Krewson C E, Klarman M L, Saltzman W M
Department of Chemical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Brain Res. 1995 May 22;680(1-2):196-206. doi: 10.1016/0006-8993(95)00261-n.
Several studies suggest the potential of nerve growth factor (NGF) in the treatment of patients with Alzheimer's disease. To characterize NGF transport within the brain interstitium, we implanted controlled release polymers containing NGF and [125I]NGF into the brains of adult male rats and measured spatial distributions of NGF for up to one week. NGF concentration in the brain was quantified using ELISA, radiation counting, and autoradiography. At 2 days post-implantation, quantities of NGF in excess of 50 pg per section were detected within thick (1 mm) coronal slices of the hemisphere ipsilateral to the site of implantation up to 3 mm rostral and caudal to the edge of the polymer. Lower levels of radioactivity (> 5 pg but < 50 pg NGF per section) could be detected throughout the rest of the brain. Levels were highest in the tissue sections containing the polymer, reaching 9.5 ng per section. Autoradiography of thin (20 microns) coronal sections indicated that local NGF concentrations immediately adjacent to the polymer approached 40 micrograms/ml. Analysis of sequential sections on the autoradiograph confirmed that NGF was transported only 2-3 mm from the polymer in any direction. At one week post-implantation, the pattern of NGF distribution was similar to that seen at 2 days, and concentrations remained high near the site of the implant. Comparison of local NGF concentration profiles to simple models of diffusion with first-order elimination suggests that the NGF moved through the tissue by diffusion through the interstitial space with a half-life on the order of 0.5 h. The limited range of NGF transport in brain tissue indicates that: (i) protein drug agents such as NGF will probably need to be delivered almost directly to the site of action for efficacy; and (ii) toxicities associated with delivery of NGF and other protein agents to non-target cells, as often occurs with systemic delivery of drugs, may be reduced by local, interstitial delivery since therapy can be restricted to a small volume of the brain.
多项研究表明神经生长因子（NGF）在治疗阿尔茨海默病患者方面具有潜力。为了描述NGF在脑间质中的转运情况，我们将含有NGF和[125I]NGF的控释聚合物植入成年雄性大鼠脑中，并测量长达一周的NGF空间分布。使用酶联免疫吸附测定法（ELISA）、放射性计数和放射自显影术对脑中的NGF浓度进行定量。植入后2天，在植入部位同侧半球的厚（1毫米）冠状切片中，在聚合物边缘向前和向后3毫米范围内检测到每切片超过50皮克的NGF量。在大脑其余部分可检测到较低水平的放射性（>5皮克但<50皮克NGF/切片）。聚合物所在的组织切片中水平最高，达到9.5纳克/切片。薄（20微米）冠状切片的放射自显影表明，紧邻聚合物的局部NGF浓度接近40微克/毫升。对放射自显影片上连续切片的分析证实，NGF在任何方向上仅从聚合物运输2 - 3毫米。植入后一周，NGF分布模式与2天时相似，植入部位附近浓度仍然很高。将局部NGF浓度分布与具有一级消除的简单扩散模型进行比较表明，NGF通过间质空间扩散在组织中移动，半衰期约为0.5小时。脑组织中NGF转运范围有限表明：（i）诸如NGF之类的蛋白质药物制剂可能需要几乎直接递送至作用部位才能有效；（ii）与将NGF和其他蛋白质制剂递送至非靶细胞相关的毒性，如药物全身递送时经常发生的情况，可通过局部间质递送降低，因为治疗可局限于脑的小体积区域。
