DISTRIBUTION OF NERVE GROWTH-FACTOR FOLLOWING DIRECT DELIVERY TO BRAIN INTERSTITIUM
DISTRIBUTION OF NERVE GROWTH-FACTOR FOLLOWING DIRECT DELIVERY TO BRAIN INTERSTITIUM
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DOI：
10.1016/0006-8993(95)00261-n
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发表时间：
1995-05-22
期刊：
影响因子：
2.9
通讯作者：
SALTZMAN, WM
中科院分区：
文献类型：
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作者：
KREWSON, CE;KLARMAN, ML;SALTZMAN, WM
几项研究表明，神经生长因子(NGF)在治疗阿尔茨海默病患者中具有潜力。为了研究神经生长因子在脑间质中的转运，我们将含有神经生长因子和[I-125]神经生长因子的控释聚合物植入成年雄性大鼠的大脑，并测量了长达一周的神经生长因子的空间分布。用酶联免疫吸附试验、放射计数和放射自显影测定脑组织中神经生长因子的浓度。在植入后2天，在植入部位同侧半球厚(1 Mm)的冠状切片中，可检测到超过50pg/切片的NGF，直到聚合物边缘的吻侧和尾侧3 mm。较低水平的放射性(每节5 pg但50 pg NGF)可以在大脑的其余部分检测到。在含有聚合物的组织切片中，含量最高，达到每一切片9.5毫微克。薄层(20微米)冠状切片的放射自显影显示，紧邻聚合物的局部NGF浓度接近40微克/毫升。对放射自显影上连续切片的分析证实，NGF在任何方向上只向聚合物输送2-3毫米。在植入后1周，NGF的分布模式与2天时相似，种植部位附近的NGF浓度仍然很高。局部NGF浓度分布与简单的一阶消除扩散模型的比较表明，NGF通过组织间扩散在组织中移动，半衰期约为0.5h。NGF在脑组织中的传输范围有限表明：(I)NGF等蛋白质药物可能需要几乎直接输送到作用部位才能有效；以及(Ii)与将NGF和其他蛋白质制剂输送到非靶细胞相关的毒性，如全身给药通常发生的那样，可以通过局部间质递送来减少，因为治疗可以限制在小体积的大脑中。
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 [I-125]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 mu m) coronal sections indicated that local NGF concentrations immediately adjacent to the polymer approached 40 mu g/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.