Cited by 149RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryBarrier Structure and Function Studies

Design and Validation of Liposomal ApoE2 Gene Delivery System to Evade Blood–Brain Barrier for Effective Treatment of Alzheimer’s Disease

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Arora, Sanjay, Layek, Buddhadev, Singh, Jagdish·2021·Molecular Pharmaceutics

Abstract

Targeting gene-based therapeutics to the brain is a strategy actively sought to treat Alzheimer’s disease (AD). Recent findings discovered the role of apolipoprotein E (ApoE) isoforms in the clearance of toxic amyloid beta proteins from the brain. ApoE2 isoform is beneficial for preventing AD development, whereas ApoE4 is a major contributing factor to the disease. In this paper, we demonstrated efficient brain-targeted delivery of ApoE2 encoding plasmid DNA (pApoE2) using glucose transporter-1 (glut-1) targeted liposomes. Liposomes were surface-functionalized with a glut-1 targeting ligand mannose (MAN) and a cell-penetrating peptide (CPP) to enhance brain-targeting and cellular internalization, respectively. Among various CPPs, rabies virus glycoprotein peptide (RVG) or penetratin (Pen) was selected as a cell-penetration enhancer. Dual (RVGMAN and PenMAN)-functionalized liposomes were cytocompatible at 100 nM phospholipid concentration and demonstrated significantly higher expression of ApoE2 in bEnd.3 cells, primary neurons, and astrocytes compared to monofunctionalized and unmodified (plain) liposomes. Dual-modified liposomes also showed ∼2 times higher protein expression than other formulation controls in neurons cultured below the in vitro BBB model. These results translated well to in vivo efficacy study with significantly higher transfection of pApoE2 in the C57BL/6 mice brain following single tail vein administration of RVGMAN and PenMAN functionalized liposomes without any noticeable signs of toxicity. These results illustrate the potential of surface-modified liposomes for safe and brain-targeted delivery of the pApoE2 gene for effective AD therapy.

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Authors
Arora, S., Layek, B., & Singh, J.
Affiliations
North Dakota State University (US)
Corresponding author
Singh, Jagdish
Venue
Molecular Pharmaceutics
Published
2020-08-11
Volume
18
Issue
2
Pages
714-725
ISSN
  • 1543-8384 (ISSN-L)
  • 1543-8392
OpenAlex
W3048402510
Cited by
149
References
86
Citations by year
2026: 18 · 2025: 31 · 2024: 36 · 2023: 25 · 2022: 25 · 2021: 14
FWCI
5.19
Type
journal article
Language
en
Open access
Locations
  • Molecular Pharmaceutics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (R01AG051574)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
Alzheimer's disease, apolipoprotein E2, gene delivery, liposomes, blood-brain barrier, glucose transporter 1, cell-penetrating peptides, penetratin, plasmid transfection, brain-targeted delivery, amyloid-beta clearance, bEnd.3 cells, astrocytes, in vitro BBB model, in vivo transfection
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Blood-Brain Barrier, Brain, Cell Line, Drug Compounding, Female, Humans, Liposomes, Male, Neurons, Gene Transfer Techniques, Models, Animal, Glucose Transporter Type 1, Mice, Rats, Apolipoprotein E2, Cell-Penetrating Peptides, Primary Cell Culture

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