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

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 TATHaFGF 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.Key words TAT-human acidic fibroblast; intranasal administration; mucosal adsorption; safety evaluation Neurodegenerative disease occurs in specific regions of the brain, and is classically associated with memory problems, olfactory deficits and movement disorders. 1-3)Intranasal drug administration has been shown to increase the delivery of peptides of a particular size and charge to the central nervous system (CNS) for the treatment of CNS diseases.4,5) For example, intranasal administration of the 26.5 kDa recombinant human nerve growth factor in rats resulted in CNS concentrations 10-45-fold higher (depending on the brain region) than concentrations observed following intravenous administration. 6)Similarly, intranasal delivery of hypocretin-1 increased targeting to various brain regions by 7-13-fold.7) Enhancement of delivery and targeting to the brain has been demonstrated with the intranasal delivery of a wide range of compounds, including galanin-like peptide, 8)insulin-like growth factor, 9)insulin, 10) interferonβ-1b, 11) transforming growth factor-β1, 12)and hypocretin-1. 7)Human acidic fibroblast growth factor (HaFGF) is involved in the regulation of synaptic plasticity and learning and memory processes through the improvement of cholinergic nerve functions. Furthermore, recombinant polypeptide fibro...

Intranasal administration of elastin-like polypeptide for therapeutic delivery to the central nervous system

“…Past studies using small peptides with CPPs have suggested CPPs may be able to increase CNS uptake via IN administration. 2 , 24 Figure 1A shows representative IVIS images of brains after treatment with each construct via IN or IV administration. The heat map clearly shows regional differences in peptide concentrations in IN-treated animals, with the highest concentrations around the olfactory bulbs.…”

“…Methods to bypass the BBB via alternative administration routes, particularly intranasal (IN) delivery, have shown positive results with small molecule drugs in the past and with some larger biomolecules more recently. 1 , 2 Direct contact with the nasal epithelium has been demonstrated to facilitate the movement of molecules down multiple pathways, resulting in significantly increased CNS levels compared to other non-invasive administration routes. 3 The usefulness of transport directly into cerebrospinal fluid is debated, but transport along the olfactory and trigeminal nerves has been well documented and can result in therapeutically relevant CNS penetration with drastically decreased peripheral impact.…”

“… 3 The usefulness of transport directly into cerebrospinal fluid is debated, but transport along the olfactory and trigeminal nerves has been well documented and can result in therapeutically relevant CNS penetration with drastically decreased peripheral impact. 2 , 4 While IN delivery can increase CNS uptake of non-BBB penetrating compounds when compared to other administration methods, in the case of macromolecules, concentrations are often still insufficient to be clinically relevant. Various methods have been employed to attempt to increase the CNS penetration of macromolecules via IN administration, including the use of gelling solutions that increase contact time with the nasal epithelium, encapsulation in liposomes, the use of different types of nanoparticles, and coadministration or conjugation with numerous molecules intended to increase absorption.…”

Tat-haFGF 14–154 Upregulates ADAM10 to Attenuate the Alzheimer Phenotype of APP/PS1 Mice through the PI3K-CREB-IRE1α/XBP1 Pathway

“…Intranasal delivery has proven to be a new and noninvasive strategy, which can circumvent the BBB and facilitate direct transport of the drugs to the brain through neuronal and extracellular pathways 44, 45. Our previous studies showed that intranasal administration of TAT-haFGF could improve cognition and reduce Aβ deposits more significantly in APP/PS1 mice compared with intravenous injection 18, 21, 22, 23. In an animal model of Parkinson’s disease induced by 6-OHDA, liposomes markedly assisted the delivery of basic fibroblast growth factor (bFGF) to the striatum and substantia nigra (SN), and they enhanced the neuroprotective effects of bFGF on dopaminergic neurons 46 .…”

“…Our previous study showed that modified protein Tat-haFGF 14–154 could penetrate the BBB and was distributed in hippocampus and cortex via intravenous injection 18 . Following intranasal administration, the distribution of Tat-haFGF 14–154 was observed at 15 min in the brains of rats 21 . Tat-PTD could increase the concentration of haFGF in brain, and Tat-haFGF 14–154 improved cognition and reduced Aβ plaques more significantly than haFGF 14–154 in senescence-accelerated mouse prone-8 (SAMP8) and APP/PS1 mice 22, 23.…”