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.

CEST MRI monitoring of tumor response to vascular disrupting therapy using high molecular weight dextrans

“…In vitro CEST images were acquired on a 9.4T Bruker Avance system equipped with a 15 mm sawtooth radiofrequency coil using the previously published protocol. 29,35,36 In brief, a modified RARE sequence (repetition time = 6.0 s, effective echo time = 43.2 ms, RARE factor = 16, slice thickness = 0.7 mm, field of view = 14 × 14 mm, matrix size = 128 × 128 with partial FT acceleration to 128 × 64, resolution = 0.11 × 0.11 mm 2 , and number of averages = 2) including a magnetization transfer (MT) module (1 CW pulse, B = 3.6 μT [150 Hz], 3 s) was used to acquire CESTweighted images from -4 ppm to 4 ppm (step = 0.2 ppm) around the water resonance (0 ppm), 36 total acquisition time = 32.8 min (including M0 image). The absolute water resonance frequency shift was measured using the modified WAter Saturation Shift Reference (WASSR) method 37 using a Lorentzian model.…”

EXCI-CEST: Exploiting pharmaceutical excipients as MRI-CEST contrast agents for tumor imaging

“…Several natural molecules and polymers (glucose, glycogen, glycosaminoglycan, sialic acid, gelatin) have already been exploited as MRI-CEST contrast agents, since these molecules have precedence of use with human exposure (Chan et al, 2012;Jin et al, 2017;Liang et al, 2015;Ling et al, 2008;Shinar et al, 2014;van Zijl et al, 2007;Walker-Samuel et al, 2013). Also metabolites, drugs and polypeptides/proteins have been investigated to demonstrate their capability to generate contrast within this approach Bar-Shir et al, 2014;Cai et al, 2015;Haris et al, 2012;Liu et al, 2016;Longo et al, 2014a;McMahon et al, 2008;Zaiss et al, 2013). Moreover, several diamagnetic CEST agents have been proposed as exogenous probes for tumor imaging (Geraldes and Laurent, 2009).…”

Molecular Imaging of Deoxycytidine Kinase Activity Using Deoxycytidine-Enhanced CEST MRI

“…Using clinically available agents as imaging probes would be a practical strategy to overcome this challenge and allow quick translation of the preclinically validated MR molecular imaging technologies. Demonstrated in recent studies by others and us, natural biocompatible agents, such as sugars (15,16), amino acids (17), and drugs (18,19), can be imaged directly using a relatively new MRI contrast mechanism, chemical exchange saturation transfer (CEST) MRI, a technique that detects small amounts of contrast agent through the saturation of rapidly exchanging protons on these agents (20). Using this approach, enzyme detection has been accomplished using its natural substrates as MRI reporters (21).…”