胶原杂化肽型放射性示踪剂用于肺纤维化中胶原转换的分子成像

Azmi A. Ahmad, Mean Ghim, Gunjan Kukreja, Afarin Neishabouri, Zhengxing Zhang, Jie Li, Mani Salarian, Jakub Toczek, Kiran Gona, Keshvad Hedayatyanfard, Tian Morrison, Jiasheng Zhang, Yiyun Henry Huang, Chi Liu, S. Michael Yu, Mehran M. Sadeghi
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引用次数: 0

摘要

肺纤维化是间质性肺疾病的特征性表现。目前的临床诊断方法提供了肺结构的快照,没有疾病活动的信息。胶原杂交肽提供了通过与变性胶原杂交来检测胶原重塑的机会。在这里,我们试图开发一种99mtc标记的胶原杂交示踪剂来跟踪体内变性胶原,并在小鼠肺纤维化模型中验证它。方法:合成由多组氨酸或多组氨酸-谷氨酸[(HE)3]肽通过3-甘氨酸连接器连接到具有9个甘氨酸-脯氨酸-羟脯氨酸重复序列[(GPO)9]的n端靶向片段组成的显像剂。用99mtc -三羰基放射性标记后,用高效液相色谱法和γ孔计数法评价标记产物的纯度和稳定性,并比较其在小鼠体内的生物分布。为了诱导肺纤维化,将8- 10周龄小鼠的肺暴露于博来霉素(或生理盐水作为对照)。诱导后3周,注射1 h后进行99mTc-(HE)3-(GPO)9的SPECT/CT成像,然后收集组织,通过γ-孔计数评估99mTc-(HE)3-(GPO)9的生物分布,并评估肺组织组织学。示踪剂摄取的特异性是用一个混乱的同源物来评估的。一组动物在诱导后3周和8-10周进行连续成像。结果:最终放射性标记产物的比活性为70.3±14.8 GBq/µmol。放射性标记的示踪剂在血液中稳定至少2小时,并显示出快速的血液清除。99mTc-(HE)3-(GPO)9在生物分布研究中表现出较低的肝脏摄取,并被选择用于体内成像研究。诱导后3周,博莱霉素处理小鼠的SPECT/CT成像显示,99mTc-(HE)3-(GPO)9特异性肺摄取高于对照组(P <;0.01)和诱导后8-10周,当纤维化消退时,博莱霉素处理小鼠(P <;0.05)。SPECT/CT定量肺摄取与γ-孔计数有显著相关性(Pearson R = 0.83, P <;0.001),示踪剂摄取与组织纤维化指标之间存在显著相关性。结论:99mTc-(HE)3-(GPO)9可用于肺纤维化中胶原转换的SPECT成像。这种方法扩大了现有纤维化诊断工具的范围,并可以通过监测抗纤维化治疗的效果来更好地管理患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Collagen Hybridizing Peptide–Based Radiotracers for Molecular Imaging of Collagen Turnover in Pulmonary Fibrosis

Pulmonary fibrosis is a characteristic feature of interstitial lung disease. Current clinical diagnostic methods provide a snapshot of the lung structure without information on disease activity. Collagen hybridizing peptides offer the opportunity to detect collagen remodeling through their hybridization with denatured collagen. Here, we sought to develop a 99mTc-labeled collagen hybridizing tracer to track denatured collagen in vivo and validate it in a murine model of pulmonary fibrosis. Methods: Imaging agents consisting of a polyhistidine or a poly–histidine–glutamic acid [(HE)3] peptide connected to an N-terminal targeting moiety with 9 glycine–proline–hydroxyproline repeats [(GPO)9] through a 3-glycine linker were synthesized. After radiolabeling with 99mTc-tricarbonyl, the labeled products’ purity and stability were evaluated by high-performance liquid chromatography and γ-well counting, and their biodistributions were compared in mice. To induce pulmonary fibrosis, the lungs of 8- to 10-wk-old mice were exposed to bleomycin (or saline as control). At 3 wk after induction, SPECT/CT imaging with 99mTc-(HE)3-(GPO)9 was performed 1 h after injection and was followed by tissue collection to assess 99mTc-(HE)3-(GPO)9 biodistribution by γ-well counting and to evaluate lung histology. The specificity of the tracer uptake was assessed using a scrambled homolog. A group of animals underwent serial imaging 3 and 8–10 wk after induction. Results: The specific activity of the final radiolabeled product was 70.3 ± 14.8 GBq/µmol. Radiolabeled tracers were stable in blood for at least 2 h and showed rapid blood clearance. 99mTc-(HE)3-(GPO)9 showed lower liver uptake in biodistribution studies and was selected for in vivo imaging studies. SPECT/CT imaging of bleomycin-treated mice 3 wk after induction showed higher specific 99mTc-(HE)3-(GPO)9 lung uptake than that of control mice (P < 0.01) and that of bleomycin-treated mice 8–10 wk after induction, when fibrosis was resolved (P < 0.05). There was a significant correlation between lung uptake quantified by SPECT/CT and γ-well counting (Pearson R = 0.83, P < 0.001) and significant correlations between tracer uptake and indices of tissue fibrosis. Conclusion: 99mTc-(HE)3-(GPO)9 enables SPECT imaging of collagen turnover in pulmonary fibrosis. This approach expands the scope of existing diagnostic tools in fibrosis and can lead to better patient management by monitoring the effect of antifibrotic therapies.

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