Exploring intranasal delivery of peptide and protein nanoparticles by a thermoresponsive hydrogel

Effective delivery of peptide or protein-based drugs (PPDs) remains a challenge as parenteral routes are invasive and PPDs are subjected to enzymatic degradation via the oral route. As such, intranasal (IN) route is an effective, non-invasive approach for delivering PPDs locally, systemically, and to the central nervous system (CNS) while maintaining the stability of the drugs. The study investigates the potential of a novel thermoresponsive polymer (PNPHO), as a carrier to facilitate IN delivery of peptide/proteins. Two types of nanoparticle formulations (Low-F and High-F) using a low and a high PNPHO concentration (20 mg/mL and 35 mg/mL) were prepared with bovine serum albumin (BSA) incorporated in it. Both formulations exhibited good physicochemical properties in terms of particle size (Low-F: 29 nm; High-F: 39 nm), polydispersity index (PDI) (< 0.3) and zeta (ζ) potential (-3 to -6 mV) with a high encapsulation efficiency (EE) (86%-96%) maintained at 4 °C during a 4-week stability study. High-F formulation demonstrated a significantly greater aerosol drug deposition in the entire nasal cavity and in the olfactory region in vitro compared to free BSA at 45° spray angle. Both formulations were found to be non-toxic when tested on nasal epithelial cell lines. Importantly, a significant increase in transepithelial resistance was observed for the nasal epithelial cells post 4 hours treatment with High-F along with a significant reduction in BSA transport across the cells compared to free drug, indicating tightening of cellular junctions and prolonged drug residence time owing to its mucoadhesive property. Altogether, the findings suggest that PNPHO polymer is a potential carrier for targeted delivery of peptide/protein using the IN route. • PNPHO, a novel thermoresponsive polymer, was evaluated for peptide/protein drug delivery via the intranasal route. • Bovine serum albumin, a model protein, was successfully incorporated into PNPHO nanoparticles at concentrations of 20 mg/mL and 35 mg/mL. • Both formulations show favourable particle sizes, low polydispersity index, stable zeta potentials, and high encapsulation efficiency at 4 °C. • At higher polymer concentration, significantly greater aerosol deposition in the nasal cavity was observed in vitro. • At higher polymer concentration, enhanced transepithelial resistance and reduced BSA transport were observed, indicating prolonged drug residence and sustained release.