Theranostics 2016; 6(10):1588-1600. doi:10.7150/thno.15492

Research Paper

Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke

Huanling Liu1,2*, Anna Jablonska1*, Yuguo Li1,3*, Suyi Cao4, Dexiang Liu1,5, Hanwei Chen1,5, Peter CM Van Zijl1,3, Jeff W.M. Bulte1,3, Miroslaw Janowski1,6, Piotr Walczak1, Guanshu Liu1,3 ✉

1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;
2. Department of Ultrasound, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong, China;
3. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States;
4. Department of Anesthesiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States;
5. Department of Radiology, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong, China;
6. NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.
*These authors contributed equally.

Abstract

ABSTRACT Citicoline (CDPC) is a natural supplement with well-documented neuroprotective effects in the treatment of neurodegenerative diseases. In the present study, we sought to exploit citicoline as a theranostic agent with its inherent chemical exchange saturation transfer (CEST) MRI signal, which can be directly used as an MRI guidance in the citicoline drug delivery. Our in vitro CEST MRI results showed citicoline has two inherent CEST signals at +1 and +2 ppm, attributed to exchangeable hydroxyl and amine protons, respectively. To facilitate the targeted drug delivery of citicoline to ischemic regions, we prepared liposomes encapsulating citicoline (CDPC-lipo) and characterized the particle properties and CEST MRI properties. The in vivo CEST MRI detection of liposomal citicoline was then examined in a rat brain model of unilateral transient ischemia induced by a two-hour middle cerebral artery occlusion. The results showed that the delivery of CPDC-lipo to the brain ischemic areas could be monitored and quantified by CEST MRI. When administered intra-arterially, CDPC-lipo clearly demonstrated a detectable CEST MRI contrast at 2 ppm. CEST MRI revealed that liposomes preferentially accumulated in the areas of ischemia with a disrupted blood-brain-barrier. We furthermore used CEST MRI to detect the improvement in drug delivery using CDPC-lipo targeted against vascular cell adhesion molecule (VCAM)-1 in the same animal model. The MRI findings were validated using fluorescence microscopy. Hence, liposomal citicoline represents a prototype theranostic system, where the therapeutic agent can be detected directly by CEST MRI in a label-free fashion.

Keywords: Ischemia, stroke, citicoline, liposome, theranostic, CEST MRI.

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How to cite this article:
Liu H, Jablonska A, Li Y, Cao S, Liu D, Chen H, Van Zijl PC, Bulte JWM, Janowski M, Walczak P, Liu G. Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke. Theranostics 2016; 6(10):1588-1600. doi:10.7150/thno.15492. Available from http://www.thno.org/v06p1588.htm