One of the main goals of nanomedicine is to encapsulate drugs inside nanoparticles and deliver them to specific, diseased targets in the body. Size is all-important when it comes to nanoparticle-mediated delivery because small increases in particle radius translate into huge improvements in drug loading and prolonged release kinetics.

There is a problem, however; the brain is a very challenging delivery environment – in part because of the blood–brain barrier and the tightly regulated space between cells. These barriers protect us by preventing harmful substances from the bloodstream entering our brains and also limit how they are distributed within the brain. Now, Justin Hanes and colleagues at the Johns Hopkins University School of Medicine in Baltimore have found that much larger particles can quickly pass through brain tissue provided they are coated with a dense layer of poly(ethylene glycol) – a harmless, hydrophilic polymer routinely used in the pharmaceutical industry.

The researchers obtained their results by looking at how individual polymer-coated nanoparticles of various sizes diffused through samples of fresh human and rodent brain tissue in a test tube. Some experiments were also performed in vivo on the rodent brain samples. Real-time multiple particle tracking experiments showed that particles at least 114 nm in diameter were capable of penetrating both human and rat brain tissue.

Reducing particle stickiness

The result also suggests that the porous mesh between cells (called the extracellular space) in human brain tissue is larger than previously thought and can exceed 200 nm. According to the Johns Hopkins team, the dense PEG coatings work by reducing the “stickiness” of the nanoparticles to various brain structures, allowing them to move through the extracellular space virtually unhindered. “Uncoated particles, on the other hand, are subject to adhesive interactions and can stick to cells, proteins and other components in the brain interstitium via electrostatic and hydrophobic interactions,” team members Elizabeth Nance and Graeme Woodworth told “We believe a high-density coating of PEG provides a protective brush-like layer on the nanoparticle surfaces, shielding them from these interactions.”

“The fact that larger nanoparticles are able to penetrate brain tissue means that better therapeutic platforms can now be designed,” they add. “We could, for instance, look at increasing the loading of therapeutics in the particles and provide longer sustained release of the drugs.”

The team, which previously showed that unexpectedly large nanoparticles – also coated with PEG – can penetrate human mucus membranes, now plans to look at how these nanoparticles travel through various types of diseased brain tissue.

The current work is reported in Science Translational Medicine.