1 Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
2 Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Cell Transplant. 2017 Jul;26(7):1235-1246. doi: 10.1177/0963689717715824.
Focused ultrasound (FUS)-mediated blood-brain barrier disruption (BBBD) can enable even large therapeutics such as stem cells to enter the brain from the bloodstream. However, the efficiency is relatively low. Our previous study showed that human neural progenitor cells (hNPCs) loaded with superparamagnetic iron oxide nanoparticles (SPIONs) in culture were attracted by an external magnetic field. In vivo, enhanced brain retention was observed near a magnet mounted on the skull in a rat model of traumatic brain injury, where BBBD also occurs. The goal of the current study was to determine whether magnetic attraction of SPION-loaded hNPCs would also enhance their retention in the brain after FUS-mediated BBBD. A small animal magnetic resonance imaging (MRI)-guided FUS system operating at 1.5 MHz was used to treat rats (∼120 g) without tissue damage or hemorrhage. Evidence of successful BBBD was validated with both radiologic enhancement of gadolinium on postsonication TI MRI and whole brain section visualization of Evans blue dye. The procedure was then combined with the application of a powerful magnet to the head directly after intravenous injection of the hNPCs. Validation of cells within the brain was performed by staining with Perls' Prussian blue for iron and by immunohistochemistry with a human-specific antigen. By injecting equal numbers of iron oxide (SPIONs) and noniron oxide nanoparticles-loaded hNPCs, each labeled with a different fluorophore, we found significantly greater numbers of SPIONs-loaded cells retained in the brain at the site of BBBD as compared to noniron loaded cells. This result was most pronounced in regions of the brain closest to the skull (dorsal cortex) in proximity to the magnet surface. A more powerful magnet and a Halbach magnetic array resulted in more effective retention of SPION-labeled cells in even deeper brain regions such as the striatum and ventral cortex. There, up to 90% of hNPCs observed contained SPIONs compared to 60% to 70% with the less powerful magnet. Fewer cells were observed at 24 h posttreatment compared to 2 h (primarily in the dorsal cortex). These results demonstrate that magnetic attraction can substantially enhance the retention of stem cells after FUS-mediated BBBD. This procedure could provide a safer and less invasive approach for delivering stem cells to the brain, compared to direct intracranial injections, substantially reducing the risk of bleeding and infection.
聚焦超声（FUS）介导的血脑屏障破坏（BBBD）可以使即使是像干细胞这样的大型治疗剂也能够从血液进入大脑。然而，效率相对较低。我们之前的研究表明，在培养物中加载超顺磁氧化铁纳米颗粒（SPION）的人神经祖细胞（hNPC）会被外部磁场吸引。在体内，在创伤性脑损伤大鼠模型中，在颅骨上安装的磁铁附近观察到增强的脑保留，其中也发生了 BBBD。目前研究的目的是确定 FUS 介导的 BBBD 后，负载 SPION 的 hNPC 被磁场吸引是否也会增强它们在大脑中的保留。使用工作频率为 1.5 MHz 的小动物磁共振成像（MRI）引导 FUS 系统治疗体重约为 120 克的大鼠，不会造成组织损伤或出血。通过在超声后 TI MRI 上钆的放射性增强和 Evans 蓝染料的全脑切片可视化来验证成功的 BBBD。然后，在将 hNPC 静脉注射后直接将强力磁铁应用于头部，将该程序与该程序相结合。通过普鲁士蓝染色检测铁和免疫组织化学检测人特异性抗原对脑内细胞进行验证。通过注射等量的负载氧化铁（SPION）和非氧化铁纳米颗粒的 hNPC，并用不同的荧光染料标记每种细胞，我们发现与非铁负载细胞相比，在 BBBD 部位保留了更多数量的负载 SPION 的细胞。在最靠近磁铁表面的颅骨附近（背侧皮质）的大脑区域中，这一结果最为明显。更强的磁铁和 Halbach 磁阵列导致 SPION 标记的细胞在更深的脑区（纹状体和腹侧皮质）中更有效地保留，高达 90%的观察到的 hNPC 含有 SPION，而使用较弱的磁铁则为 60%至 70%。与 2 小时相比，治疗后 24 小时观察到的细胞更少（主要在背侧皮质）。这些结果表明，磁场吸引可以大大增强 FUS 介导的 BBBD 后干细胞的保留。与直接颅内注射相比，该方法为将干细胞递送到大脑提供了一种更安全，侵入性更小的方法，大大降低了出血和感染的风险。
Cell Transplant. 2016
Annu Int Conf IEEE Eng Med Biol Soc. 2013
Bioengineering (Basel). 2025-6-16
Adv Drug Deliv Rev. 2024-8
Stem Cell Rev Rep. 2023-8
Adv Drug Deliv Rev. 2022-12
Drug Deliv Transl Res. 2021-12
Hong Kong Med J. 2016-8
Curr Pharm Des. 2016
Cell Transplant. 2016
Zotero 插件
