Nanogels for oligonucleotide delivery to the brain.
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.
Vinogradov
Serguei V
SV
College of Pharmacy, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
Batrakova
Elena V
EV
Kabanov
Alexander V
AV
D000818:Animals; D001710:Biotin; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005782:Gels; D007202:Indicators and Reagents; D007328:Insulin / Q000737:chemistry; D007553:Isotope Labeling; D051379:Mice; D018613:Microscopy, Confocal; D036103:Nanotechnology; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010316:Particle Size; D011092:Polyethylene Glycols; D012235:Rhodamines; D014018:Tissue Distribution; D014168:Transferrin / Q000737:chemistry; D014316:Tritium
D005452:Fluoresceins; D005456:Fluorescent Dyes; D005782:Gels; D007202:Indicators and Reagents; D007328:Insulin; D009841:Oligonucleotides; D012235:Rhodamines; D014168:Transferrin; D014316:Tritium; D011092:Polyethylene Glycols; D001710:Biotin