(173c) Enhancing Nanoparticle Penetration in the Brain by Convection Enhanced Delivery and Enzymatic Degradation of the Extracellular Matrix

Nanoparticles offer significant potential for the treatment of brain diseases because of their high loading capacity, low clearance, and targeting capabilities. Delivery of nanoparticles to the brain is inhibited by the highly selective nature of the blood-brain barrier (BBB). Convection enhanced delivery (CED) overcomes the BBB by direct infusion into the extracellular space of the brain. However, the penetration of nanoparticles into tissue can be hindered by steric interactions with the extracellular matrix (ECM).

We have examined the use of proteases to degrade the ECM and enhance nanoparticles penetration under convective flow. The kinetics of two enzymes, hyaluronidase and chondroitinase, were determined by infusions into the caudate of the adult rat brain. Degradation at 0.5, 1, 3, 6, 12, and 24 hours was determined by immunohistochemistry staining for the presence of hyaluronan and chondroitin sulfate proteoglycans. Significant degradation was not observed until 3 hours and essentially complete degradation was observed at 12 hours.

To simultaneously deliver enzymes and nanoparticles we fabricated a dual channel microfluidic probe (Figure 1). We performed a two-stage procedure where an enzyme solution was infused into the caudate of adult rats and allowed to degrade the ECM followed by nanoparticle infusion. We used 20 and 100 nm fluorescent polystyrene beads as a model nanoparticle. Preliminary results suggest that both 20 nm and 100 nm particles can penetrate on the millimeter scale into native brain tissue, but the distribution is highly asymmetric when compared to infusions of proteins.