Nanogels for Oligonucleotide Delivery to the Brain

Serguei V. Vinogradov, Elena V. Batrakova, Alexander V. Kabanov

Research output: Contribution to journalArticle

294 Citations (Scopus)

Abstract

Systemic delivery of oligonucleotides (ODN) to the central nervous system is needed for development of therapeutic and diagnostic modalities for treatment of neurodegenerative disorders. Macromolecules injected in blood are poorly transported across the blood-brain barrier (BBB) and rapidly cleared from circulation. In this work we propose a novel system for ODN delivery to the brain based on nanoscale network of cross-linked poly(ethylene glycol) and polyethylenimine ("nanogel"). The methods of synthesis of nanogel and its modification with specific targeting molecules are described. Nanogels can bind and encapsulate spontaneously negatively charged ODN, resulting in formation of stable aqueous dispersion of polyelectrolyte complex with particle sizes less than 100 nm. Using polarized monolayers of bovine brain microvessel endothelial cells as an in vitro model this study demonstrates that ODN incorporated in nanogel formulations can be effectively transported across the BBB. The transport efficacy is further increased when the surface of the nanogel is modified with transferrin or insulin. Importantly the ODN is transported across the brain microvessel cells through the transcellular pathway; after transport, ODN remains mostly incorporated in the nanogel and ODN displays little degradation compared to the free ODN. Using mouse model for biodistribution studies in vivo, this work demonstrated that as a result of incorporation into nanogel 1 h after intravenous injection the accumulation of a phosphorothioate ODN in the brain increases by over 15 fold while in liver and spleen decreases by 2-fold compared to the free ODN. Overall, this study suggests that nanogel is a promising system for delivery of ODN to the brain.

Original languageEnglish (US)
Pages (from-to)50-60
Number of pages11
JournalBioconjugate Chemistry
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2004

Fingerprint

Oligonucleotides
Brain
Microvessels
Blood-Brain Barrier
Insulin
Endothelial cells
Neurology
Polyelectrolytes
Macromolecules
Liver
Polyethylene glycols
Monolayers
Transcytosis
Polyethyleneimine
Blood
Particle size
Ethylene Glycol
NanoGel
Transferrin
Degradation

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Vinogradov, S. V., Batrakova, E. V., & Kabanov, A. V. (2004). Nanogels for Oligonucleotide Delivery to the Brain. Bioconjugate Chemistry, 15(1), 50-60. https://doi.org/10.1021/bc034164r

Nanogels for Oligonucleotide Delivery to the Brain. / Vinogradov, Serguei V.; Batrakova, Elena V.; Kabanov, Alexander V.

In: Bioconjugate Chemistry, Vol. 15, No. 1, 01.01.2004, p. 50-60.

Research output: Contribution to journalArticle

Vinogradov, SV, Batrakova, EV & Kabanov, AV 2004, 'Nanogels for Oligonucleotide Delivery to the Brain', Bioconjugate Chemistry, vol. 15, no. 1, pp. 50-60. https://doi.org/10.1021/bc034164r
Vinogradov, Serguei V. ; Batrakova, Elena V. ; Kabanov, Alexander V. / Nanogels for Oligonucleotide Delivery to the Brain. In: Bioconjugate Chemistry. 2004 ; Vol. 15, No. 1. pp. 50-60.
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