Transferrin-modified chitosan nanoparticles for targeted nose-to-brain delivery of proteins

Abstract

Nose-to-brain delivery presents a promising alternative route compared to classical blood–brain barrier passage, especially for the delivery of high molecular weight drugs. In general, macromolecules are rapidly degraded in physiological environment. Therefore, nanoparticulate systems can be used to protect biomolecules from premature degradation. Furthermore, targeting ligands on the surface of nanoparticles are able to improve bioavailability by enhancing cellular uptake due to specific binding and longer residence time. In this work, transferrin-decorated chitosan nanoparticles are used to evaluate the passage of a model protein through the nasal epithelial barrier in vitro. It was demonstrated that strain-promoted azide–alkyne cycloaddition reaction can be utilized to attach a functional group to both transferrin and chitosan enabling a rapid covalent surface-conjugation under mild reaction conditions after chitosan nanoparticle preparation. The intactness of transferrin and its binding efficiency were confirmed via SDS-PAGE and SPR measurements. Resulting transferrin-decorated nanoparticles exhibited a size of about 110–150 nm with a positive surface potential. Nanoparticles with the highest amount of surface bound targeting ligand also displayed the highest cellular uptake into a human nasal epithelial cell line (RPMI 2650). In an air–liquid interface co-culture model with glioblastoma cells (U87), transferrin-decorated nanoparticles showed a faster passage through the epithelial cell layer as well as increased cellular uptake into glioblastoma cells. These findings demonstrate the beneficial characteristics of a specific targeting ligand. With this chemical and technological formulation concept, a variety of targeting ligands can be attached to the surface after nanoparticle formation while maintaining cargo integrity. Graphical abstract

Nose‐to‐brain delivery of nanotherapeutics: Transport mechanisms and applications

“…Application of such NPs to brain tumors has occurred only recently, however, and focus has been on the modification of delivery carriers that utilize the transnasal entry into the brain. For example, Tf‐modified chitosan NPs have been shown to enter the BBB via the nose‐to‐brain pathway and penetrate at a faster rate in the presence of glioma cells (Gabold et al, 2022). Sandbhor et al investigated the potential of employing the noninvasive intranasal pathway to target the DNA methylating agent temozolomide to glioma.…”

Enhancing paracellular and transcellular permeability using nanotechnological approaches for the treatment of brain and retinal diseases

“…Polymeric nanoparticles, notably chitosan NPs are the most popular nanocarriers used in nose-to-brain delivery and are at the forefront of neuropharmacological treatments due to their mucoadhesive properties and the ability of CS NPs to open the TJ existing within the nasal epithelial barrier. 153,154 Wilson et al reported the delivery of sitagliptin (SIT) into the brain of rats using SIT-loaded chitosan particles of 188.4 AE 48.1 nm mean size and z = +20.8 mV. 155 Gabold et al studied the passage of b-galactosidase through human nasal epithelial cells (RPMI 2650) using transferrin-decorated chitosan NP carriers.…”

“…155 Gabold et al studied the passage of b-galactosidase through human nasal epithelial cells (RPMI 2650) using transferrin-decorated chitosan NP carriers. 153 Readers are referred to the excellent review by Donnelly and Paredes. 154 Galladro-Tolers delivered peptide modified Au NPs IN (Fig.…”

Nasal Delivery to the Brain: Harnessing Nanoparticles for Effective Drug Transport

“…The outcomes demonstrated a statistically significant rise in drug concentration in the brain and improvements in the mice’s behavior ( p < 0.05) with the developed NPs. Similarly, transferrin chitosan NPs were assessed for their potential to deliver proteins [ 117 ]. This study highlights the advantageous properties of such formulation strategies and suggests that a range of targeted ligands could be attached to their surface while preserving the integrity of the cargo.…”