(280j) Convection-Enhanced Transport of Polymeric Nanoparticles In the Perivascular Space of the Brain

Convection-enhanced delivery (CED) is a novel therapy for the treatment of brain gliomas and other neural tissue disorders that involves direct infusion of therapeutics into the brain tissue interstitium through an implanted needle or microcatheter. Owing to the high pressure at the tip of the needle, infused material flows radially outward from the needle through the interstitium. For chemotherapy, CED increases the penetration of infusate into tissue so that infused therapeutics reach malignant cells that have infiltrated otherwise healthy tissue. Several potent chemotherapeutics that selectively target malignant cells have been developed in recent years. However, they are fragile proteins that are susceptible to elimination and degradation during transit through neural tissue. Encapsulating these drugs in polymeric nanoparticles or liposomes may protect them in transit during CED and provide long-term controlled release after they are distributed throughout the tissue. Our aim is to understand how such polymeric nanoparticles are transported in the brain when infused under pressure.

Recent studies suggest that the infusate in CED is transported preferentially in the perivascular space (PVS), which refers to the thin fluid-filled layer that surrounds each arterial blood vessel. Furthermore, CED experiments involving infusions into rodents suggest that arterial pulsation associated with heartbeat can strongly affect the transport of therapeutic molecules by CED (1). Other researchers have observed that the perivascular spaces are preferential pathways for nanoparticle transport in the brain (2).

We present the results of in vivo experiments that demonstrate preferential transport of nanoparticles in the PVS during CED infusions. Using two-photon excited fluorescence microscopy, we record in real time the transport of fluorescently-labeled nanoparticles in the rat cortex during CED. Results show that at the advancing front of infusate, suspended nanoparticles are confined to thin regions surrounding arterioles.

We then present an analytical model to describe quantitatively the enhancement of fluid transport in the PVS by peristaltic pumping associated with arterial pulsation. We assume that the relevant Reynolds number is small and that peristaltic pumping produces a train of sinusoidal waves on the walls of the arterial blood vessels. The governing equations for fluid transport in the PVS (generalized Darcy's equations) are transformed into the reference frame of the traveling wave. Using a long-wavelength approximation and lubrication analysis, we derive a relationship between the pressure gradient and the time-averaged flow rate in the PVS. Our results show that in the absence of an imposed pressure gradient due to CED, fluid flow in the PVS can be induced by the peristaltic motion of the blood vessel walls. In the presence of an imposed pressure gradient due to CED, the contribution of peristaltic pumping to the overall flow rate in the PVS can be significant.

References:

[1] Hadaczek, P. et al., ?The ?perivascular pump' driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain?, Molecular Therapy 14 (1), 69-78 (2006)

[2] Neeves, K.B. et al., ?Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles?, Brain Research 1180, 121-132 (2007)