64Cu-Labeled LyP-1-Dendrimer for PET-CT Imaging of Atherosclerotic Plaque

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• 作者：Jai Woong Seo ; Hyounggee Baek ; Lisa M. Mahakian ; Jiro Kusunose ; Juliana Hamzah ; Erkki Ruoslahti ; Katherine W. Ferrara
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：February 19, 2014
• 年：2014
• 卷：25
• 期：2
• 页码：231-239
• 全文大小：414K
• ISSN：1520-4812

文摘

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 [<sup>18sup>F]FBA-LyP-1 was low (0.31 卤 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)<sub>4sub>- and (ARAL)<sub>4sub>-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)<sub>4sub>- and (ARAL)<sub>4sub>-dendrimer-6-BAT were labeled with <sup>64sup>Cu (t<sub>1/2sub> = 12.7 h) and intravenously injected into the atherosclerotic (ApoE<sup>鈥?鈥?/sup>) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)<sub>4sub>-dendrimer-<sup>64sup>Cu than the (ARAL)<sub>4sub>-dendrimer-<sup>64sup>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)<sub>4sub>-dendrimer-<sup>64sup>Cu (1.1 卤 0.26%ID/g) than the (ARAL)<sub>4sub>-dendrimer-<sup>64sup>Cu (0.22 卤 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)<sub>4sub>-dendrimer-FAM as compared to the (ARAL)<sub>4sub>-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)<sub>4sub>-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.