title: Use of a non-covalent cell-penetrating peptide strategy to enhance the nasal delivery of interferon beta and its PEGylated form.
abstract: The conjugation of therapeutic proteins to polyethylene glycol (PEG) is known as PEGylation. It improves their retention in the body and reduces the frequency of injections. Development of noninvasive delivery systems for biopharmaceuticals can improve the patients' quality of life. The present study aimed to evaluate the cell-penetrating peptides (CPPs), which act as bioenhancers, for the nasal delivery of protein drug interferon beta (IFN-β) and its PEGylated form (PEG-IFN-β). The ability of CPPs to enhance the nasal mucosal absorption of unmodified IFN-β was assessed in rats. It was shown that only d-amino acid forms of amphipathic CPPs, penetratin and PenetraMax significantly enhanced the nasal absorption of IFN-β. Especially, D-penetratin (up to 2mM) enhanced the absorption of INF-β in a dose-dependent manner. The maximum absolute bioavailability reached 8.26% following in situ nasal coadministration of IFN-β with d-penetratin (2mM). Furthermore, it was found that the coadministration of d-penetratin also facilitated the nasal absorption of PEG-IFN-β, which remained in the circulation for more than 6h. Moreover, the toxicity assessments showed no damage to the epithelial membranes after nasal administration of CPPs including penetratin and PenetraMax. Altogether, this study provides the first evidence that the noncovalent coadministration of PEGylated proteins with CPPs could be a potent strategy for the noninvasive and sustained nasal delivery of therapeutic proteins.
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwase
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kamei
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 415-22, Egypt.
authors.forename: El-Sayed
authors.initials: el-S
authors.lastname: Khafagy
authors.affiliation: Toray Industries, Inc., 2-1-1 Nihonbashimuromachi, Chuo-ku, Tokyo 103-8666, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan. Electronic address: mmtakeda@pharm.kobegakuin.ac.jp.
authors.forename: Mariko
authors.initials: M
authors.lastname: Takeda-Morishita
mesh_terms: D000818:Animals; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009296:Nasal Cavity / Q000187:drug effects / Q000378:metabolism; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D016899:Interferon-beta
keywords: Bioavailability; Cell-penetrating peptides; Interferon β; Nasal absorption; PEGylation; Penetratin