- The use of the delivery system in mouse models results in an unprecedented siRNA breakdown throughout the whole blood-brain barrier.
- Technology has the potential to address a variety of human neurological problems
News – In the last few decades, researchers have identified biological pathways leading to neurodegenerative diseases and developed promising molecular agents to target them. However, the translation of these findings into clinically agreed treatments has progressed at a much slower rate, partly due to the challenges facing scientists in delivering treatment. -medicine throughout the blood-brain barrier (BBB) and into the brain. To enable successful delivery of therapeutic agents to the brain, a team of bioengineers, physicians, and colleagues at Brigham and Women’s Hospital and Boston Children’s Hospital created a nanoparticle platform, which will aid in effective therapeutic delivery of encapsulated agents in mice with complete physical or BBB fracture. In a mouse model of traumatic brain injury (TBI), they found that the delivery system showed three times more accumulation in the brain than conventional delivery methods and was also therapeutically effective, which could open up opportunities for treatment of a number of neurological disorders. Results were published in Advances in science.
Previously developed procedures for the delivery of chemotherapy into the brain after TBI are dependent on the short-term window after physical injury to the head, when the BBB is broken for time. However, after the BBB is repaired within a few weeks, doctors do not have the tools to deliver drugs effectively.
“It is very difficult to provide small and large molecular therapeutic agents across the BBC,” said co-author Nitin Joshi, PhD, associate bioengineer at the Center for Nanomedicine in the Department of Anesthesiology, Perioperative and Brigham’s Pain. “Our solution was to incorporate therapeutic agents into biocompatible nanoparticles with precision engineered surface properties that would allow their efficient transport into the brain, independent of the BBC state. “
The technology could allow physicians to treat secondary TBI-related injuries that could lead to Alzheimer’s, Parkinson’s Disease, and other neurodegenerative diseases, which may improve in the coming months and years when the BBB will heal.
“Being able to deliver productions across the BBC without inflammation has been something of a holy grail in the field,” said co-author Jeff Karp, PhD, of Brigham’s Department of Anesthesiology, Perioperative and Pain Pain. “Our simple approach is relevant to many neurological disorders where it desires to give the brain therapeutic agents.”
Rebekah Mannix, MD, MPH, of the Department of Emergency Medicine at Boston Children’s Hospital and co-author of the study, confirmed that the BBB restricts the delivery of therapeutic agents to the central nervous system (CNS) for a wide range of chronic diseases and chronic. “The technology developed for this release could allow the delivery of a large number of diverse drugs, including antibiotics, antineoplastic agents, and neuropeptides,” she said. be a game changer for many diseases that appear in the CNS. “
The therapy used in this study was a small molecule interconnected RNA (siRNA) designed to inhibit the tau protein, which is believed to play a major role in neurodegeneration . Poly (lactic-co-glycolic acid), or PLGA, a bioavailable and biocompatible polymer used in a number of existing products approved by the U.S. Food and Drug Administration, has been used as the main ingredient for nanoparticles. The researchers systematically and systematically analyzed the surface properties of the nanoparticles to obtain the highest level over the entire BBB, without damage in healthy mice. As a result a unique nanoparticle design was identified that optimized the transport of the encapsulated siRNA over the whole BBB and significantly improved brain cell uptake.
A 50 percent reduction in tau expression was observed in TBI mice that received anti-tau siRNA through the novel delivery system, regardless of whether the design was internally or externally introduced. broken BBB temporary window. In contrast, tau in mice that received the siRNA through a conventional delivery system was not affected.
“As well as demonstrating the usefulness of this state-of-the-art platform for the delivery of drugs into the brain, this report establishes for the first time that systematic modeling of surface chemistry and coat density can be pull to access nanoparticles over tight-knit biological barriers, ”said first author Wen Li, PhD, of the Department of Anesthesiology, Perioperative and Pain Medicine.
In addition to targeting tau, the researchers have begun studies to attack other targets using the novel delivery platform.
“For clinical translation, we want to look beyond tau to ensure that our system is accessible to other targets,” Karp said. “We used the TBI model to study and develop this technology, but of course anyone studying brain disorders may find this work beneficial. Certainly our work has been cut short. -out, but I think this gives us a great move to move towards a number of therapeutic targets.
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This work was supported by the National Institutes of Health (HL095722), Fundac? A? O para a Cie? Ncia ea Tecnologia through MIT-Portugal (TB / ECE / 0013/2013), and the Harvard Football Players Health Check, funded by a grant from the National Football League Players Association. Karp has been a paid consultant and or equity owner for several biotechnology companies (listed here). Joshi, Karp, Mannix, Li, Qiu and Langer have one unpublished patent based on the nanoparticle work presented in this manuscript.
Paper called: Li, W et al. “Independent delivery of BBB pathophysiology of siRNA in traumatic brain injury” Advances in science DOI: 10.1126 / sciadv.abd6889