In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity.
In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity.
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DOI：
10.1039/c2ib00161f
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Nguyen QT
中科院分区：
文献类型：
--
作者：
Olson ES;Whitney MA;Friedman B;Aguilera TA;Crisp JL;Baik FM;Jiang T;Baird SM;Tsimikas S;Tsien RY;Nguyen QT
凝血酶和其他凝血酶已被证明在动脉粥样硬化疾病的发展过程中是重要的。由于缺乏强大的分子显像剂来成像蛋白酶在体内的活性，对这些蛋白酶的研究目前受到限制。活化细胞穿透肽（Activatable cell penetrating peptides, ACPPs）已被用于监测肿瘤中MMP的活性，原则上，它可以被修饰以检测其他蛋白酶。我们已经开发了一种探针，将蛋白酶激活受体1 （PAR-1）的肽序列DPRSFL结合到ACPP中，并表明它被纯化的凝血酶优先切割。血清中活性凝血酶可切割DPRSFL-ACPP， lepirudin或阿加曲班可抑制其90%以上。在活体小鼠的晚期动脉粥样硬化病变中，DPRSFL-ACPP切割产物积累，预先注射水蛭素后，保留量减少85%。ACPP裂解产物的摄取在与更严重疾病相关的组织学特征斑块中最高。与对照ACPP相比，新切除的人动脉粥样硬化浸泡在DPRSFL-ACPP中保留了63%的裂解产物。综上所述，DPRSFL-ACPP可用于凝血和动脉粥样硬化中凝血酶活性的研究，具有良好的空间和时间分辨率。对凝血酶敏感的ACPPs可能发展成为早期发现和术中成像高风险动脉粥样硬化斑块的探针。
Thrombin and other coagulation enzymes have been shown to be important during atherosclerotic disease development. Study of these proteases is currently limited because of lack of robust molecular imaging agents for imaging protease activity in vivo. Activatable cell penetrating peptides (ACPPs) have been used to monitor MMP activity in tumors and, in principle, can be modified to detect other proteases. We have developed a probe that incorporates the peptide sequence DPRSFL from the proteinase activated receptor 1 (PAR-1) into an ACPP and shown that it is preferentially cleaved by purified thrombin. Active thrombin in serum cleaves DPRSFL–ACPP with >90% inhibition by lepirudin or argatroban. The DPRSFL–ACPP cleavage product accumulated in advanced atherosclerotic lesions in living mice, with 85% reduction in retention upon pre-injection of mice with hirudin. Uptake of the ACPP cleavage product was highest in plaques with histological features associated with more severe disease. Freshly resected human atheromas bathed in DPRSFL–ACPP retained 63% greater cleavage product compared to control ACPP. In conclusion, DPRSFL–ACPP can be used to study thrombin activity in coagulation and atherosclerosis with good spatial and temporal resolution. Thrombin-sensitive ACPPs may be developed into probes for early detection and intraoperative imaging of high risk atherosclerotic plaques.
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