Nanoparticle Transport in the Brain

纳米颗粒在大脑中的运输

• 批准号: 1133426
• 负责人: Chris Schaffer
• 金额: $ 35.06万
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1133426&HistoricalAwards=false
• 关键词: Nanoparticle; Transport; Brain

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.

[133426 . PI] olbricht纳米颗粒在大脑皮层的运动和运输将被实验和分析研究。双光子激发荧光（2PEF）显微镜将用于实时观察和跟踪将纳米颗粒直接注入麻醉大鼠皮层的运动。最近的证据表明，纳米颗粒沿着血管周围空间（皮层血管周围的薄环形区域）快速移动，可能是由心跳驱动的血管壁脉动推动其通过血管周围空间。该项目包括三种方法。首先，将使用2PEF显微镜测量注入大鼠皮层血管周围空间内外的纳米粒子的速度。将确定颗粒大小和心跳速率对这些速度的影响，并将在刚性纳米颗粒和可变形脂质体之间进行比较。其次，纳米颗粒的运动将在体外薄神经组织切片中进行研究，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影响。近年来，许多用于治疗包括癌症在内的严重脑部疾病的新型治疗性化合物都很难输送到脑组织中。大多数静脉注射的药物被血脑屏障阻止进入脑组织。对流增强输送（CED）是一种绕过血脑屏障的创新方法，通过细针或导管注入药物和载药纳米颗粒，这些细针或导管通过颅骨上的一个小孔插入大脑。尽管这种方法很有前景，但在实践中，预测注入的药物和纳米颗粒的空间分布或保证它们到达目标组织已被证明是困难的。例如，在针对最常见的脑癌——脑胶质瘤的CED治疗中，药物通常无法深入大脑，无法到达容易渗入健康组织的恶性细胞。为了优化CED治疗，有必要了解纳米颗粒在脑组织中运输的基本机制。在这个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药物在整个大脑中的分布。