Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

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Abstract

The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood–brain barrier and deliver DNA to the brain following intravenous administration.

On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood–brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.

In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body.

Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain.
LanguageEnglish
Pages235-242
Number of pages8
JournalJournal of Controlled Release
Volume217
Early online date8 Sep 2015
DOIs
Publication statusPublished - 8 Nov 2015

Fingerprint

Lactoferrin
Intravenous Administration
Gene Expression
Dendrimers
Brain
Gene Transfer Techniques
Brain Diseases
Blood-Brain Barrier
DNA
poly(propyleneimine)
Brain Neoplasms
Genetic Therapy
Parkinson Disease
Alzheimer Disease
Plasmids
Endothelial Cells
Kidney
Lung

Keywords

  • brain delivery
  • blood brain barrier
  • gene expression
  • dendrimer
  • lactoferrin

Cite this

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title = "Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex",
abstract = "The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood–brain barrier and deliver DNA to the brain following intravenous administration.On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood–brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body.Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain.",
keywords = "brain delivery, blood brain barrier, gene expression, dendrimer, lactoferrin",
author = "Sukrut Somani and Gillian Robb and Pickard, {Benjamin S.} and Christine Dufes",
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AU - Somani, Sukrut

AU - Robb, Gillian

AU - Pickard, Benjamin S.

AU - Dufes, Christine

PY - 2015/11/8

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N2 - The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood–brain barrier and deliver DNA to the brain following intravenous administration.On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood–brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body.Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain.

AB - The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood–brain barrier and deliver DNA to the brain following intravenous administration.On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood–brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body.Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain.

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