(64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque.

Title(64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque.
Publication TypeJournal Article
Year of Publication2014
AuthorsSeo JWoong, Baek H, Mahakian LM, Kusunose J, Hamzah J, Ruoslahti E, Ferrara KW
JournalBioconjug Chem
Volume25
Issue2
Pagination231-9
Date Published2014 Feb 19
ISSN1520-4812
KeywordsAmino Acid Sequence, Animals, Apolipoproteins E, Atherosclerosis, Copper Radioisotopes, Dendrimers, Mice, Mice, Knockout, Multimodal Imaging, Peptides, Cyclic, Positron-Emission Tomography, Tissue Distribution, Tomography, X-Ray Computed
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.

DOI10.1021/bc400347s
Alternate JournalBioconjug. Chem.
PubMed ID24433095
PubMed Central IDPMC4311647
Grant ListR01 CA103828 / CA / NCI NIH HHS / United States
R01 CA112356 / CA / NCI NIH HHS / United States
R01 CA134659 / CA / NCI NIH HHS / United States
R01-CA103828 / CA / NCI NIH HHS / United States
R01CA112356 / CA / NCI NIH HHS / United States
R01CA134659 / CA / NCI NIH HHS / United States