Research ArticlesNanomedicine

A Dense Poly(Ethylene Glycol) Coating Improves Penetration of Large Polymeric Nanoparticles Within Brain Tissue

Science Translational Medicine  29 Aug 2012:
Vol. 4, Issue 149, pp. 149ra119
DOI: 10.1126/scitranslmed.3003594

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Brain-Penetrating Particles

It was once thought that particles larger than 60 nm would be stuck in the brain extracellular space (ECS), unable to penetrate further. This has been a particularly bothersome rule of thumb for the design of drug delivery systems that rely on larger particles or viruses to carry therapeutics. Now, Nance and colleagues have challenged this hypothesis by exploring particles that are >60 nm, discovering that large particles, with the right coating, can indeed diffuse throughout the ECS of both rat and human brains.

The authors first coated fluorescent polystyrene particles with a dense layer of the bio-inert polymer poly(ethylene glycol) (commonly known as PEG) or with a carboxyl moiety (COOH). Using a multiple-particle tracking method, the authors reported that 114-nm PEG-coated particles penetrated ex vivo human brain tissue with ease, whereas similarly sized COOH-coated particles were stopped in their tracks. Nance et al. attributed this difference to the dense, near-neutral PEG coating, claiming that it allows the particles to experience the brain ECS more as a fluid than an impermeable solid. The importance of the PEG coating was further confirmed in living mice, where real-time video microscopy revealed that the 100-nm PEG-coated particles penetrated farther into the mouse brain than the 100-nm COOH-coated ones.

With a brain ECS pore size cutoff >100 nm, many doors can be opened in nanomedicine. Larger particles permit the inclusion of higher quantities of drug, which can be distributed for longer periods of time to more areas within the brain. Nance and colleagues preliminarily demonstrated such drug delivery capabilities using paclitaxel-loaded, 85-nm biodegradable nanoparticles, showing that only particles with the PEG coating could diffuse rapidly throughout rat brain tissue ex vivo. Although these densely coated particles may make drug delivery more efficient, they have yet to be tested in a disease model to confirm efficacy over conventional nanoparticles. Although currently limited to direct infusion into the brain, for eventual use in humans, it is hoped that they may be administered systemically for treating diseases with an impaired blood-brain barrier.