(148c) Transport of Nanoparticles in the Brain

We report the results of experimental studies of the motion of fluid and nanoparticles in the brain. This is an important problem for drug delivery in neural tissue, and it is directly relevant to convective-enhanced delivery (CED), a treatment in which fluid containing therapeutic molecules is injected directly into the interstitium of the brain. In some strategies, the therapeutic molecules are packaged in nanoparticles and released over time after the nanoparticles have reached targeted tissue. Numerous studies show that the efficacy of CED therapy depends on a uniform spatial distribution of therapeutic throughout the afflicted tissue, which is difficult to achieve in clinical practice. Many investigators have found indirectly that fluid motion in CED is enhanced in perivascular spaces, which are thin regions of relatively high hydraulic conductivity immediately outside blood vessel walls.

Using two-photon excitation microscopy, we have measured the velocities of fluid and nanoparticles in real time during CED into the cortex of living, anesthetized rodents. Two-photon microscopy is especially useful in highly scattering materials such as tissue, and in this case the motion the motion of fluorescent nanoparticles and fluid can be detected deep into the cortex. During CED infusion at constant volumetric flow rate into the cortex, we have measured simultaneously the velocity of fluid and rigid fluorescent nanoparticles in the interstitial space and in the perivascular space. Nanoparticles ranged in size from 20 to 200 nm.

We have found that nanoparticle motion is significantly hindered in the interstitial space; the fluid velocity can exceed the nanoparticle velocity by more than an order of magnitude for larger nanoparticles. However, the difference in velocity is much less for nanoparticles in the perivascular space. Furthermore, the velocity of a nanoparticle in the perivascular space does not decrease with distance from the infusion source, suggesting that motion in the perivascular space resembles flow in a closed annular tube rather than motion from a point source in a porous medium. These results could help explain the distribution of nanoparticles in CED therapy and could be used to improve numerical simulations of the therapy.