Blood-brain barrier crossing using magnetic stimulated nanoparticles
Blood-brain barrier crossing using magnetic stimulated nanoparticles
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DOI：
10.1016/j.jconrel.2022.03.007
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发表时间：
2022-03-29
影响因子：
10.8
通讯作者：
Wang, Ya
中科院分区：
文献类型：
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作者：
Chen, Jingfan;Yuan, Muzhaozi;Wang, Ya
由于血脑屏障（BBB）的低渗透性和高选择性，现有的脑治疗技术受到常规药物穿过BBB效率低下的限制。磁性纳米粒子（MNP）作为纳米载体在外加静磁场（SMF）下有效地穿越血脑屏障（BBB）显示出巨大的潜力。为了量化SMF对MNP朝向BBB穿越的体内动力学的影响，我们开发了一种基于生理学的药物动力学（PBPK）模型，用于在小鼠中腹膜内（IP）注射由金涂覆并与聚（乙二醇）（PEG）缀合的超顺磁性氧化铁纳米颗粒（SPIO-Au-PEG NPs）。与大多数报道的忽略脑渗透性的PBPK模型不同，我们首先通过测定脑血液和脑组织中SPIO-Au-PEG NPs的浓度来获得具有和不具有SMF的脑渗透性。通过对流扩散方程模拟大脑中的浓度，并在COMSOL Multiphysics中进行数值求解。结合脑渗透性后的PBPK模型的结果显示出与体内结果的良好一致性（回归系数R2 = 0.848），验证了使用所提出的PBPK模型预测暴露于SMF下SPIO-Au-PEG NPs的体内生物分布的能力。此外，体内结果显示，SMF暴露下从血液到脑的分布系数（4.01%）略好于对照组（3.68%）。此外，与非胰岛素组相比，用胰岛素修饰SPIO-Au-PEG NPs（SPIO-Au-PEG-胰岛素）显示脑生物利用度提高了24.47%。在SMF刺激下，SPIO-Au-PEG-胰岛素的脑生物利用度比无SMF组进一步提高了3.91%。本文建立的PBPK模型及体内验证为进一步研究脑内无创靶向给药奠定了基础。
Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly (ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.848) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the distribution coefficient from blood to brain under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47% in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91% compared to the group without SMF. The PBPK model and in vivo validation in this paper lay a solid foundation for future study on non-invasive targeted drug delivery to the brain.