Intracranial delivery of recombinant nerve growth factor: release kinetics and protein distribution for three delivery systems.

Abstract

Three different polymeric delivery systems, composed of either poly(ethylene-co-vinyl acetate) (EVAc) or poly(lactide-co-glycolide) (PLGA), were used to administer recombinant human nerve growth factor (rhNGF) intracranially in rats. The delivery systems were characterized with respect to release kinetics, both in the brain and in well-stirred buffer solutions. During incubation in buffered saline, the delivery systems released rhNGF in distinct patterns: sustained (EVAc), immediate (PLGA1) and delayed (PLGA2). One 10-mg delivery system was implanted in each rat and an ELISA technique was used to determine the amount of rhNGF in 1-mm coronal brain slices produced immediately after removal of the delivery system. High levels of rhNGF (as high as 60,000 ng in a brain slice of approximately 50 microliters) were recovered from the brain tissue at 1, 2, and 4 weeks after implantation. With all three delivery systems, the amount of rhNGF in each brain slice decreased exponentially with distance from the implant site: the distance over which concentration decreased by 10-fold was 2-3 mm for all delivery systems. When rhNGF release was moderate (10 to 200 ng rhNGF/day), the total amount of rhNGF in the brain increased linearly with release rate, suggesting an overall rate of rhNGF elimination of 0.4 hr-1 or a half-life of 1.7 hr. With higher release rates (500 to 50,000 ng rhNGF/day), total amounts of rhNGF in the brain were considerably higher than anticipated based on this rate of elimination. Polymeric controlled release can provide high, localized doses of rhNGF in the brain. All of the experimental data were consistent with penetration of rhNGF through the brain tissue with a diffusion coefficient approximately 8 x 10(-7) cm2/s, which is approximately 50% of the diffusion coefficient in water.