title: A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue.
abstract: Prevailing opinion suggests that only substances up to 64 nm in diameter can move at appreciable rates through the brain extracellular space (ECS). This size range is large enough to allow diffusion of signaling molecules, nutrients, and metabolic waste products, but too small to allow efficient penetration of most particulate drug delivery systems and viruses carrying therapeutic genes, thereby limiting effectiveness of many potential therapies. We analyzed the movements of nanoparticles of various diameters and surface coatings within fresh human and rat brain tissue ex vivo and mouse brain in vivo. Nanoparticles as large as 114 nm in diameter diffused within the human and rat brain, but only if they were densely coated with poly(ethylene glycol) (PEG). Using these minimally adhesive PEG-coated particles, we estimated that human brain tissue ECS has some pores larger than 200 nm and that more than one-quarter of all pores are ≥ 100 nm. These findings were confirmed in vivo in mice, where 40- and 100-nm, but not 200-nm, nanoparticles spread rapidly within brain tissue, only if densely coated with PEG. Similar results were observed in rat brain tissue with paclitaxel-loaded biodegradable nanoparticles of similar size (85 nm) and surface properties. The ability to achieve brain penetration with larger nanoparticles is expected to allow more uniform, longer-lasting, and effective delivery of drugs within the brain, and may find use in the treatment of brain tumors, stroke, neuroinflammation, and other brain diseases where the blood-brain barrier is compromised or where local delivery strategies are feasible.
authors.affiliation: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Nance
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Woodworth
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Sailor
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Shih
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Xu
authors.forename: Ganesh
authors.initials: G
authors.lastname: Swaminathan
authors.forename: Dennis
authors.initials: D
authors.lastname: Xiang
authors.forename: Charles
authors.initials: C
authors.lastname: Eberhart
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D020099:Coated Materials, Biocompatible; D004058:Diffusion; D004337:Drug Carriers; D005260:Female; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D053758:Nanoparticles; D036103:Nanotechnology; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism*; D010316:Particle Size; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry*; D011137:Polystyrenes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties; D013997:Time Factors
chemical_list: D020099:Coated Materials, Biocompatible; D004337:Drug Carriers; D011137:Polystyrenes; D011092:Polyethylene Glycols; D017239:Paclitaxel