The 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.
