Brain Targeting of Citicoline Sodium via Hyaluronic Acid-Decorated Novel Nano-Transbilosomes for Mitigation of Alzheimer's Disease in a Rat Model: Formulation, Optimization, in vitro and in vivo Assessment

Kariman M AbouElhassan; Hatem A Sarhan; Amal K Hussein; Ashraf Taye; Yasmin M Ahmed; Mohamed A Safwat

doi:10.2147/IJN.S381353

Brain Targeting of Citicoline Sodium via Hyaluronic Acid-Decorated Novel Nano-Transbilosomes for Mitigation of Alzheimer's Disease in a Rat Model: Formulation, Optimization, in vitro and in vivo Assessment

Int J Nanomedicine. 2022 Dec 14:17:6347-6376. doi: 10.2147/IJN.S381353. eCollection 2022.

Authors

Kariman M AbouElhassan^{1

2}, Hatem A Sarhan¹, Amal K Hussein¹, Ashraf Taye³, Yasmin M Ahmed⁴, Mohamed A Safwat⁵

Affiliations

¹ Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
² Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt.
³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt.
⁴ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, 62514, Egypt.
⁵ Department of Pharmaceutics, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt.

Abstract

Background: Alzheimer's disease (AD) is one of the furthermost advanced neurodegenerative disorders resulting in cognitive and behavioral impairment. Citicoline sodium (CIT) boosts the brain's secretion of acetylcholine, which aids in membrane regeneration and repair. However, it suffers from poor blood-brain barrier (BBB) permeation, which results in lower levels of CIT in the brain.

Purpose: This study targeted to encapsulate CIT into novel nano-platform transbilosomes decorated with hyaluronic acid CIT-HA*TBLs to achieve enhanced drug delivery from the nose to the brain.

Methods: A method of thin-film hydration was utilized to prepare different formulae of CIT-TBLs using the Box-Behnken design. The optimized formula was then hyuloranated via integration of HA to form the CIT-HA*TBLs formula. Furthermore, AD induction was performed by aluminum chloride (Alcl₃), animals were allocated, and brain hippocampus tissue was isolated for ELISA and qRT-PCR analysis of malondialdehyde (MDA), nuclear factor kappa B (NF-kB), and microRNA-137 (miR-137) coupled with immunohistochemical amyloid-beta (Aβ_1-42) expression and histopathological finding.

Results: The hyuloranated CIT-HA*TBLs formula, which contained the following ingredients: PL (300 mg), Sp 60 (43.97 mg), and SDC (20 mg). They produced spherical droplets at the nanoscale (178.94 ±12.4 nm), had a high entrapment efficiency with 74.92± 5.54%, had a sustained release profile of CIT with 81.27 ±3.8% release, and had ex vivo permeation of CIT with 512.43±19.58 μg/cm². In vivo tests showed that CIT-HA*TBL thermogel dramatically reduces the hippocampus expression of miR-137 and (Aβ_1-42) expression, boosting cholinergic neurotransmission and decreasing MDA and NF-kB production. Furthermore, CIT-HA*TBLs thermogel mitigate histopathological damage in compared to the other groups.

Conclusion: Succinctly, the innovative loading of CIT-HA*TBLs thermogel is a prospectively invaluable intranasal drug delivery system that can raise the efficacy of CIT in Alzheimer's management.

Keywords: Alzheimer’s disease; Box–Behnken design; brain targeting; in vivo study; intranasal drug delivery; transbilosomes.

MeSH terms

Alzheimer Disease* / drug therapy
Animals
Brain
Cytidine Diphosphate Choline / pharmacology
Cytidine Diphosphate Choline / therapeutic use
Drug Carriers / therapeutic use
Hyaluronic Acid / pharmacology
MicroRNAs*
NF-kappa B
Rats
Sodium / therapeutic use

Substances

Drug Carriers
Cytidine Diphosphate Choline
Hyaluronic Acid
NF-kappa B
Sodium
MicroRNAs
MIRN137 microRNA, rat