J. Mike Walker '66 Department of Mechanical Engineering, Texas A&M University, College Station, TX 77843, United States of America.
Department of Psychological and Brain Sciences, Texas A&M University, College Station, TX 77843, United States of America.
J Control Release. 2022 May;345:557-571. doi: 10.1016/j.jconrel.2022.03.007. Epub 2022 Mar 8.
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 R = 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.
由于血脑屏障（BBB）的低通透性和高选择性，现有的脑部治疗技术受到传统药物难以有效穿透 BBB 的限制。磁性纳米颗粒（MNPs）在外加静态磁场（SMF）下作为高效穿透 BBB 的纳米载体具有巨大潜力。为了定量评估 SMF 对 MNPs 体内穿透 BBB 动力学的影响，我们建立了一个基于生理学的药代动力学（PBPK）模型，用于研究腹腔内（IP）注射的超顺磁性氧化铁纳米颗粒（包覆金并与聚乙二醇（PEG）偶联）在小鼠体内的动力学。与大多数忽略脑通透性的报道 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，获得有无 SMF 时的脑通透性。脑内的浓度通过对流-扩散方程模拟，并在 COMSOL Multiphysics 中数值求解。将脑通透性纳入 PBPK 模型后的结果与体内结果吻合较好（回归系数 R=0.848），验证了该 PBPK 模型预测 SMF 暴露下 SPIO-Au-PEG NPs 体内分布的能力。此外，体内结果表明，SMF 暴露下血液向大脑的分布系数（4.01%）略优于对照组（3.68%）。此外，与非胰岛素组相比，SPIO-Au-PEG-胰岛素（SPIO-Au-PEG-insulin）的修饰使大脑生物利用度提高了 24.47%。与无 SMF 组相比，SPIO-Au-PEG-insulin 在 SMF 刺激下的脑生物利用度进一步提高了 3.91%。本文中的 PBPK 模型和体内验证为未来非侵入性靶向脑部药物输送的研究奠定了基础。
