Evaluation of the Safety and Brain-Related Tissues Distribution Characteristics of TAT-HaFGF via Intranasal Administration

• Published in: Biological & pharmaceutical bulletin Vol. 37; no. 7; pp. 1149 - 1157
• Main Authors: Xu, Jinmei, Xiang, Qi, Su, Junhui, Yang, Penghui, Zhang, Qihao, Su, Zhijian, Xiao, Fei, Huang, Yadong
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 2014; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Administration, Intranasal; Animals; Brain - drug effects; Brain - metabolism; Bufo bufo; Cilia - drug effects; Female; Fibroblast Growth Factors - administration & dosage; Fibroblast Growth Factors - adverse effects; Fibroblast Growth Factors - pharmacokinetics; Gene Products, tat - administration & dosage; Gene Products, tat - adverse effects; Gene Products, tat - pharmacokinetics; intranasal administration; Male; mucosal adsorption; Nasal Absorption - drug effects; Nasal Mucosa - drug effects; Nasal Mucosa - metabolism; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - adverse effects; Neuroprotective Agents - pharmacokinetics; Olfactory Bulb - drug effects; Olfactory Bulb - metabolism; Rats, Sprague-Dawley; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - pharmacokinetics; safety evaluation; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; TAT-human acidic fibroblast; Tissue Distribution
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b14-00023

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.