Treating brain disorders with new nanoparticle drug delivery system

A new nanoparticle drug-delivery system could help scientists overcome the long-standing problem of delivering therapeutics across the blood-brain barrier and into the brain.

Progress has been made over the past few decades in identifying biological pathways that lead to neurodegenerative diseases, which has led to the development of promising molecular agents to target them. However, the translation of these findings into clinically approved treatments has been slow due to the challenges of delivering therapeutics across the blood-brain barrier.

To help solve this issue, a team of bioengineers, physicians, and collaborators at Brigham and Women’s Hospital and Boston Children’s Hospital have now created a nanoparticle platform which can facilitate the effective delivery of encapsulated agents in mice with a physically breached or intact blood-brain barrier.

Breaching the blood-brain barrier

The team used a mouse model of a traumatic brain injury (TBI) and observed that the delivery system showed three times more accumulation in the brain than conventional methods of delivery and was therapeutically effective. This new technology could now enable physicians to treat secondary injuries associated with TBIs that can lead to Alzheimer’s, Parkinson’s, and other neurodegenerative diseases, which can develop during ensuing months and years once the barrier has healed.

Corresponding author Nitin Joshi, an associate bioengineer at the Center for Nanomedicine in the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine, said: “It’s very difficult to get both small and large molecule therapeutic agents delivered across the blood-brain barrier. Our solution was to encapsulate therapeutic agents into biocompatible nanoparticles with precisely engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB.”

Central nervous system promise

The blood-brain barrier also inhibits the delivery of therapeutic agents to the central nervous system for a wide range of acute and chronic diseases. For the study, the team used a small interfering RNA (siRNA) molecule designed to inhibit the expression of the tau protein, which is believed to play a key role in neurodegeneration. Poly(lactic-co-glycolic acid) was used as the base material for nanoparticles and the researchers systematically engineered and studied the surface properties of the nanoparticles to maximise their penetration, leading to the identification of a unique nanoparticle design that maximized the transport of the encapsulated siRNA.

The team saw a 50% reduction in the expression of tau, irrespective of the formulation being infused within or outside the temporary window of breached blood-brain barrier. In contrast, tau was not affected in mice that received the siRNA through a conventional delivery system.

Rebekah Mannix, Division of Emergency Medicine at Boston Children’s Hospital and a co-senior author on the study, said: “The technology developed for this publication could allow for the delivery of large number of diverse drugs, including antibiotics, antineoplastic agents, and neuropeptides. This could be a game changer for many diseases that manifest in the central nervous system.”

“In addition to demonstrating the utility of this novel platform for drug delivery into the brain, this report establishes for the first time that systematic modulation of surface chemistry and coating density can be leveraged to tune the penetration of nanoparticles across biological barriers with tight junction,” said first author Wen Li, PhD, of the Department of Anesthesiology, Perioperative and Pain Medicine.

In addition to targeting tau, the researchers have studies underway to attack alternative targets using the novel delivery platform.

Co-senior author Jeff Karp, PhD, of the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine, said: “For clinical translation, we want to look beyond tau to validate that our system is amenable to other targets. We used the TBI model to explore and develop this technology, but essentially anyone studying a neurological disorder might find this work of benefit. We certainly have our work cut out, but I think this provides significant momentum for us to advance towards multiple therapeutic targets and be in the position to move ahead to human testing.”