Researchers Develop New Nanoparticle Drug-Delivery System To Treat Brain Disorders

Researchers Develop New Nanoparticle Drug-Delivery System To Treat Brain Disorders

Researchers have been working on biological pathways that lead to neurodegenerative diseases and develop molecular agents to target them. The challenge in treating these brain diseases is the blood-brain barrier (BBB) which is very specifically permeable in nature which means that they allow only selected things.

A team of multidisciplinary researchers at Brigham and Women’s Hospital and Boston Children’s Hospital created a nanoparticle platform, which can facilitate medically effective delivery of encapsulated agents in mice with a physically breached or intact blood brain barrier. This helped to have a successful delivery of therapeutic agents to the brain.

The team observed that in a mouse model of traumatic brain injury (TBI) the delivery system showed three times more accumulation in the brain than conventional methods and it was therapeutically effective as well paving way for treatment of many neurological disorders.  

Previous approaches for delivering therapeutics after TBI were relying on a brief window of time after physical injury to the head ,when the BBB is temporarily breached. The problem was that after the BBB was repaired within a few weeks; the physicians lacked tools for effective drug delivery.  

Nitin Joshi, Ph.D., an associate bioengineer at the Center for Nanomedicine in the Brigham’s Department of Anesthesiology, said that it was very difficult for them to get both the small and large molecule therapeutic agents to be delivered across the BBB. So, they came up with a solution where they would encapsulate therapeutic agents into biocompatible nanoparticles with engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB. 

This technology now can enable physicians to treat secondary injuries associated with TBI that can lead to neurodegenerative diseases like Alzheimer’s, Parkinson’s ,etc , which can develop during ensuing months and years once the BBB has healed. 

Jeff Karp, Ph.D., of the Brigham’s Department of Anesthesiology, added that in order to deliver agents across the BBB in absence of inflammation was of a holy grail in the field. This approach is simple enough and can be applied to many neurological disorders requiring delivery of therapeutic agents to the brain. 

Rebekah Mannix, MD, a co-senior author on the study, further emphasized that the BBB inhibits delivery of therapeutic agents to the central nervous system (CNS) for a wide range of acute and chronic diseases. She added that this could play an important role in curing many diseases and allow for delivery of a large number of diverse drugs, including antibiotics, antineoplastic agents, and neuropeptides.  

siRNA or small interfering RNA was the therapeutic used in the study and was designed to inhibit the expression of tau protein. (This protein is believed to play a key role in neurodegeneration.) 

Poly(lactic-co-glycolic acid), or PLGA, a biodegradable and biocompatible polymer used in several existing products approved by the U.S.Food and Drug Administration, was used as the base material for nanoparticles.  

Researchers systematically studied the surface properties of nanoparticles to maximize their penetration across the intact ,undamaged BBB in healthy mice. This gave an identification to a unique nanoparticle design that maximized the transport of encapsulated siRNA across the intact BBB and significantly improved the uptake by brain cells. 

A 50 percent reduction in the expression of tau was observed in TBI mice who received anti-tau siRNA through the novel delivery system, irrespective of the formulation being infused within or outside the temporary window of breached BBB. In contrast, tau was not affected in mice that received the siRNA through a conventional delivery system.

Wen Li, Ph.D., of the Department of Anesthesiology, said that this report establishes for the first that systematic modulation of surface chemistry and coating density can be leveraged to tune the penetration of nanoparticles across biological barriers with tight junctions.   

Researchers have also studied methods to attack alternative targets using the novel delivery platform. Karp added that they wanted to look beyond tau to validate that the new system is amenable to other targets. They hoped that this research would help anyone studying a neurological disorder . This research has provided them a significant momentum advance toward multiple therapeutic targets and be in the position to move ahead to human testing.

Journal Reference:
BBB pathophysiology independent delivery of siRNA in traumatic brain injury, Science Advances. DOI: 10.1126/sciadv.abd6889

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