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ImmunoPET of CD146 in a Murine Hindlimb Ischemia Model
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-06-11 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00424 Carolina A. Ferreira 1 , Reinier Hernandez 2 , Yunan Yang 2 , Hector F. Valdovinos 3 , Jonathan W. Engle 3 , Weibo Cai 1, 2, 3, 4
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-06-11 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00424 Carolina A. Ferreira 1 , Reinier Hernandez 2 , Yunan Yang 2 , Hector F. Valdovinos 3 , Jonathan W. Engle 3 , Weibo Cai 1, 2, 3, 4
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Peripheral arterial disease (PAD) consists of a persistent obstruction of lower-extremity arteries further from the aortic bifurcation attributable to atherosclerosis. PAD is correlated with an elevated risk of morbidity and mortality as well as of deterioration of the quality of life with claudication and chronic leg ischemia being the most frequent complications. Therapeutic angiogenesis is a promising therapeutic strategy that aims to restore the blood flow to the ischemic limb. In this context, assessing the efficacy of pro-angiogenic treatment using a reliable noninvasive imaging technique would greatly benefit the implementation of this therapeutic approach. Herein, we describe the angiogenesis and perfusion recovery characteristics of a mouse model of PAD via in vivo positron emission tomography (PET) imaging of CD146 expression. For that, ischemia was generated by ligation and excision of the right femoral artery of Balb/C mice and confirmed through laser Doppler imaging. The angiogenic process, induced by ischemia, was noninvasively monitored and quantified through PET imaging of CD146 expression in the injured leg using a 64Cu-labeled anti-CD146 monoclonal antibody, 64Cu-NOTA-YY146, at post-operative days 3, 10, and 17. The CD146-specific character of 64Cu-NOTA-YY146 was verified via a blocking study performed in another cohort at day 10 after surgery. Tracer uptake was correlated with in situ CD146 expression by histological analysis. PET scan results indicated that 64Cu-NOTA-YY146 uptake in the injured leg was significantly higher, with the highest uptake with a value of 14.1 ± 2.0 %ID/g at post-operative day 3, compared to the normal contralateral hindlimb, at all time points (maximum uptake of 2.2 ± 0.2 %ID/g). The pre-injection of a blocking dose resulted in a significantly lower tracer uptake in the ischemic hindlimb on day 10 after surgery, confirming tracer specificity. CD146/CD31 immunofluorescent co-staining showed an excellent correlation between the high uptake of the tracer with in situ CD146 expression levels and a marked co-localization of CD146 and CD31 signals. In conclusion, persistent and CD146-specific tracer accumulation in the ischemic hindlimb was observed, confirming the feasibility of 64Cu-NOTA-YY146 to be used as an imaging agent to monitor the progression of angiogenesis and recovery in future PAD research.
中文翻译：
CD146在小鼠后肢缺血模型中的ImmunoPET
周围动脉疾病（PAD）包括下肢动脉的持续阻塞，该阻塞是由于动脉粥样硬化而导致的主动脉分叉处的进一步阻塞。PAD与发病和死亡的风险升高以及生活质量下降相关，with行和慢性腿部缺血是最常见的并发症。治疗性血管生成是一种有前途的治疗策略，旨在恢复缺血肢体的血流。在这种情况下，使用可靠的非侵入性成像技术评估促血管生成治疗的疗效将大大有利于这种治疗方法的实施。本文中，我们通过CD146表达的体内正电子发射断层扫描（PET）成像描述了PAD小鼠模型的血管生成和灌注恢复特性。为了那个原因，结扎和切除Balb / C小鼠的右股动脉产生局部缺血，并通过激光多普勒成像确认。通过PET成像对受伤腿中CD146表达进行无创监测和量化缺血诱导的血管生成过程。64铜标记的抗CD146单克隆抗体，64的Cu-NOTA-YY146，在术后天3，10，和17的CD146特异性字符64的Cu-NOTA-YY146证实通过阻断研究在另一个实施在手术后第10天进行队列研究。通过组织学分析示踪剂摄取与原位CD146表达相关。PET扫描结果表明64在所有时间点，与正常对侧后肢相比，在受伤的腿中，Cu-NOTA-YY146的摄取明显更高，在术后第3天的摄取最高，值为14.1±2.0％ID / g。为2.2±0.2％ID / g）。在手术后第10天，预注射封闭剂量可导致缺血后肢的示踪剂摄取显着降低，从而证实了示踪剂的特异性。CD146 / CD31免疫荧光共染色显示示踪剂的高摄取与原位CD146表达水平之间有极好的相关性，并且CD146和CD31信号的显着共定位。总之，观察到缺血后肢中持久性和CD146特异性示踪剂蓄积，证实了64示踪剂的可行性。Cu-NOTA-YY146将用作成像剂，以在未来的PAD研究中监测血管生成和恢复的进程。
更新日期：2018-06-11
中文翻译：
CD146在小鼠后肢缺血模型中的ImmunoPET
周围动脉疾病（PAD）包括下肢动脉的持续阻塞，该阻塞是由于动脉粥样硬化而导致的主动脉分叉处的进一步阻塞。PAD与发病和死亡的风险升高以及生活质量下降相关，with行和慢性腿部缺血是最常见的并发症。治疗性血管生成是一种有前途的治疗策略，旨在恢复缺血肢体的血流。在这种情况下，使用可靠的非侵入性成像技术评估促血管生成治疗的疗效将大大有利于这种治疗方法的实施。本文中，我们通过CD146表达的体内正电子发射断层扫描（PET）成像描述了PAD小鼠模型的血管生成和灌注恢复特性。为了那个原因，结扎和切除Balb / C小鼠的右股动脉产生局部缺血，并通过激光多普勒成像确认。通过PET成像对受伤腿中CD146表达进行无创监测和量化缺血诱导的血管生成过程。64铜标记的抗CD146单克隆抗体，64的Cu-NOTA-YY146，在术后天3，10，和17的CD146特异性字符64的Cu-NOTA-YY146证实通过阻断研究在另一个实施在手术后第10天进行队列研究。通过组织学分析示踪剂摄取与原位CD146表达相关。PET扫描结果表明64在所有时间点，与正常对侧后肢相比，在受伤的腿中，Cu-NOTA-YY146的摄取明显更高，在术后第3天的摄取最高，值为14.1±2.0％ID / g。为2.2±0.2％ID / g）。在手术后第10天，预注射封闭剂量可导致缺血后肢的示踪剂摄取显着降低，从而证实了示踪剂的特异性。CD146 / CD31免疫荧光共染色显示示踪剂的高摄取与原位CD146表达水平之间有极好的相关性，并且CD146和CD31信号的显着共定位。总之，观察到缺血后肢中持久性和CD146特异性示踪剂蓄积，证实了64示踪剂的可行性。Cu-NOTA-YY146将用作成像剂，以在未来的PAD研究中监测血管生成和恢复的进程。
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