Nanoparticle Transport in the Brain

1133426 PI：Olbricht将通过实验和分析研究纳米颗粒在大脑皮层中的运动和传输。双光子激发荧光(2PEF)显微镜将用于可视化和实时跟踪直接注入活体麻醉大鼠大脑皮质的纳米颗粒的运动。最近的证据表明，纳米颗粒沿着血管周围的空间--皮质血管周围的薄环形区域--快速移动，并可能在心跳驱动的血管壁脉动的推动下穿过血管周围空间。该项目包括三种方法。首先，2PEF显微镜将被用来测量在大鼠大脑皮质血管周围间隙内和血管周围间隙外注入的纳米颗粒的速度。将确定颗粒大小和心率对这些速度的影响，并将硬质纳米颗粒和可变形脂质体进行比较。其次，将在体外研究纳米粒子在神经组织薄片中的运动，以提供支持和扩展体内测量的数据。第三，将对血管周围空间的流体动力学进行分析，以帮助解释数据和检查难以通过实验测试的效果。近年来开发的许多用于治疗包括癌症在内的严重脑部疾病的新治疗化合物很难输送到脑组织。大多数静脉注射的药物都被血脑屏障阻止进入脑组织。对流增强递送(CED)是一种创新的方法，它通过细针或导管注入药物和载药纳米颗粒，然后通过头骨上的一个小孔插入大脑。尽管这种方法前景看好，但事实证明，它很难预测注入的药物和纳米颗粒的空间分布，也很难保证它们到达目标组织。例如，在CED治疗最常见的脑癌形式--脑胶质瘤时，药物往往不能深入大脑，无法到达容易渗透到健康组织的恶性细胞。为了优化CED的治疗，了解纳米颗粒在脑组织中传输的基本机制是必不可少的。该项目中进行的实验和分析将提供研究人员和临床医生可以用来规划CED策略的结果，科学家和工程师可以用来开发基于计算机的模型来预测注射的药物在整个大脑中的分布。

1133426 PI: OlbrichtThe motion and transport of nanoparticles in the brain cortex will be examined experimentally and analytically. Two-photon excited fluorescence (2PEF) microscopy will be used to visualize and track in real time the motion of nanoparticles infused directly into the cortex of live, anesthetized rats. Recent evidence suggests that nanoparticles travel rapidly along perivascular spaces -- thin annular regions surrounding cortical blood vessels -- and may be propelled through perivascular spaces by heartbeat-driven pulsations of blood vessel walls. The project comprises three approaches. First, 2PEF microscopy will be used to measure the velocities of infused nanoparticles inside the perivascular space and outside the perivascular space in the rat cortex. Effects of particle size and heartbeat rate on these velocities will be determined, and comparisons will be made between rigid nanoparticles and deformable liposomes. Second, the motion of nanoparticles will be studied in vitro in thin neural tissue slices to provide data that support and extend the in vivo measurements. Third, an analysis of the hydrodynamics in the perivascular space will be carried out to help interpret data and examine effects that are difficult to test experimentally.Many new therapeutic compounds that have been developed in recent years to treat serious brain disorders, including cancer, are difficult to deliver to brain tissue. Most drugs administered intravenously are prevented from entering brain tissue by the blood-brain barrier. Convection-enhanced delivery (CED) is an innovative method that circumvents the blood-brain barrier by infusing drugs and drug-laden nanoparticles through a fine needle or catheter that is inserted into the brain through a small hole in the skull. Although the method is promising, it has proven difficult in practice to predict the spatial distribution of infused drugs and nanoparticles or to guarantee that they reach targeted tissue. For example, in CED therapy for brain gliomas, the most prevalent form of brain cancer, the drugs often do not penetrate far enough into the brain to reach malignant cells that readily infiltrate healthy tissue. To optimize CED therapy, it is essential to understand the fundamental mechanisms of nanoparticle transport in brain tissue. The experiments and analysis carried out in this project will provide results that researchers and clinicians can use in planning CED strategies and that scientists and engineers can use in developing computer-based models to predict the distribution of infused drugs throughout the brain.