Use of a non-covalent cell-penetrating peptide strategy to enhance the nasal delivery of interferon beta and its PEGylated form

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 2 mM) 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 (2 mM). 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 6 h. 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.