Breaking through the blood-brain barrier nanoparticle opens the journey of drug delivery to the brain

  Our reporter Chen Xi

  Research results show that the human serum albumin drug delivery nanosystem can significantly improve the efficiency of therapeutic drugs into the brain and the ability to retain them in the brain.

A mouse model of Alzheimer's disease shows that the nanomedicine can improve neuronal morphology changes, save memory impairment, and slow down the pathogenesis of the disease.

  For a long time, when the brain needs to be treated with drugs due to diseases, due to the existence of the blood-brain barrier, it is a very difficult task to deliver drugs to the required brain tissue by oral or intravenous injection.

  On April 10, the reporter learned from Tianjin University that the team of Professor Chang Jin, director of the Institute of Nanobiomedicine of the School of Life Sciences of the school, took a new approach by instilling nanoparticle drugs from the nasal cavity to find a way for the drugs to bypass the blood-brain barrier and enter the brain. "shortcut".

At present, the research has made new progress.

  The blood-brain barrier is the "brass wall and iron wall" that protects the brain

  Usually drugs to treat brain diseases need to be taken orally or intravenously, and the blood-brain barrier is the only way for these drugs to enter the brain and reach the lesion.

  In the past few decades, scientists have identified the biological pathways that lead to neurodegenerative diseases and developed molecular formulations targeting these pathways.

However, its clinical progress has been extremely slow, partly due to the challenges faced by the drug when it crosses the blood-brain barrier.

  What is the "brass wall and iron wall" of the blood-brain barrier that makes drug molecules so insurmountable?

  "In layman's terms, the blood-brain barrier is the'gate' of the brain." Xue Xue, a researcher at the State Key Laboratory of Medicinal Chemistry and Biology of Nankai University, introduced that the blood-brain barrier is one of the important self-protection mechanisms of human beings. It is composed of brain capillary endothelium. Cells, glial cells and choroid plexus are formed, allowing only specific types of molecules to enter the brain neurons and other surrounding cells from the blood, which can prevent a variety of harmful substances from entering the brain tissue.

As the human body’s "secret place", the brain controls many important functions of the human body. The blood-brain barrier can block harmful substances in the blood and protect the safety of brain tissue.

But this also means that it also prevents most small molecule drugs, macromolecular peptides, proteins and gene drugs from entering the brain, severely limiting the treatment of central nervous system diseases.

  Nanoparticles "capture" the blood-brain barrier to deliver medicines

  How to cross the blood-brain barrier to deliver drugs to the brain to act on the lesion has become a thorny problem facing the medical community.

  Earlier this year, “Science” sub-Journal “Science Progress” published a research paper. Scientists at Harvard Medical School and Massachusetts Institute of Technology used nanoparticles to break through the blood-brain barrier, providing a wealth of solutions to the problem of drugs entering the brain. Potential new method.

  The research team found that secondary injuries related to traumatic brain injury may 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 relied on a short window of time when the blood-brain barrier was temporarily destroyed after trauma. After the blood-brain barrier was repaired, there was a lack of effective drug delivery tools.

The nanoparticle delivery platform developed by scientists can not only be used to deliver protein inhibitors, but also can be used to deliver a variety of drugs including antibiotics, anti-tumor drugs, neuropeptides, etc.

The research team said that although this result was explored and developed using traumatic brain injury models, basically neurological diseases can benefit from this work.

  On March 10, in the “Science” sub-Journal “Science Translational Medicine”, researchers from Northwestern University in the United States issued a paper saying that they have developed a spherical nucleic acid drug that consists of core nanoparticles and targeted small molecules. A combination of interfering RNA (siRNA), through the precise design of the active agent and receptor on the surface of the nanoparticle, the drug can cross the blood-brain barrier after intravenous injection and systemic administration, and promote the death of tumor cells.

  "These surfactants and receptors are just like nano-carriers'soldiers' attacking the blood-brain barrier, the'weapon' of the'city wall'. By screening suitable'weapons' and carrying the'number of weapons', the nano-carrier'soldiers' succeeded. It achieves the greatest degree of siRNA loading and the efficiency of crossing the blood-brain barrier, so as to achieve a good therapeutic effect on the damaged brain." Xue Xue introduced.

