Saltzman W M, Mak M W, Mahoney M J, Duenas E T, Cleland J L
School of Chemical Engineering, Cornell University, Ithaca, New York 14853, USA.
Pharm Res. 1999 Feb;16(2):232-40. doi: 10.1023/a:1018824324275.
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.
使用由聚（乙烯 - 共 - 醋酸乙烯酯）（EVAc）或聚（丙交酯 - 共 - 乙交酯）（PLGA）组成的三种不同的聚合物递送系统，将重组人神经生长因子（rhNGF）颅内注射到大鼠体内。
对递送系统在脑内和充分搅拌的缓冲溶液中的释放动力学进行了表征。
在缓冲盐水中孵育期间，递送系统以不同模式释放rhNGF：持续释放（EVAc）、立即释放（PLGA1）和延迟释放（PLGA2）。将一个10毫克的递送系统植入每只大鼠体内，并使用ELISA技术测定在取出递送系统后立即制备的1毫米冠状脑切片中rhNGF的量。在植入后1、2和4周，从脑组织中回收了高水平的rhNGF（在约50微升的脑切片中高达60,000纳克）。使用所有三种递送系统时，每个脑切片中rhNGF的量随着距植入部位的距离呈指数下降：所有递送系统中浓度下降10倍的距离为2 - 3毫米。当rhNGF释放适中（10至200纳克rhNGF/天）时，脑中rhNGF的总量随释放速率呈线性增加，表明rhNGF的总体消除速率为0.4小时-1或半衰期为1.7小时。在较高释放速率（500至50,000纳克rhNGF/天）下，脑中rhNGF的总量明显高于基于该消除速率预期的量。
聚合物控释可在脑内提供高剂量的局部rhNGF。所有实验数据均与rhNGF以约8×10（-7）平方厘米/秒的扩散系数穿透脑组织一致，该扩散系数约为水中扩散系数的50％。
