Beijing Anzhen Hospital, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education; Beijing collaborative innovative research center for cardiovascular diseases; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029 China.
Beijing Laboratory of Biomedical Materials, Key Laboratory of Carbon Fiber and Functional Polymers (Beijing University of Chemical Technology), Ministry of Education, Beijing University of Chemical Technology, Beijing 100029 China.
Theranostics. 2018 Jan 1;8(2):437-449. doi: 10.7150/thno.22467. eCollection 2018.
Thoracic aortic dissection (TAD) is an aggressive and life-threatening vascular disease and there is no effective means of early diagnosis of dissection. Type IV collagen (Col-IV) is a major component of the sub-endothelial basement membrane, which is initially exposed followed by endothelial injury as early-stage event of TAD. So, we want to build a noninvasive diagnostic method to detect early dissection by identifying the exposed Col-IV via MRI.
Col-IV-targeted magnetic resonance/ fluorescence dual probe (Col-IV-DOTA-Gd-rhodamine B; CDR) was synthesized by amide reaction and coordination reaction. Flow cytometry analysis was used to evaluate the cell viability of SMC treated with CDR and fluorescence assays were used to assess the Col-IV targeting ability of CDR . We then examined the sensitivity and specificity of CDR at different stages of TAD via MRI and bioluminescence imaging .
The localization of Col-IV (under the intima) was observed by histology images. CDR bound specifically to Col-IV-expressing vascular smooth muscle cells and BAPN-induced dissected aorta. The CDR signal was co-detected by magnetic resonance imaging (MRI) and bioluminescence imaging as early as 2 weeks after BAPN administration (pre-dissection stage). The ability to detect rupture of dissected aorta was indicated by a strong normalized signal enhancement (NSE) in vivo. Moreover, NSE was negatively correlated with the time of dissection rupture after BAPN administration (r = 0.8482).
As confirmed by studies, the CDR can identify the exposed Col-IV in degenerated aorta to monitor the progress of aortic dissection from the early stage to the rupture via MRI. Thus, CDR-enhanced MRI proposes a potential method for dissection screening, and for monitoring disease progression and therapeutic response.
胸主动脉夹层（TAD）是一种侵袭性的危及生命的血管疾病，目前尚无有效的早期诊断方法。IV 型胶原蛋白（Col-IV）是内皮下基底膜的主要成分，是 TAD 早期阶段的早期事件，首先暴露，然后内皮损伤。因此，我们希望通过 MRI 识别暴露的 Col-IV 来建立一种非侵入性的诊断方法来检测早期夹层。
通过酰胺反应和配位反应合成 Col-IV 靶向磁共振/荧光双探针（Col-IV-DOTA-Gd-罗丹明 B；CDR）。通过流式细胞术分析评估 CDR 处理的 SMC 的细胞活力，通过荧光测定评估 CDR 的 Col-IV 靶向能力。然后通过 MRI 和生物发光成像检查 CDR 在 TAD 的不同阶段的敏感性和特异性。
组织学图像观察到 Col-IV（在内膜下）的定位。CDR 特异性结合 Col-IV 表达的血管平滑肌细胞和 BAPN 诱导的夹层主动脉。CDR 信号最早在 BAPN 给药后 2 周（夹层前阶段）通过磁共振成像（MRI）和生物发光成像同时检测到。破裂的夹层主动脉的检测能力通过体内的强归一化信号增强（NSE）来指示。此外，NSE 与 BAPN 给药后夹层破裂的时间呈负相关（r=0.8482）。
研究证实，CDR 可以识别退变主动脉中的暴露 Col-IV，通过 MRI 从早期阶段监测主动脉夹层的进展直至破裂。因此，CDR 增强 MRI 提出了一种用于夹层筛查的潜在方法，用于监测疾病进展和治疗反应。
