Localized delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound.
Localized delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound.
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DOI：
10.1016/j.biomaterials.2016.01.021
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发表时间：
2016-03
期刊：
影响因子：
14
通讯作者：
Corbin IR
中科院分区：
文献类型：
--
作者：
Mulik RS;Bing C;Ladouceur-Wodzak M;Munaweera I;Chopra R;Corbin IR
在微泡存在下的聚焦超声暴露可以实现短暂的、非侵入性的和局部的血脑屏障（BBB）开放，提供了将治疗剂靶向递送到脑中的方法。用二十二碳六烯酸（DHA）重构的低密度脂蛋白（LDL）纳米颗粒可能在大脑中具有显著的治疗价值，因为已知DHA具有神经保护作用。在正常大鼠的局部脑区使用脉冲超声暴露实现BBB开放，之后静脉内施用含有荧光探针DiR（1，1 ′-双十八烷基-3，3，3 ′，3 ′-四甲基吲哚三羰花青碘化物）或DHA的LDL纳米颗粒。给予LDL-DiR的大鼠脑组织的荧光成像显示出暴露半球中荧光信号的强烈定位。LDL-DHA给药在大脑暴露区域产生2倍以上的DHA，Resolvin D1水平相应增加，表明DHA被掺入细胞并代谢。组织学评价未表明与正常大脑相比，暴露大脑区域的组织损伤增加的任何证据。这项工作表明，使用全身给药的LDL纳米颗粒结合脑中的脉冲聚焦超声暴露，可以将DHA局部递送到脑中。该技术可用于急性脑损伤区域或作为靶向脑中浸润肿瘤细胞的手段。
Focused ultrasound exposures in the presence of microbubbles can achieve transient, non-invasive, and localized blood-brain barrier (BBB) opening, offering a method for targeted delivery of therapeutic agents into the brain. Low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) could have significant therapeutic value in the brain, since DHA is known to be neuroprotective. BBB opening was achieved using pulsed ultrasound exposures in a localized brain region in normal rats, after which LDL nanoparticles containing the fluorescent probe DiR (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide) or DHA were administered intravenously. Fluorescent imaging of brain tissue from rats administered LDL-DiR demonstrated strong localization of fluorescence signal in the exposed hemisphere. LDL-DHA administration produced 2× more DHA in the exposed region of the brain, with a corresponding increase in Resolvin D1 levels, indicating DHA was incorporated into cells and metabolized. Histological evaluation did not indicate any evidence of increased tissue damage in exposed brain regions compared to normal brain. This work demonstrates that localized delivery of DHA to the brain is possible using systemically-administered LDL nanoparticles combined with pulsed focused ultrasound exposures in the brain. This technology could be used in regions of acute brain injury or as a means to target infiltrating tumor cells in the brain.