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Over the past few decades, researchers have identified biological pathways that lead to neurodegenerative diseases and developed promising molecular agents to combat them. However, translating these findings into clinically approved treatments has been much slower, in part due to the challenges scientists face in delivering therapeutics across the blood-brain barrier (BBB) and into the brain. To facilitate the successful delivery of therapeutics to the brain, a team of bioengineers, doctors, and staff at Brigham and Women’s Hospital and Boston Children’s Hospital developed a nanoparticle platform that enables the therapeutically effective delivery of encapsulated drugs in mice with a physical injury or Injury can ease intact BBB. In a mouse model of traumatic brain injury (TBI), they observed that the delivery system in the brain had a three times higher accumulation than conventional delivery methods and was also therapeutically effective, which could open up possibilities for the treatment of numerous neurological disorders. The results were published in Science Advances.
Previously developed approaches to deliver therapeutics to the brain after TBI are based on the short window of time after a physical injury to the head when the BBB is temporarily injured. However, after the BBB has been repaired within a few weeks, doctors lack tools for effective drug delivery.
“It is very difficult to get both small and large molecule therapeutics across the BBB,” said author Nitin Joshi, Ph.D., associate bioengineer at the Center for Nanomedicine in the Department of Anaesthesiology, Perioperative and Pain Medicine in Brigham. “Our solution was to encapsulate therapeutics in biocompatible nanoparticles with precisely designed surface properties that enable them to be transported into the brain in a therapeutically effective manner regardless of the state of the BBB.”
The technology could allow doctors to treat secondary injuries associated with TBI that can lead to Alzheimer’s, Parkinson’s, and other neurodegenerative diseases that can develop in the months and years that follow after the BBB has healed.
“Being able to get drugs across the BBB without inflammation has been a holy grail in this area,” said co-senior author Jeff Karp, Ph.D., of the Department of Anaesthesiology, Perioperative and Pain in Brigham medicine. “Our radically simple approach is applicable to many neurological conditions where delivery of therapeutics to the brain is desired.”
Rebekah Mannix, MD, MPH, of the Department of Emergency Medicine at Boston Children’s Hospital and co-senior author on the study, also noted that the BBB inhibits the delivery of therapeutics to the central nervous system (CNS) for a wide range of patients, both acute and chronic diseases. “The technology developed for this paper could enable the delivery of a large number of different drugs, including antibiotics, antineoplastics and neuropeptides,” she said. “This could mean a change for many diseases that manifest in the CNS.”
The therapeutic used in this study was 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), or PLGA, a biodegradable and biocompatible polymer used in several existing products approved by the US Food and Drug Administration, has been used as the base material for nanoparticles. The researchers systematically developed and examined the surface properties of the nanoparticles in order to maximize their penetration through the intact, undamaged BBB in healthy mice. This led to the identification of a unique nanoparticle design that maximized the transport of the encapsulated siRNA through the intact BBB and significantly improved uptake by brain cells.
A 50 percent decrease in tau expression was observed in TBI mice that received anti-tau siRNA via the novel delivery system, regardless of which formulation was infused inside or outside the temporary window of the injured BBB. In contrast, tau was unaffected in mice that received the siRNA via a conventional delivery system.
“This report not only demonstrates the usefulness of this novel platform for drug delivery into the brain, but for the first time notes that systematic modulation of surface chemistry and coating density can be used to optimize the penetration of nanoparticles across biological barriers with tight connections. “said first author Wen Li, Ph.D., of the Department of Anaesthesiology, Perioperative, and Pain Medicine.
In addition to targeting tau, the researchers have studies underway to attack alternative targets using the novel delivery platform.
“For clinical translation, we want to look beyond Tau to confirm that our system is suitable for other goals,” said Karp. “We used the TBI model to research and develop this technology, but basically anyone studying a neurological disorder could find this work useful. We have certainly stopped our work, but I think there is give us significant impetus to work toward multiple therapeutic goals and be able to proceed with human testing. ”
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BBB pathophysiology independent delivery of siRNA in traumatic brain injuries, Science Advances. DOI: 10.1126 / sciadv.abd6889 Provided by Brigham and Women’s Hospital
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