Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain

Gavin D Kenny, Alison S Bienemann, Aristides D Tagalakis, John A Pugh, Katharina Welser, Frederick Campbell, Alethea B Tabor, Helen C Hailes, Steven S Gill, Mark F Lythgoe, Cameron W McLeod, Edward A White, Stephen L Hart

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Convection enhanced delivery (CED) is a method of direct injection to the brain that can achieve widespread dispersal of therapeutics, including gene therapies, from a single dose. Non-viral, nanocomplexes are of interest as vectors for gene therapy in the brain, but it is essential that administration should achieve maximal dispersal to minimise the number of injections required. We hypothesised that anionic nanocomplexes administered by CED should disperse more widely in rat brains than cationics of similar size, which bind electrostatically to cell-surface anionic moieties such as proteoglycans, limiting their spread. Anionic, receptor-targeted nanocomplexes (RTN) containing a neurotensin-targeting peptide were prepared with plasmid DNA and compared with cationic RTNs for dispersal and transfection efficiency. Both RTNs were labelled with gadolinium for localisation in the brain by MRI and in brain sections by LA-ICP-MS, as well as with rhodamine fluorophore for detection by fluorescence microscopy. MRI distribution studies confirmed that the anionic RTNs dispersed more widely than cationic RTNs, particularly in the corpus callosum. Gene expression levels from anionic formulations were similar to those of cationic RTNs. Thus, anionic RTN formulations can achieve both widespread dispersal and effective gene expression in brains after administration of a single dose by CED.

Original languageEnglish
Pages (from-to)9190-200
Number of pages11
JournalBiomaterials
Volume34
Issue number36
Early online date12 Aug 2013
DOIs
Publication statusPublished - Dec 2013

Fingerprint

Nucleic acids
Nucleic Acids
Brain
Convection
Gene therapy
Gene expression
Genetic Therapy
Magnetic resonance imaging
Therapeutics
Gene Expression
Neurotensin
Injections
Rhodamines
Fluorophores
Corpus Callosum
Gadolinium
Fluorescence microscopy
Direct injection
Proteoglycans
Fluorescence Microscopy

Keywords

  • Animals
  • Brain/drug effects
  • Cell Line, Tumor
  • Gene Expression Regulation/drug effects
  • Gene Transfer Techniques
  • Genes, Reporter
  • Liposomes/chemistry
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Nanoparticles/chemistry
  • Nanospheres
  • Nucleic Acids/pharmacology
  • Peptides/metabolism
  • Plasmids/metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Cell Surface/metabolism
  • Spectrophotometry, Atomic
  • Tissue Distribution/drug effects
  • Transfection

Cite this

Kenny, Gavin D ; Bienemann, Alison S ; Tagalakis, Aristides D ; Pugh, John A ; Welser, Katharina ; Campbell, Frederick ; Tabor, Alethea B ; Hailes, Helen C ; Gill, Steven S ; Lythgoe, Mark F ; McLeod, Cameron W ; White, Edward A ; Hart, Stephen L. / Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain. In: Biomaterials. 2013 ; Vol. 34, No. 36. pp. 9190-200.
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abstract = "Convection enhanced delivery (CED) is a method of direct injection to the brain that can achieve widespread dispersal of therapeutics, including gene therapies, from a single dose. Non-viral, nanocomplexes are of interest as vectors for gene therapy in the brain, but it is essential that administration should achieve maximal dispersal to minimise the number of injections required. We hypothesised that anionic nanocomplexes administered by CED should disperse more widely in rat brains than cationics of similar size, which bind electrostatically to cell-surface anionic moieties such as proteoglycans, limiting their spread. Anionic, receptor-targeted nanocomplexes (RTN) containing a neurotensin-targeting peptide were prepared with plasmid DNA and compared with cationic RTNs for dispersal and transfection efficiency. Both RTNs were labelled with gadolinium for localisation in the brain by MRI and in brain sections by LA-ICP-MS, as well as with rhodamine fluorophore for detection by fluorescence microscopy. MRI distribution studies confirmed that the anionic RTNs dispersed more widely than cationic RTNs, particularly in the corpus callosum. Gene expression levels from anionic formulations were similar to those of cationic RTNs. Thus, anionic RTN formulations can achieve both widespread dispersal and effective gene expression in brains after administration of a single dose by CED.",
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Kenny, GD, Bienemann, AS, Tagalakis, AD, Pugh, JA, Welser, K, Campbell, F, Tabor, AB, Hailes, HC, Gill, SS, Lythgoe, MF, McLeod, CW, White, EA & Hart, SL 2013, 'Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain', Biomaterials, vol. 34, no. 36, pp. 9190-200. https://doi.org/10.1016/j.biomaterials.2013.07.081

Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain. / Kenny, Gavin D; Bienemann, Alison S; Tagalakis, Aristides D; Pugh, John A; Welser, Katharina; Campbell, Frederick; Tabor, Alethea B; Hailes, Helen C; Gill, Steven S; Lythgoe, Mark F; McLeod, Cameron W; White, Edward A; Hart, Stephen L.

