03 Jan Nanoparticles May Enable Delivery of Drugs Across Blood Brain Barrier
MedicalResearch.com Interview with:
Nitin Joshi, Ph.D.
Engineering in Medicine/Department of Medicine
Brigham and Women’s Hospital
Dr. Jeffrey M Karp Ph.D
Professor of Medicine at Brigham and Women’s Hospital
Harvard Medical School
MedicalResearch.com: What is the background for this study? Would you explain what is meant by the blood brain barrier? How will nanoparticles facilitate transport of drugs into the brain?
Response: Over the past few decades, researchers have identified promising therapeutic agents that can target the biological pathways involved in brain diseases. Unfortunately, clinical translation of these therapeutics is limited by their inability to cross the blood brain barrier (BBB) and enter the brain at therapeutically effective levels. The BBB is a highly selective semipermeable border of cells that prevents molecules in the circulating blood from non-selectively crossing into the brain tissue. We have developed a simple targeted nanoparticle platform that can stably encapsulate therapeutic agents and enable their therapeutically effective delivery into the brain. In this work, we have demonstrated the utility of this platform for the treatment of traumatic brain injury (TBI), which is a leading cause of death and disability in children and young adults, with millions of people suffering TBI each year in accidents, sports, and military conflicts. Following primary injury, which is a result of the mechanical impact to the brain, secondary injury gradually occurs over months to years and can lead to neurological dysfunctions, including Alzheimer’s and Parkinson’s diseases.
After TBI, the BBB is physically breached for a short time and previous approaches to achieve therapeutically effective transport of drugs across the BBB have been severely limited to utilizing this very short window. However, the extent to which the BBB is physically breached in TBI varies greatly across the patient population. Therefore, current approaches are applicable to only a subset of injuries with substantially breached BBB. Moreover, BBB can self-repair within a few hours to weeks post-injury to restore its integrity. Hence, physical breaching of BBB offers a limited window for therapeutic interventions, which is not ideal as the secondary injury can last months to years and may require repeated dosing over long term.
The nanoparticle platform developed in this work can enable therapeutically effective delivery of drugs into the brain, irrespective of the state of the BBB. We achieved this by precise engineering of the surface properties of nanoparticles, which maximized their transport across the BBB. 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 U.S. Food and Drug Administration was used as the base material for nanoparticles. We systematically engineered and studied the surface properties of the nanoparticles to maximize their penetration across 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 across the intact BBB and also significantly improved the uptake by the brain cells.
MedicalResearch.com: What are the main findings?
Response: Intravenous injection in TBI mice of nanoparticles with precisely engineered surface properties resulted in 3-fold higher brain delivery of siRNA compared to conventionally used nanoparticles, irrespective of the nanoparticles being infused within or outside the window of physically breached BBB.
Compared to TBI mice treated with saline, engineered nanoparticles loaded with anti-Tau siRNA (a proof of concept drug) showed 50% reduction in the expression of Tau – a protein, which has been reported to be involved in the progression of secondary injury following TBI. On the other hand, free siRNA or siRNA loaded into conventionally used nanoparticles did not show any effect.
This reports also establishes for the first time that that systematic modulation of surface chemistry and coating density can be leveraged to tune the penetration of nanoparticles across the biological barriers with tight junctions.
MedicalResearch.com: What should readers take away from your report?
Response: 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 can facilitate therapeutically effective delivery of promising therapeutic agents into the brain and is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: As the next step, 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.
MedicalResearch.com: Is there anything else you would like to add?
Response: This work was supported by the National Institutes of Health (HL095722), Fundação para a Ciência e a Tecnologia through MIT-Portugal (TB/ECE/0013/2013), and the Football Players Health Study at Harvard, funded by a grant from the National Football League Players Association.
Joshi, Karp, Mannix, Li, Qiu and Langer have one unpublished patent based on the nanoparticle work presented in this manuscript. Karp has been a paid consultant and or equity holder for multiple biotechnology companies (listed here).
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