(64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque.
(64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque.
复制标题
（64）用于动脉粥样硬化斑块的PET-CT成像的Cu标记的LYP-1树突中分析。
DOI：
10.1021/bc400347s
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发表时间：
2014-02-19
影响因子：
4.7
通讯作者：
Ferrara, Katherine W.
中科院分区：
文献类型：
--
作者：
Seo, Jai Woong;Baek, Hyounggee;Mahakian, Lisa M.;Kusunose, Jiro;Hamzah, Juliana;Ruoslahti, Erkki;Ferrara, Katherine W.
检测和定量巨噬细胞积聚的能力可以为动脉粥样硬化斑块提供重要的诊断和预后信息。我们以前已经表明，LyP-1，一种环状9-氨基酸肽，结合活化的巨噬细胞上的p32蛋白，促进PET的动脉粥样硬化斑块的可视化。然而，单体[18F]FBA-LyP-1的体内斑块累积较低（0.31 ± 0.05%ID/g）。为了增加LyP-1构建体对p32的亲合力，我们使用赖氨酸作为核心结构元件在固相上合成了树枝状形式的LyP-1。将成像探针（FAM或6-BAT）缀合至树状聚合物上的赖氨酸或半胱氨酸，用于光学和PET研究。树状聚合物的N-末端进一步用氨氧基修饰，以缀合带有酮的LyP-1和ARAL肽。肽与两种树枝状聚合物的肟连接产生具有光学（FAM）和PET探针（6-BAT）的（LyP-1）4-和（ARAL）4-树枝状聚合物。对于PET-CT研究，用64 Cu标记（LyP-1）4-和（ARAL）4-树枝状聚合物-6-BAT（t1/2 = 12.7 h）并静脉内注射到动脉粥样硬化（ApoE-/-）小鼠中。循环2小时后，PET-CT共配准图像显示主动脉根和降主动脉中（LyP-1）4-树枝状聚合物-64 Cu的摄取高于（ARAL）4-树枝状聚合物-64 Cu。在注射后3小时获得的离体图像和生物分布也证明在主动脉中（LyP-1）4-树枝状聚合物-64Cu（1.1 ± 0.26%ID/g）的摄取显著高于（ARAL）4-树枝状聚合物-64Cu（0.22 ± 0.05%ID/g）。类似地，皮下注射LyP-1-树枝状载体导致在24小时内在含噬斑区域中的优先积累。在同一模型系统中，主动脉斑块内的离体荧光图像显示，与（ARAL）4-树枝状聚合物-FAM相比，（LyP-1）4-树枝状聚合物-FAM的积累和渗透增加。综上所述，结果表明，（LyP-1）4-树枝状聚合物可用于斑块的体内PET成像，并且LyP-1可进一步用于递送具有多价载体或纳米颗粒的治疗剂。
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 [18F]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 64Cu (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-64Cu than the (ARAL)4-dendrimer-64Cu 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-64Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-64Cu (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.
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通讯作者：
Weissleder, Ralph