Nanoparticle Platform Delivers Drugs Across Blood-Brain Barrier in Mice

By Marilynn Larkin

January 15, 2021

NEW YORK (Reuters Health) - A novel nanoparticle drug delivery system had a therapeutic effect in a mouse model of traumatic brain injury (TBI), regardless of whether the blood-brain barrier (BBB) was physically breached or intact, researchers say.

"Delivery of drugs into the brain has been challenging," Dr. Jeffrey Karp of Brigham and Women's Hospital in Boston said in an email to Reuters Health. "In the case of TBI, there is a short window for treatment, when the blood vessels in the brain are leaky due to the injury and drugs move freely into the brain. However, this approach offers a limited and unpredictable window for treatment, as the blood vessels self-repair and become tightly sealed again."

Coauthor Dr. Nitin Joshi, also of Brigham and Women's, explained by email, "Utilizing nanoparticles, we achieved effective delivery of biological agents such as small interfering RNA (siRNA) into the brain, when blood vessels were damaged and leaky, and when blood vessels were tightly sealed after repair, or before injury."

As reported in Science Advances, the authors' nanoparticle platform transports a therapeutic agent - in this case, an siRNA targeting tau - into the brain by encapsulating it in a biodegradable and biocompatible polymer called poly(lactic-co-glycolic acid), or PLGA. The polymer is used in several therapeutic products approved by the US Food and Drug Administration.

The platform enabled the effective delivery of the siRNA across the BBB in mice, leading to a 50% reduction in tau expression, whether the formulation was infused within or outside the temporary window that occurs with a breached BBB.

By contrast, tau expression was not affected in mice that received the siRNA through a conventional delivery system.

The authors conclude, "Together, our data suggest that this nanoparticle platform is a promising next-generation drug delivery approach for the treatment of TBI."

Coauthor Dr. Rebekah Mannix of Harvard Medical School, noted in an email to Reuters Health, "In this work, we used the TBI model to develop the technology, but our...approach can be useful for other neurological diseases where drug delivery to the brain is needed. This new technology has potential to deliver large molecule biological agents like proteins, which are typically challenging to formulate. As the next step, we want to explore potential targets for several neurological diseases."

Dr. Noelle Comolli, Chair of Chemical Engineering at Villanova University in Pennsylvania, commented by email, "These nanoparticle platforms are becoming increasingly common, and similar to the lipid nanoparticle coating used in the new mRNA vaccines for COVID. These show great promise, since the increased permeability can be used in so many applications, not just TBI."

"The polymer (PLGA) and varying coatings are not new, and have been used in many applications already, which makes this even more promising," said Dr. Comolli, who was not involved in the study. "What is new is the very small size and study on the exact effect of surface coating and density of surface coating on crossing the BBB."

"Because this is a similar design to many other nanoparticle designs that may NOT be intended to cross the BBB, we may want to be more cautious from now on about checking that our designs do not unintentionally cross the BBB," she added.

"This design is based primarily on its small size and strong lipophilicity on the surface to get through this tight junction," she said. "I would also be concerned about unintentional crossing of any tight junction - i.e., where else in the body does this end up? And how targeted must the injection site be in order to minimize unwanted accumulation in the wrong area?"

SOURCE: Science Advances, online January 1, 2021.