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Theranostics 2018; 8(2):437-449. doi:10.7150/thno.22467 This issue Cite

Research Paper

Identification of type IV collagen exposure as a molecular imaging target for early detection of thoracic aortic dissection

Ke Xu^1*, Chen Xu^2*, Yanzhenzi Zhang¹, Feiran Qi¹, Bingran Yu², Ping Li¹, Lixin Jia¹, Yulin Li^1✉, Fu-jian Xu^2✉, Jie Du^1✉

1. 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;
2. 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.
* These authors contributed equally to this work.

✉ Corresponding authors: Email: jieduedu.cn (J.D.); xufjbuct.edu.cn (Fj.X.); lyllyl_1111com (Yl. L.)

Abstract

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.

Methods: 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 in vitro. We then examined the sensitivity and specificity of CDR at different stages of TAD via MRI and bioluminescence imaging in vivo.

Results: 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 (r² = 0.8482).

Conclusion: As confirmed by in vivo 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.

Keywords: Thoracic aortic dissection, Early diagnosis, Risk prediction, Magnetic resonance imaging, Fluorescence imaging.

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