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The Optimization Design Of Lactoferrin Loaded HupA Nanoemulsion For Targeted Drug Transport Via Intranasal Route

Authors Jiang Y, Liu C, Zhai W, Zhuang N, Han T, Ding Z

Received 7 May 2019

Accepted for publication 21 October 2019

Published 27 November 2019 Volume 2019:14 Pages 9217—9234


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Mian Wang

Video abstract presented by Yueyao Jiang.

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Yueyao Jiang, Chenqi Liu, Wanchen Zhai, Ning Zhuang, Tengfei Han, Zhiying Ding

School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People’s Republic of China

Correspondence: Zhiying Ding
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, People’s Republic of China
Tel +8613843180286

Background: Huperzine A (HupA) is a selective acetylcholinesterase inhibitor used to treat Alzheimer’s disease. The existing dosage of HupA lacks brain selectivity and can cause serious side effects in the gastrointestinal and peripheral cholinergic systems.
Purpose: The aim of this study was to develop and characterize a HupA nanoemulsion (NE) and a targeted HupA-NE modified with lactoferrin (Lf) for intranasal administration.
Methods: The NE was formulated using pseudo-ternary phase diagrams and optimized with response surface methodology. Particle size distribution and zeta potential were evaluated, and transmission electron microscopy was performed. We investigated the transport mechanisms of HupA-NEs into hCMEC/D3 cells, an in vitro model of the blood-brain barrier. HupA-NE, Lf-HupA-NE, and HupA solution were intranasally administered to rats to investigate the brain-targeting effects of these formulations. A drug targeting index (DTI) was calculated to determine brain-targeting efficiency.
Results: Optimized HupA-NE had a particle size of 15.24±0.67 nm, polydispersity index (PDI) of 0.128±0.025, and zeta potential of −4.48±0.97 mV. The composition of the optimized HupA-NE was 3.00% isopropyl myristate (IPM), 3.81% Capryol 90, and 40% Cremophor EL + Labrasol. NEs, particularly Lf-HupA-NE, were taken up into hCMEC/D3 cells to a greater extent than pure drug alone. Western blot analysis showed that hCMEC/D3 cells contained P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance associated protein 1 (MRP1) transporters. The likely mechanisms resulting in higher NE transport to the brain were uptake by specific transporters and transcytosis. In vivo, intranasal Lf-HupA-NE significantly enhanced drug delivery to the brain compared to HupA-NE, which was confirmed by differences in pharmacokinetic parameters. The DTI of Lf-HupA-NE (3.2±0.75) demonstrated brain targeting, and the area under the curve for Lf-HupA-NE was significantly higher than that for HupA-NE.
Conclusion: Lf-HupA-NE is a promising nasal drug delivery carrier for facilitating delivery of HupA to the central nervous system.

Keywords: nanoemulsion, lactoferrin, brain targeting, intranasal delivery

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