  Also using nanoparticles as a carrier, Xue Xue’s team developed a galactose-modified "triple interaction" stable polymerized siRNA nanomedicine, which uses fasting and glucose supplementation to control blood sugar changes as a biological strategy to trigger cerebral vascular endothelial cells Glut1 (Glut1) circulates on the Glut1. Glut1 specifically recognizes polymerized siRNA nano-drugs. Through the transfer protein-mediated endocytosis, the polymerized siRNA nano-drugs migrate from the luminal surface of cerebral vascular endothelial cells to the basal surface, enhancing the siRNA Delivery in the blood-brain barrier.

  "Studies have shown that polymerized siRNA nanomedicine has good blood stability and can effectively penetrate the blood-brain barrier through Glut1-mediated transport of blood sugar control." Xue Xue introduced that in order to confuse the "guard" of the blood-brain barrier, increase the passage In terms of efficiency, the research team also added camouflage, disguising polymerized siRNA nanomedicine as red blood cell membrane.

  Industry experts said that the current research on using nanoparticles as carriers to deliver drugs to the brain is promising, and scientists also have high hopes for nanoparticles to break through the blood-brain barrier.

  There is still a long way to go before clinical application

  However, most of the nanoparticle technology is still in the animal experiment stage, and many mechanisms are not particularly clear. The safety of its clinical application has also been questioned by scientists.

For example, if metals such as gold are used as nanoparticle carriers, short-term use may be no problem.

However, the treatment of Alzheimer's disease, Parkinson's disease and other diseases may require patients to take long-term medication. The accumulation of gold elements accumulates in the brain, and the way in which they are metabolized from the human body is a question.

  In recent years, the team of Professor Chang Jin of Tianjin University has taken a different approach, using nanoparticles made of human serum albumin to carry drugs, trying to instill the drugs from the nasal cavity, bypassing the blood-brain barrier and "cutting the road" into the brain to treat brain diseases with drugs. Found a "shortcut".

  The team grasped the currently recognized possible factors for Alzheimer's disease, namely, Aβ amyloid deposition triggered by metal ion aggregation and acetylcholine imbalance, and proposed a method that can inhibit and reduce metal ion aggregation while simultaneously regulating acetylcholine imbalance. The combined treatment method achieves the treatment of the disease.

  Among the existing drugs, the research team selected two drugs, clioquinol and donepezil, and packed them into nanoparticles made of human serum albumin.

"The nanoparticles we have developed have good biological safety." According to Wu Xiaoli, a researcher of the research team, in order to cross the natural barrier of the nasal mucosa, the researchers also added two special "small" Equipment": One is a transmembrane peptide (TAT) that can cross the nasal mucosa, which can improve the efficiency of nanoparticles to cross the nasal mucosa; the other is a targeted agent ganglioside (GM1), which can help The drugs that have passed through the nasal mucosa quickly accumulate to the lesions in the brain.

  The research results show that the human serum albumin drug delivery nanosystem can significantly improve the efficiency and retention of therapeutic drugs into the brain.

A mouse model of Alzheimer's disease shows that the nanomedicine can improve neuronal morphology changes, save memory impairment, and slow down the pathogenesis of the disease.

  "In the future, nanoparticles can be used as a carrier platform to carry a variety of drugs. At the same time, nanoparticles can be loaded with various targets to make drug delivery more precise." Wu Xiaoli said, and her research team currently controls nanotechnology and targeting. By combining technologies such as luminescence, optogenetics, and acoustic genetics, a variety of nanomaterials with excellent properties have been synthesized, and a series of multimodal probe-guided visualization nanomedicines have been independently developed, which can be applied to the visualization treatment of various diseases .

  Although various technologies still have a long way to go before they are actually applied to the clinic, it can be said that nanoparticles have begun a new journey of delivering drugs to the brain.