Radioisotopes / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D064847:Multimodal Imaging; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D001057:Apolipoproteins E; D003301:Copper Radioisotopes; D050091:Dendrimers; C461500:LyP-1 protein, mouse; D010456:Peptides, Cyclic