Polymer NPs injected intravenously circulate in the blood vessels (white signal) and deposited around large brain vessels and microvessels (white arrows) of 48 hours zebrafish larvae. Blue arrows: venous vessels; red arrows: arterial vessels. Picture acquired at 2 hours post intravenous injection. Credit: Jean-Michel Rabanel.Treating neurodegenerative diseases like Alzheimer’s and Parkinson’s is challenging because of the presence of the blood brain barrier, which effectively blocks potentially harmful agents from reaching the brain. Nanoparticles (NPs) made of the biocompatible polymers polylactic acid (PLA) and polyethylene glycol (PEG) can limit clearance by the immune system and access the brain, according to scientists [Rabanel et al., Journal of Controlled Release 328 (2020) 679-695, https://doi.org/10.1016/j.jconrel.2020.09.042].
“The blood-brain barrier filters out harmful substances to prevent them reaching the brain. But this same barrier also blocks the passage of drugs,” explains Charles Ramassamy of INRS in Canada, who led the study. “Typically, high doses are required to get a small amount of a drug into the brain. What remains in the bloodstream can induce side effects.”
Polymeric NPs are a promising candidate for all types of drug delivery but could have unique advantages for overcoming the blood brain barrier. Ramassamy and his team used a simple synthetic approach to create particles with a PLA core and a shell of PEG chains. The size of the particle, as well as the length and density of PEG chains can be varied, allowing the researchers to select combinations with the most promising properties, which were then tested in vivo using zebrafish.
“The zebrafish is a good model for the blood brain barrier [because it] retains many of the features of mammals,” explains first author of the study, Jean-Michel Rabanel. “The great advantage is that the biodistribution of NPs can be imaged in real time.”
The researchers’ observations confirm that particles cross the blood brain barrier through active cellular processes known as endocytosis and exocytosis. In zebrafish, the team found that the NPs are also translocated across vascular walls and end up in specific regions, including the brain.
“A layer of PEG… makes [the NPs] invisible to the immune system, so their half-life in the bloodstream is longer,” explains Ramassamy.
The length of PEG chains on the surface of the NPs seems to influence the endocytosis pathway, while the density of chains has an effect on the interaction of NPs with vascular endothelial cells.
“Drug nanotransporters have numerous advantages to target toxic or degradation-sensitive drugs across cell barriers,” points out Rabanel. “[Our results] could have implications for blood brain barrier particle adhesion and translocation to the brain, but we still need to optimize transport efficiency and understand the interactions between NPs and the vascular endothelium.”
The team now plans to explore other surface parameters and, ultimately, test NPs in other animal models, particularly mammals that are closer to humans.