Over the last few decades, scientists have established the biological pathways that cause neurodegenerative diseases and have created potential molecular agents to target these pathways.
Yet, there has been a delay in translating these discoveries into clinically approved treatments, partially due to the challenges faced by researchers in delivering therapeutics into the brain through the blood-brain barrier (BBB).
To enable the successful delivery of therapeutic agents into the brain, a group of physicians, bioengineers, and colleagues from Brigham and Women’s Hospital and Boston Children’s Hospital developed a nanoparticle platform with the ability to facilitate therapeutically efficacious delivery of encapsulated agents in mice with an intact or physically breached BBB.
In a mouse model of traumatic brain injury (TBI), they found that the delivery system exhibited three times more accumulation in the brain compared to traditional methods of delivery and was also therapeutically efficacious. This could pave the way for the treatment of various neurological disorders. The study results were reported in Science Advances.
The earlier methods for delivering therapeutics into the brain following TBI depend on the short window of time following a physical injury to the head when the BBB is breached temporarily. But as soon as the BBB heals in a few weeks, physicians do not have the tools needed for effective delivery of drugs.
It’s very difficult to get both small and large molecule therapeutic agents delivered across the BBB. 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.
Nitin Joshi, PhD, Associate Bioengineer, Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Joshi is the corresponding author of the study.
Physicians can use this technology to treat secondary injuries linked to TBI that can cause Parkinson’s, Alzheimer’s, and other neurodegenerative diseases, which can develop during the months and years following the healing of the BBB.
To be able to deliver agents across the BBB in the absence of inflammation has been somewhat of a holy grail in the field. Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.
Jeff Karp, PhD, Study Co-Senior Author, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
According to Rebekah Mannix, MD, MPH, a co-senior author of the study from the Division of Emergency Medicine at Boston Children’s Hospital, the BBB suppresses the delivery of therapeutic agents to the central nervous system (CNS) for various chronic and acute diseases.
“The technology developed for this publication could allow for the delivery of large number of diverse drugs, including antibiotics, antineoplastic agents, and neuropeptides,” she added. “This could be a game changer for many diseases that manifest in the CNS.”
For this study, a small interfering RNA (siRNA) molecule designed to suppress the tau protein expression was used as the therapeutic. It is believed that this molecule plays a vital role in neurodegeneration. The base material for nanoparticles was poly(lactic-co-glycolic acid) (PLGA)—a biocompatible and biodegradable polymer used in various existing products approved by the U.S. Food and Drug Administration.
The team systematically designed and analyzed the surface properties of the nanoparticles to improve their penetration through the undamaged, intact BBB in healthy mice.
This resulted in the finding of an exclusive nanoparticle design that optimized the transport of the encapsulated siRNA through the intact BBB and considerably enhanced the uptake by brain cells.
A 50% decrease in the tau protein expression was found in TBI mice that received anti-tau siRNA through the novel delivery system, regardless of the formulation infused within or outside the temporary window of breached BBB. On the contrary, there was no impact on the tau protein in mice that received the siRNA with a traditional delivery 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.
Wen Li, PhD, Study First Author, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital
Apart from targeting tau, the team is now performing various studies to attack alternative targets with the novel delivery platform.
According to Karp, “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 toward multiple therapeutic targets and be in the position to move ahead to human testing,” Karp concluded.
Li, W., et al. (2021) BBB pathophysiology-independent delivery of siRNA in traumatic brain injury. Science Advances. doi.org/10.1126/sciadv.abd6889.