In: Biomaterials, Vol. 34, No. 36, 12.2013, p. 9190-200.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain

AU - Kenny, Gavin D

AU - Bienemann, Alison S

AU - Tagalakis, Aristides D

AU - Pugh, John A

AU - Welser, Katharina

AU - Campbell, Frederick

AU - Tabor, Alethea B

AU - Hailes, Helen C

AU - Gill, Steven S

AU - Lythgoe, Mark F

AU - McLeod, Cameron W

AU - White, Edward A

AU - Hart, Stephen L

N1 - Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

PY - 2013/12

Y1 - 2013/12

N2 - Convection enhanced delivery (CED) is a method of direct injection to the brain that can achieve widespread dispersal of therapeutics, including gene therapies, from a single dose. Non-viral, nanocomplexes are of interest as vectors for gene therapy in the brain, but it is essential that administration should achieve maximal dispersal to minimise the number of injections required. We hypothesised that anionic nanocomplexes administered by CED should disperse more widely in rat brains than cationics of similar size, which bind electrostatically to cell-surface anionic moieties such as proteoglycans, limiting their spread. Anionic, receptor-targeted nanocomplexes (RTN) containing a neurotensin-targeting peptide were prepared with plasmid DNA and compared with cationic RTNs for dispersal and transfection efficiency. Both RTNs were labelled with gadolinium for localisation in the brain by MRI and in brain sections by LA-ICP-MS, as well as with rhodamine fluorophore for detection by fluorescence microscopy. MRI distribution studies confirmed that the anionic RTNs dispersed more widely than cationic RTNs, particularly in the corpus callosum. Gene expression levels from anionic formulations were similar to those of cationic RTNs. Thus, anionic RTN formulations can achieve both widespread dispersal and effective gene expression in brains after administration of a single dose by CED.

AB - Convection enhanced delivery (CED) is a method of direct injection to the brain that can achieve widespread dispersal of therapeutics, including gene therapies, from a single dose. Non-viral, nanocomplexes are of interest as vectors for gene therapy in the brain, but it is essential that administration should achieve maximal dispersal to minimise the number of injections required. We hypothesised that anionic nanocomplexes administered by CED should disperse more widely in rat brains than cationics of similar size, which bind electrostatically to cell-surface anionic moieties such as proteoglycans, limiting their spread. Anionic, receptor-targeted nanocomplexes (RTN) containing a neurotensin-targeting peptide were prepared with plasmid DNA and compared with cationic RTNs for dispersal and transfection efficiency. Both RTNs were labelled with gadolinium for localisation in the brain by MRI and in brain sections by LA-ICP-MS, as well as with rhodamine fluorophore for detection by fluorescence microscopy. MRI distribution studies confirmed that the anionic RTNs dispersed more widely than cationic RTNs, particularly in the corpus callosum. Gene expression levels from anionic formulations were similar to those of cationic RTNs. Thus, anionic RTN formulations can achieve both widespread dispersal and effective gene expression in brains after administration of a single dose by CED.

KW - Animals

KW - Brain/drug effects

KW - Cell Line, Tumor

KW - Gene Expression Regulation/drug effects

KW - Gene Transfer Techniques

KW - Genes, Reporter

KW - Liposomes/chemistry

KW - Magnetic Resonance Imaging

KW - Male

KW - Mice

KW - Nanoparticles/chemistry

KW - Nanospheres

KW - Nucleic Acids/pharmacology

KW - Peptides/metabolism

KW - Plasmids/metabolism

KW - Rats

KW - Rats, Wistar

KW - Receptors, Cell Surface/metabolism

KW - Spectrophotometry, Atomic

KW - Tissue Distribution/drug effects

KW - Transfection

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DO - 10.1016/j.biomaterials.2013.07.081

M3 - Article

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VL - 34

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EP - 9200

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

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ER -