人酸性成纤维细胞生长因子与穿膜肽融合蛋白在鼠体内的药代动力学及血脑屏障通透性研究
Pharmacokinetics of a fusion protein for human acidic fibroblast growth factor and transcriptional activator protein in rat and its penetration across blood-brain barrier
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摘要:
研究穿膜肽 (transcriptional activator protein, TAT) 和人酸性成纤维细胞生长因子 (human acidic fibroblast growth factor, haFGF) 融合蛋白TAT-haFGF14−154静脉注射 (iv) 后在大鼠血浆中的药代动力学特性, 并探讨其在大鼠和小鼠体内血脑屏障的通透性, 为阿尔茨海默症 (Alzheimer’s disease, AD) 的临床治疗用药提供依据。酶联免疫吸附实验 (ELISA) 检测静脉注射后TAT-haFGF14−154在大鼠血浆和小鼠脑匀浆液的含量, 免疫组织化学法检测大鼠和小鼠脑中的分布。结果表明, 大鼠单次颈静脉注射TAT-haFGF14−154 300 μg·kg−1后, 血药浓度-时间曲线符合二室开放模型, 加权为1/C2, 属于线性动力学消除, 其中, 分布半衰期为 (0.049 ± 0.03) h, 消除半衰期为 (0.55 ± 0.05) h。结果提示, TAT-haFGF14−154在体内消除较快, 可以迅速穿过血脑屏障, 分布于大脑皮质和海马区, 并定位于细胞核。
Abstract:This paper is to report the study of the pharmacokinetics of a fusion protein TAT-haFGF14−154 for human acidic fibroblast growth factor and transcriptional activator protein in rat plasma, and the investigation of their penetration across blood-brain barrier in mice and rats, in order to provide a basis for clinical development and treatment of Alzheimer’s disease. Enzyme-linked immunosorbent assay (ELISA) was used to determine concentration of TAT-haFGF14−154 in rat plasma and in mouse brain homogenate; and immunohistochemistry was used to analyze the distribution in brain. The concentration-time curve fitted two-compartment open model which was linear kinetics elimination after a single intravenous injection of TAT-haFGF14−154 in rat at the dose of 300 μg·kg−1. The half life time was 0.049 ± 0.03 h for distribution phase and 0.55 ± 0.05 h for elimination phase, and the weight was 1/C2. The result showed that TAT-haFGF14−154 could be detected in the brain by ELISA and immunohistochemistry, the elimination of TAT-haFGF14−154 in rat was swift, and TAT-haFGF14−154 could penetrate across the blood-brain barrier, distribute in pallium and hippocampus and locate in the nucleus.
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