Nose-to-brain delivery of nano-engineered biomaterials for effective targeting to the brain

Abstract

Thermoresponsive hydrogels provide a platform for sustained delivery of nanoparticles via nose-to-brain route by resisting mucociliary clearance to the enhanced mean residence time (MRT) of the formulation in the nasal cavity overcoming neurotoxicity induced by uncontrolled delivery of nanoparticles and accumulation in the brain when delivered alone. The reported study presents the synthesis of pullulan (PLN) based nanoparticles (PNP-EHBr) loaded with eletriptan hydrobromide (EHBr) via ionic gelation method having size between 26.65 nm and 29.59 nm after stability studies of 4 h incubation with an average zeta potential of 22.5 ± 0.1 mV and entrapment efficiency of 92.048%. F-127/F-68 based hyaluronic acid-co-pectin hydrogels of EHBr-loaded PLN nanoparticles thermoresponsive hydrogels (HAP-PNP-EHBr/T-Hg) were characterized via Fourier transform infrared spectroscopy (FTIR), X-ray diffraction, thermal analysis (TGA/DSC), and scanning electron microscopy and evaluated for their gelation time, gelation temperature, gel strength, cloud point, sol–gel fraction, ex-vivo permeation, etc. HAP-PNP-EHBr/T-Hg showed drug release in a controlled pattern in both phosphate-buffered saline (PBS) and simulated nasal fluid (SNF) i.e., 90.12 and 87.99, respectively, over 48 h, while PNP-EHBR, 99.44 and 97.53 in PBS and SNF, respectively, over 8 h. The controlled release and absorption of EHBr from HAP-PNP-EHBr/T-Hg and PNP-EHBr was estimated by an in-vivo pharmacokinetic study using high-performance liquid chromatography, MRT and area under the curve (AUC) were increased up to 11.337 ± 0.32 h and 3,104.73 ± 75.841 ng/mL*h, 11.088 ± 0.177 h and 3,906.64 ± 152.86 ng/mL*h in brain and blood respectively after IN administration. This work demonstrates the successful synthesis of a twofold drug delivery system with PLN-based nanoparticles (PNP-EHBr) loaded with EHBr laden F-127/F-68 based hyaluronic acid-co-pectin hydrogels (HAP-PNP-EHBr/T-Hg).

Highlights:

• HAP-PNP-EHBr/T-Hg containing PNP-EHBr was synthesized.

• HAP-PNP-EHBr/T-Hg delivered EHBr effectively into the brain through PNP-EHBr after IN administration.

• HAP-PNP-EHBr/T-Hg displayed adequate gel strength, mucoadhesive strength, T-_gel, t-_gel, drug release in-vitro, and ex-vivo permeation.

• HAP-PNP-EHBr/T-Hg following IN administration displayed enhanced MRT and AUC compared to PNP-EHBr after IN and IV administration.

Graphical abstract

Keywords:

• Biodegradable polymers
• controlled delivery
• nose-to-brain delivery
• polymeric nanoparticles
• self-assembling micelles
• thermoresponsive hydrogels

Disclosure statement

No potential conflict of interest have been reported by the author(s).

Ethical statement

• Ethics approval and consent to participate: COM-SD-1645/PHM

• Consent for publication: N/A

• Availability of data and materials: N/A

Additional information

Funding

The authors would acknowledge the Higher Education Commission of Pakistan for the financial support through Project No.5296/Federal/NRPU/R&D/HEC/2016. This research was fully sponsored by the NRPU-HEC.