Dilation and degradation of the brain extracellular matrix enhances penetration of infused polymer nanoparticles

Abstract

This study investigates methods of manipulating the brain extracellular matrix (ECM) to enhance the penetration of nanoparticle drug carriers in convection-enhanced delivery (CED). A probe was fabricated with two independent microfluidic channels to infuse, either simultaneously or sequentially, nanoparticles and ECM-modifying agents. Infusions were performed in the striatum of the normal rat brain. Monodisperse polystyrene particles with a diameter of 54 nm were used as a model nanoparticle system. Because the size of these particles is comparable to the effective pore size of the ECM, their transport may be significantly hindered compared with the transport of low molecular weight molecules. To enhance the transport of the infused nanoparticles, we attempted to increase the effective pore size of the ECM by two methods: dilating the extracellular space and degrading selected constituents of the ECM. Two methods of dilating the extracellular space were investigated: co-infusion of nanoparticles and a hyperosmolar solution of mannitol, and pre-infusion of an isotonic buffer solution followed by infusion of nanoparticles. These treatments resulted in an increase in the nanoparticle distribution volume of 50% and 123%, respectively. To degrade hyaluronan, a primary structural component of the brain ECM, a pre-infusion of hyaluronidase (20,000 U/mL) was followed after 30 min by infusion of nanoparticles. This treatment resulted in an increase in the nanoparticle distribution of 64%. Our results suggest that both dilation and enzymatic digestion can be incorporated into CED protocols to enhance nanoparticle penetration.

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

“…Interestingly, however, Chen et al demonstrated that coating the nanoparticles with albumin to shield the hydrophobic particle surface significantly improved their distribution. 46 Furthermore, Neeves et al 48 demonstrated that preinfusing the striatum with isotonic saline significantly improved the distribution of 53 nm diameter polystyrene nanoparticles in the striatum of rats. This effect was greater than was observed with preinfusion of hyaluronidase to degrade the brain extracellular matrix or with hyperosmotic mannitol to osmotically expand the extracellular space.…”

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

“…By contrast, CED of polymeric nanoparticles, such as nanoparticles made of poly(lactide-coglycolide) (PLGA), offers the possibility of controlled agent release. However, CED of PLGA nanoparticles, which are typically 100-200 nm in diameter, has been limited by the failure of particles to move by convection through the brain interstitial spaces (20)(21)(22)(23), which are 38-64 nm in normal brain (24) and 7-100 nm in regions with tumor (25). Therefore, to overcome the first and second challenges, it is necessary to synthesize polymer nanocarriers that are much smaller than conventional particles and still capable of efficient drug loading and controlled release.…”

Convection-enhanced delivery to the central nervous system

“…24,33,42,106 While small-and most large-molecular-weight compounds will distribute by convective flow in a similar manner, viruses, virus-sized particles, and nanoparticles have restricted flow (tissue distribution volume to infusion volume ratio of 2:1 to 3:1). 13,42,106 This reduction in delivery efficiency is attributed to limits in the size of the extracellular space in the CNS, which has been estimated to be on the order of 100 nm, 75,108 and to certain features of the infused nanoparticle. 42 …”