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Published on: February 9, 2019
Hyaluronic Acid-Based Hybrid Nanoparticles as Promising Carriers for the Intranasal Administration of Dimethyl
Carla Serri1, Miriam Piccioni2, Vincenzo Guarino3
1Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy.
Purpose:
Dimethyl fumarate (DMF), the first-line oral therapy for relapsing-remitting multiple sclerosis, is rapidly metabolized into monomethyl fumarate. The DMF oral administration provokes gastrointestinal discomfort causing treatment withdrawal. The present study aimed to develop an innovative formulation for DMF nasal administration. Lipid-polymer hybrid nanoparticles (LPNs) were developed to improve DMF stability, limiting gastrointestinal side effects and increasing brain bioavailability by nose-to-brain targeting application.
Methods:
DMF-loaded and unloaded LPNs with or without hyaluronic acid (HA) were prepared using the nanoprecipitation via magnetic/mechanical stirring technique. Particle morphology and surface properties were evaluated; drug content, viscosity, and mucoadhesion were determined. Physico-chemical stability of LPNs and DMF in the LPNs was also explored. In vitro DMF permeation experiments were performed utilizing the PermeaPad®. The cytotoxicity and cellular uptake studies were performed using RPMI 2650 and SK-N-BE2 cell lines. DMF nose-to-brain delivery was evaluated by intranasally administering DMF-loaded LPNs to rats.
Results:
LPNs with average sizes of 120-250 nm and a negative zeta potential -17.3 to -43 mV were obtained, primarily influenced by the presence of HA. HA assured drug stability up to 60 days and promoting the in vitro permeation of DMF compared to the free-DMF. HA greatly improved the viscosity and mucoadhesive properties. LPNs with and without HA did not exhibit any cytotoxicity and showed a rapid cell uptake starting from 15 min to 2 h with a best internalization after 1 h of treatment in both epithelial and neuronal cell lines. Nasal administration of DMF-loaded LPNs allowed to quantify up to about 12 μg/mL of DMF in the rat cerebrospinal fluid.
Conclusion:
The results highlight the role of HA in improving LPNs properties and performance as carrier of DMF for nasal administration. In particular, LPNs appear able to enter neurons and monolayers of epithelial cells, allowing to promote the nose-to-brain DMF delivery.
Insights
This study developed novel lipid-polymer hybrid nanoparticles (LPNs) for nasal delivery of dimethyl fumarate (DMF), improving brain bioavailability and reducing side effects for multiple sclerosis treatment.
Area of Science:
- Nanotechnology in Drug Delivery
- Neuroscience and Pharmacology
- Materials Science
Background:
- Dimethyl fumarate (DMF) is a first-line oral therapy for relapsing-remitting multiple sclerosis.
- Oral DMF administration causes gastrointestinal discomfort, leading to treatment withdrawal.
- Current delivery methods have limitations in stability, side effect profile, and brain bioavailability.
Purpose of the Study:
- To develop an innovative nasal formulation of dimethyl fumarate (DMF) using lipid-polymer hybrid nanoparticles (LPNs).
- To enhance DMF stability and brain bioavailability via nose-to-brain targeting.
- To mitigate gastrointestinal side effects associated with oral DMF administration.
Main Methods:
- Lipid-polymer hybrid nanoparticles (LPNs) loaded with DMF were prepared using nanoprecipitation.
- Formulations with and without hyaluronic acid (HA) were characterized for particle size, zeta potential, drug content, viscosity, and mucoadhesion.
- In vitro permeation, cytotoxicity, cellular uptake, and in vivo nose-to-brain delivery in rats were evaluated.
Main Results:
- LPNs (120-250 nm) with negative zeta potential were successfully prepared; HA improved stability, permeation, viscosity, and mucoadhesion.
- LPNs showed no cytotoxicity and rapid cellular uptake in epithelial and neuronal cell lines.
- Nasal administration of DMF-loaded LPNs resulted in approximately 12 μg/mL of DMF in rat cerebrospinal fluid.
Conclusions:
- Hyaluronic acid significantly enhances the properties and performance of LPNs for nasal DMF delivery.
- LPNs demonstrate potential for direct nose-to-brain delivery of DMF, entering both epithelial and neuronal cells.
- This novel LPN formulation offers a promising alternative to oral DMF for multiple sclerosis treatment, potentially improving efficacy and patient compliance.
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