Evaluation of the safety and brain-related tissues distribution characteristics of TAT-HaFGF via intranasal administration.
Evaluation of the safety and brain-related tissues distribution characteristics of TAT-HaFGF via intranasal administration.
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DOI：
10.1248/bpb.b14-00023
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发表时间：
2014-07
影响因子：
2
通讯作者：
Jinmei Xu;Q. Xiang;Junhui Su;Peng-hui Yang;Qi‐hao Zhang;Zhijian Su;F. Xiao;Yadong Huang
中科院分区：
文献类型：
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作者：
Jinmei Xu;Q. Xiang;Junhui Su;Peng-hui Yang;Qi‐hao Zhang;Zhijian Su;F. Xiao;Yadong Huang
由神经退行性疾病引发的残疾主要导致老年人的死亡，并且患有神经退行性疾病的患者也表现出嗅觉功能的缺陷。因此，通过鼻内给药将药物分布到脑中已成为治疗中枢神经系统（CNS）疾病中最困难的挑战之一。TAT-人酸性成纤维细胞生长因子（HaFGF）融合蛋白是一种新的融合蛋白，具有HaFGF的神经保护作用，在神经退行性疾病的治疗中具有良好的前景。TAT（细胞穿透肽）含有相对高丰度的带正电荷的氨基酸，如赖氨酸和精氨酸，其对鼻上皮膜上的负电荷具有强大的吸引力。本研究的重点是评价TAT-HaFGF鼻内给药后的安全性和吸收特性。TAT-HaFGF鼻内给药（100、300、600 µ g/kg）5周后，苏木精-伊红（HE）染色显示任何研究的组织和器官均无病理学变化。免疫组织化学染色观察嗅标记蛋白（OMP）在鼻上皮感觉神经元中的表达变化。使用原位腭模型和光学显微镜进行的鼻纤毛毒性研究表明，TAT-HaFGF没有鼻纤毛毒性。使用放射性同位素示踪法评估鼻内给药后TAT-HaFGF的分布。15 min后在脑中观察到放射性。30 min时放射性增强，1 h时放射性减弱。所有结果证实了TAT-HaFGF通过鼻内给药的体内安全性。
Disabilities triggered by neurodegeneration mainly result in mortality in the elderly, and patients with neurodegenerative disease also display deficits in olfactory function. Therefore drug distribution to the brain through intranasal administration has become one of the most difficult challenges in the treatment of central nervous system (CNS) diseases. TAT-human acidic fibroblast growth factor (HaFGF) is a new fused protein retaining the neuroprotective activities of HaFGF, and is a promising prospect in the treatment of neurodegenerative diseases. TAT (a cell-penetrating peptide) contains a high relative abundance of positively charged amino acids such as lysine and arginine, which have a powerful attraction to the negatively charge on the nasal epithelial membrane. The present study focused on the evaluation of the safety and absorption characteristics of TAT-HaFGF following intranasal administration. After TAT-HaFGF intranasal administration (100, 300, 600 µg/kg) for 5 weeks, hematoxylin-eosin (HE) staining showed no pathology in any of the investigated tissues and organs. The expression of olfactory marker protein (OMP) was observed with immunohistochemical staining, which showed no altered expression in the sensory neurons of the nasal epithelium. Nasal ciliotoxicity studies carried out using an in situ palate model and optical microscope showed that TAT-HaFGF had no nasal ciliotoxicity. The distribution of the TAT-HaFGF following intranasal administration was assessed using a radioisotopic tracing method. Radioactivity was observed in the brain after 15 min. This became stronger at 30 min and weaker at 1 h. All of the results confirmed the in vivo safety of TAT-HaFGF via intranasal administration.