title: Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.
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.
authors.affiliation: 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;
authors.forename: Huanling
authors.initials: H
authors.lastname: Liu
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;
authors.forename: Anna
authors.initials: A
authors.lastname: Jablonska
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;; 3. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States;
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Li
authors.affiliation: 4. Department of Anesthesiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States;
authors.forename: Suyi
authors.initials: S
authors.lastname: Cao
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;; 5. Department of Radiology, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong, China;
authors.forename: Dexiang
authors.initials: D
authors.lastname: Liu
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;; 5. Department of Radiology, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong, China;
authors.forename: Hanwei
authors.initials: H
authors.lastname: Chen
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;; 3. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States;
authors.forename: Peter Cm
authors.initials: PC
authors.lastname: Van Zijl
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;; 3. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States;
authors.forename: Jeff W M
authors.initials: JW
authors.lastname: Bulte
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;; 6. NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Janowski
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;
authors.forename: Piotr
authors.initials: P
authors.lastname: Walczak
authors.affiliation: 1. Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States;; 3. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States;
authors.forename: Guanshu
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D003566:Cytidine Diphosphate Choline / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D007270:Injections, Intra-Articular; D008081:Liposomes / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D018697:Nootropic Agents / Q000008:administration & dosage*; D051381:Rats; D020521:Stroke / Q000000981:diagnostic imaging* / Q000188:drug therapy*
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D018697:Nootropic Agents; D003566:Cytidine Diphosphate Choline
keywords: CEST MRI.; Ischemia; citicoline; liposome; stroke; theranostic