(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
Date Published2014 Feb 19
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

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.

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