Nanoparticle Transport in the Brain

1133426 PI：Olbricht纳米粒子在大脑皮层中的运动和运输将通过实验和分析进行检查。 双光子激发荧光（2PEF）显微镜将用于可视化和跟踪在真实的时间的纳米粒子的运动直接注入到活的，麻醉大鼠的皮质。 最近的证据表明，纳米粒子沿着血管周围的空间（围绕皮层血管的薄环形区域）快速沿着移动，并且可能通过心跳驱动的血管壁脉动推动通过血管周围的空间。 该项目包括三种方法。 首先，2PEF显微镜将用于测量大鼠皮质中血管周围空间内部和血管周围空间外部的输注纳米颗粒的速度。将确定颗粒大小和心跳速率对这些速度的影响，并在刚性纳米颗粒和可变形脂质体之间进行比较。 第二，纳米粒子的运动将在薄的神经组织切片中进行体外研究，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，以帮助解释数据并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严重脑疾病（包括癌症）的新治疗化合物很难输送到脑组织。 大多数静脉给药的药物都被血脑屏障阻止进入脑组织。 对流增强递送（CED）是一种创新方法，其通过经由颅骨中的小孔插入大脑的细针或导管注入药物和载药纳米颗粒来绕过血脑屏障。 尽管该方法很有前途，但在实践中已证明难以预测输注药物和纳米颗粒的空间分布或保证它们到达靶组织。 例如，在用于脑胶质瘤（脑癌的最普遍形式）的CED疗法中，药物通常不能渗透到大脑中足够远以到达容易渗透健康组织的恶性细胞。 为了优化CED治疗，必须了解纳米颗粒在脑组织中转运的基本机制。 在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于规划CED策略的结果，以及科学家和工程师可以用于开发基于计算机的模型来预测整个大脑中注入药物的分布。

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.