MRI引导聚焦超声开放血脑屏障靶向传递不同分子数量级药物的研究

Targeted Delivery of Different Molecular Order of Magnitude of Drugs by MRI-guided Focused Ultrasound-induced Blood-brain Barrier Disruption

探讨MRI引导聚焦超声开放兔血脑屏障(BBB)后药物在脑内的摄入量与药物分子量之间的关系及药物在靶区空间分布情况。25只新西兰大白兔被随机平均分为5组,在MRI引导聚焦超声开放BBB后,分别静脉注入荧光标记的不同分子数量级的右旋糖酐(10,150 and 2000 k Da),采用激光共聚焦显微镜检测其在靶区的荧光强度,并将切片行免疫荧光染色观察右旋糖酐与神经元标志物共区域化现象。10k Da的右旋糖酐以最高浓度呈片状分布在整个超声照射区域,而150 k Da和2000 k Da的右旋糖酐以较低的浓度在靶区呈点状分布(P<0.01);通过与神经元标志物共区域化,10k Da的右旋糖酐更为均一的分布在整个神经元胞浆和胞核内,而150 k Da和2000 k Da的右旋糖酐在神经元胞浆内主要以囊泡样结构分布,且后者该结构的数量较少。MRI引导聚焦超声开放BBB后,药物在脑内的摄入量与药物分子量有关,分子量越小靶区药物浓度越高,其在神经元内的分布越均一。本研究将有助于治疗脑部疾病药物的合理设计、选择和应用。

To investigatethe relationship between the molecular weights of drugs and the quantity of brain uptake, the exact spatial distribution of drugs in the target region after blood-brain barrier （ BBB） disrupted by magnetic reso-nance image （MRI）-guided focused ultrasound （FUS）. Following BBB disruptions in rabbits （n=25） were achieved by MRI-guided FUS, fluorescence labeled dextrans （10, 150 and 2000 kDa） were administered intravenously. The laser confocal microscope was used to detect the fouroscence intensity in the target region, and colocalization with neu-ron marker of dextrans was detected after the slices were stained by immunofluorescence. The 10 kDa dextran was flak-ily distributed throughout the sonicated region at the highest concentration, however, 150 kDa and 2000 kDa dextran exhibited punctate distribution with lower concentration. Through colocalized with neuron marker, the 10 kDa dextran exhibited more homogeneous distribution throughout the cytosol and nucleus of neurons. In contrast, dextrans of 150 and 2000 kDa were mainly localized in vesicle-like structures in the cytosol of the neuron, especially 2000 kDa dex-tran with smaller amount of vesicular-like localization. In conclusion, after BBB was opened by MRI-guided FUS, the quantity of brain uptake was associated with the molecular weights of drugs. The smaller the molecular weights, the higher the concentration in the target region, and the more homogeneous drug distributed in the neurons. This study contributes to the rational design, selection and application of drug therapies for CNS diseases.