The blood-brain barrier (BBB) refers to the barrier between blood plasma and brain cells formed by brain capillary walls and glial cells, and the barrier between plasma and cerebrospinal fluid formed by the choroid plexus. Only certain types of molecules are allowed to enter the brain neurons and other surrounding cells from the bloodstream.
The existence of the blood-brain barrier is of great significance in preventing harmful substances from entering the brain from the blood. However, the blood-brain barrier also prevents the transfer of most small molecule drugs and macromolecules (such as peptides, proteins and gene-based drugs), limiting the treatment of central nervous system diseases (such as neurodegenerative diseases, brain tumors, brain infections and strokes, etc.).
Recently, Harvard Medical School, Massachusetts Institute of Technology and other units have collaborated to publish a research paper titled: BBB pathophysiology–independent delivery of siRNA in traumatic brain injury in Science Advances, a sub-Journal of Science.
The research team has developed a nanoparticle delivery platform that can break through the blood-brain barrier and successfully deliver therapeutic drugs to the brain. In the mouse model of traumatic brain injury (TBI), the efficiency of the nanoparticle delivery system is three times that of the previous traditional delivery methods, and the therapeutic effect is significant. This research opens up new possibilities for the treatment of various neurological diseases.
Secondary injuries related to traumatic brain injury (TBI) can lead to Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. Previously developed methods to deliver therapeutic drugs into the brain after traumatic brain injury (TBI) rely on a short window of time when the blood-brain barrier is temporarily destroyed after trauma. After the blood-brain barrier is repaired, there is a lack of effective drug delivery tools.
Due to the existence of the blood-brain barrier, it is very difficult to break through the blood-brain barrier to deliver large or small molecule therapeutic drugs. Therefore, when the blood-brain barrier is normal, the successful delivery of drugs has always been the holy grail in this field.
In order to break through this problem, the research team plans to encapsulate therapeutic drugs into biocompatible nanoparticles with precisely designed surface properties. Such nanoparticles can efficiently deliver drugs to the brain without being affected by the state of the blood-brain barrier.
Polylactic acid-glycolic acid copolymer (PLGA) is a biodegradable biocompatible polymer with good biocompatibility, non-toxicity, good encapsulation and film-forming properties, and is widely used in pharmaceuticals, medical engineering materials and modern industrial fields, and has been approved by the U.S. Food and Drug Administration (FDA) as pharmaceutical excipients. Therefore, the research team chose PLGA as the basic material for nanoparticles.
Researchers systematically designed and studied the surface properties of nanoparticles to maximize their penetration of the intact blood-brain barrier in healthy mice.
The therapeutic drug used in this study is a small interfering RNA (siRNA) designed to inhibit the expression of tau protein. Many previous studies have shown that tau protein plays a key role in neurodegenerative diseases.
In order to verify the effect, the research team used this new nanoparticle delivery system to deliver anti-tau protein siRNA to a mouse model of traumatic brain injury (TBI).
After traumatic brain injury (TBI), the window period when the blood-brain barrier was destroyed, or after the blood-brain barrier was restored two weeks later, the nanoparticle system delivered tau protein siRNA, which resulted in a 50% decrease in tau protein expression in the mouse brain . This indicates that the nanoparticle delivery system can efficiently break through the normal blood-brain barrier and deliver therapeutic drugs to the brain. As a control conventional delivery method, there was no significant change in tau protein in the mouse brain.
The research team reported that although the traumatic brain injury (TBI) model was used to explore and develop this new technology, basically neurological diseases can benefit from this work. This nanoparticle delivery platform is not only limited to the delivery of tau protein inhibitors, but can also be used to deliver a variety of drugs, including antibiotics, anti-tumor drugs, neuropeptides, etc., which may change the rules of the game for central nervous system diseases. The research team also reported that the results of this study provided a huge motivation for multiple treatment goals and for conducting human experiments.
Reference:
- Li, W., Qiu, J., Li, X. L., Aday, S., Zhang, J., Conley, G., … & Joshi, N. (2021). BBB pathophysiology–independent delivery of siRNA in traumatic brain injury. Science advances, 7(1), eabd6889.