Intracranial delivery of recombinant nerve growth factor: Release kineticsand protein distribution for three delivery systems

Purpose, Three different polymeric delivery systems, composed of either pol y(ethylene-co-vinyl acetate) (EVAc) or poly(lactide-co-glycolide) (PLGA), w ere used to administer recombinant human nerve growth factor (rhNGF) intrac ranially in rats. Methods, The delivery systems were characterized with respect to release ki netics, both in the brain and in well-stirred buffer solutions. Results, During incubation in buffered saline, the delivery systems release d rhNGF in distinct patterns: sustained (EVAc), immediate (PLGA(1)), and de layed (PLGA(2)). 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. Hig h levels of rhNGF las high as 60,000 ng in a brain slice of similar to 50 m u L) were recovered from the brain tissue at 1, 2, and 4 weeks after implan tation. With all three delivery systems, the amount of rhNGF in each brain slice decreased exponentially with distance from the implant site: the dist ance over which concentration decreased by 10-fold was 2-3 mm for all deliv ery 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, s uggesting 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 a mounts of rhNGF in the brain were considerably higher than anticipated base d on this rate of elimination. Conclusions. Polymeric controlled release can provide high. localized doses of rhNGF in the brain. All of the experimental data were consistent with p enetration of rhNGF through the brain tissue with a diffusion coefficient s imilar to 8 x 10(-7) cm(2)/s, which is similar to 50% of the diffusion coef ficient in water.