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.

Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor

“…PEGylated nanoparticles in the sub-100-nm diameter size range are known to be able to move through brain tissue (10), and our findings show that sub-100-nm nanoparticles that have nearneutral zeta potentials and contain a PEG coating with protein ligands can spread through the brain tissue. Thus, if these nanoparticles can transcytose across the intact BBB, they may be useful for delivering a broad spectrum of therapeutic and imaging agents.…”

“…After our experimental studies were completed, another group reported that nanoparticles in the sub-100-nm range can in fact move through brain tissue, especially when they have near-neutral zeta potentials and are coated with a dense polyethylene glycol (PEG) layer (10). Moreover, nanoparticle zeta potentials that are slightly negative to near-neutral are desirable, given that highly negatively and positively charged nanoparticles are known to (i) disrupt the BBB (11), (ii) facilitate formation of protein coronas that may mask or alter the function of the targeting ligand (12), and (iii) illicit unwanted immune responses and more rapid blood clearance via increased uptake through the mononuclear phagocyte system (13).…”

‘Stealth’ nanoparticles evade neural immune cells but also evade major brain cell populations: Implications for PEG-based neurotherapeutics

“…PEGylated materials evade the MPS, enhancing bioavailability, and possess the ability to cross the BBB, for which the exact mechanism is unknown but could include transcytosis or receptor-mediated endocytosis [15]. PEG-coated nanoparticles accumulate in brain tissue more effectively than non-PEG-coated nanoparticles, and those coated with high density PEG also display greater diffusion through brain parenchyma [4,16]. Of high relevance for clinical applications, PEG-coated nanoparticle accumulation is enhanced in pathological foci including gliosarcoma and Multiple Sclerosis models [17,18], possibly due to inflammation-induced BBB hyperpermeability -similar to enhanced nanoparticle permeability/retention (EPR effect) in brain tumors [19].…”

Nanomedicine in cerebral palsy

“…Nanotechnology-based approaches are providing potential platforms for CNS therapy. The physicochemical properties of the nanoparticles can be tailored to overcome the BBB 43 and to improve penetration and diffusion through the brain parenchyma, 44 allowing for controlled, sustained release of a therapeutic. These approaches have shown significant promise in preclinical studies for the treatment of many CNS diseases, including cancer, neuroinflammation, and neurodegeneration.…”