Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.
Label-free CEST MRI Detection of Citicoline-Liposome Drug Delivery in Ischemic Stroke.
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作者：
Liu H;Jablonska A;Li Y;Cao S;Liu D;Chen H;Van Zijl PC;Bulte JW;Janowski M;Walczak P;Liu G
胞二磷胆碱（CDPC）是一种天然补充剂，在治疗神经退行性疾病中具有良好的神经保护作用。在本研究中，我们试图利用胞二磷胆碱作为治疗诊断剂，其固有的化学交换饱和转移（CEST）MRI信号，可以直接用作MRI指导胞二磷胆碱药物输送。我们的体外CEST MRI结果显示胞磷胆碱在+1和+2 ppm处具有两个固有CEST信号，分别归因于可交换的羟基和胺质子。为了促进胞二磷胆碱靶向给药到缺血区域，我们制备了包封胞二磷胆碱的脂质体（CDPC-lipo），并表征了颗粒性质和CEST MRI性质。然后在由两小时大脑中动脉闭塞诱导的单侧短暂缺血的大鼠脑模型中检查脂质体胞二磷胆碱的体内CEST MRI检测。结果表明，CPDC-lipo向脑缺血区的递送可以通过CEST MRI进行监测和定量。当动脉内给药时，CDPC-lipo在2 ppm时清楚地显示出可检测的CEST MRI对比度。CEST MRI显示脂质体优先积聚在血脑屏障破坏的缺血区域。我们还使用CEST MRI检测在相同的动物模型中使用靶向血管细胞粘附分子（VCAM）-1的CDPC-lipo的药物递送的改善。使用荧光显微镜验证MRI结果。因此，脂质体胞二磷胆碱代表了原型治疗诊断系统，其中治疗剂可以以无标记的方式直接通过CEST MRI检测。
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.