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

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  • Xu Jinmei
    College of Pharmacy, Jinan University
  • Xiang Qi
    Institute of Biomedicine, Jinan University National Engineering Research Center of Genetic Medicine, Jinan University
  • Su Junhui
    College of Pharmacy, Jinan University
  • Yang Penghui
    Institute of Biomedicine, Jinan University
  • Zhang Qihao
    Institute of Biomedicine, Jinan University
  • Su Zhijian
    Institute of Biomedicine, Jinan University National Engineering Research Center of Genetic Medicine, Jinan University
  • Xiao Fei
    Department of Pharmacology, School of Medicine, Jinan University
  • Huang Yadong
    Institute of Biomedicine, Jinan University National Engineering Research Center of Genetic Medicine, Jinan University

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

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Abstract

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.

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