Real-time imaging of perivascular transport of nanoparticles during convection-enhanced delivery in the rat cortex.

Convection-enhanced delivery (CED) is a promising technique for administering large therapeutics that do not readily cross the blood brain barrier to neural tissue. It is of vital importance to understand how large drug constructs move through neural tissue during CED to optimize construct and delivery parameters so that drugs are concentrated in the targeted tissue, with minimal leakage outside the targeted zone. Experiments have shown that liposomes, viral vectors, high molecular weight tracers, and nanoparticles infused into neural tissue localize in the perivascular spaces of blood vessels within the brain parenchyma. In this work, we used two-photon excited fluorescence microscopy to monitor the real-time distribution of nanoparticles infused in the cortex of live, anesthetized rats via CED. Fluorescent nanoparticles of 24 and 100 nm nominal diameters were infused into rat cortex through microfluidic probes. We found that perivascular spaces provide a high permeability path for rapid convective transport of large nanoparticles through tissue, and that the effects of perivascular spaces on transport are more significant for larger particles that undergo hindered transport through the extracellular matrix. This suggests that the vascular topology of the target tissue volume must be considered when delivering large therapeutic constructs via CED.