Intranasal Drug Delivery into Mouse Nasal Mucosa and Brain Utilizing Arginine-Rich Cell-Penetrating Peptide-Mediated Protein Transduction
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The nasal pathway represents a non-invasive administration route of pharmaceutical agents with local, systemic, and central nervous system action. Intranasal application has a relatively short time to onset of effect and high bioavailability because it avoids hepatic first-pass metabolism. However, sustained delivery is important because drugs can be rapidly eliminated via mucociliary clearance. Protein transduction using arginine-rich cell-penetrating peptides (poly-arginine) shows high delivery efficiency, no cell specificity, and minimal cytotoxicity. We investigated the effect of poly-arginine on protein delivery into the nasal mucosa and brain of mice, and its ability to prolong contact between the delivered molecule and nasal mucosa by preventing mucociliary clearance. Enhanced green fluorescent protein (EGFP) fused to a nine-arginine peptide (EGFP-9R group) or EGFP (EGFP group) was administered once to the bilateral nasal cavities of mice. Histopathological evaluation was conducted for 3–120 h to evaluate side effects, and the number of sneezes was recorded before and after administration. EGFP was detected in cells lining the nasal cavity and their vicinity for 3–96 and 3–24 h in the EGFP-9R and EGFP groups, respectively. EGFP was detected in the brain at 3–96 h in the EGFP-9R group but not in the EGFP group. Nasal symptoms and histopathological assessment revealed no deterioration in either group. These results suggest that protein transduction using poly-arginine can deliver therapeutically relevant molecules for allergic rhinitis, and can be applied for olfactory disturbance and other central nervous system diseases. Further research is necessary to establish therapy protocols using this technique.
KeywordsCell-penetrating peptide Poly-arginine Intranasal drug delivery Nose-to-brain drug delivery Allergic rhinitis
The authors thank members of the Molecular Physiology Department at Kumamoto University for their important contributions to these experiments. This research received no specific grants from funding agencies in the public, commercial, or not-for-profit sectors.
Toru Miwa – Conceptualization; Investigation; Project administration; Software; Visualization; Writing – original draft; Writing – review & editing. Kyoko Tachii – Data curation; Formal analysis; Investigation. Fan-Yan Wei – Methodology; Resources. Taku Kaitsuka – Methodology; Resources; Validation. Kazuhito Tomizawa – Supervision; Conceptualization. All authors have approved the final version of this manuscript.
Compliance with Ethical Standards
Conflict of interest
Toru Miwa, Kyoko Tachii, Fan-Yan Wei, Taku Kaitsuka, and Kazuhito Tomizawa declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Committee on the Use and Care of Animals at Kumamoto University; Number: H28-053). This article does not contain any studies with human participants performed by any of the authors.
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