Nearly a year ago news
Drug Delivery Nanoparticles Given Neurotransmitter “Passports” to Cross Blood-Brain Barrier
July 27, 2020
Source: John M Lund Photography Inc/Getty Images
Biomedical engineers at Tufts University School of Engineering have developed tiny lipid-based nanoparticles that incorporate neurotransmitters, which can help to carry drugs, large molecules, and even gene editing proteins across the blood-brain barrier (BBB) and into the brain in mice. The researchers believe the new neurotransmitter-derived lipidoids—or NT-lipidoids—could overcome many of the current limitations encountered in delivering intravenously administered therapeutics into the central nervous system (CNS), and open up the potential to use a range of therapeutics that would otherwise not have access to the brain.
“The power of our method is that it is extremely versatile and relatively non-disruptive,” said Qiaobing Xu, PhD, associate professor of biomedical engineering at Tufts University and corresponding author of the team’s published paper in
Science Advances. “We can deliver a wide range of molecules by packaging them into the lipid-based nanoparticles without chemically modifying the drugs themselves. We can also achieve delivery across the blood-brain barrier without disrupting the integrity of the barrier.” Xu and colleagues described the technology in a paper titled, “
Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection.”
The blood-brain barrier comprises a layer of endothelial cells that line the blood vessels in the brain, which allows only select types of molecules to pass from the bloodstream into the fluid surrounding the neurons and other cells of the brain. The BBB prevents the transfer of most small-molecule drugs and macromolecules, such as peptides, proteins, and gene-based drugs, which has limited the treatment of CNS diseases, such as neurodegenerative disorders, brain tumors, brain infections, and stroke, the authors noted. “Safe and efficient delivery of BBB–impermeable cargos into the brain through intravenous injection remains a challenge.”
Current strategies for delivering drugs into the brain, such as direct injection, or disruption of the BBB to make it “leaky,” are fraught with risks, including infection, tissue damage, and neurotoxicity. “Although extensive efforts have been undertaken to enhance brain delivery efficiency, each method has both advantages and disadvantages; thus, the development of safe and efficient delivery of BBB-impermeable cargos into the brain through intravenous injection remains a big challenge,” the investigators noted.
The use of carriers, such as modified viruses and monoclonal antibodies to ferry cargo into the brain, has limitations, including production cost and safety. Other carriers, such as nanoparticles, nanocapsules, and polymers, have shown promise but the modifications required to ensure delivery can be complicated. “Crossing the BBB with various nanoparticles, such as liposomes, cationic polymers, inorganic nanoparticles, and nanocapsules, has shown promise in delivery of various cargos into the CNS, but complicated modifications are always needed to ensure that the particles produced are BBB-permeable,” they continued. Ideally, a brain delivery platform should be “simple, efficient, and able to deliver different types of BBB-impermeable cargos, such as small molecular drugs and biologics.”
The study’s authors made use of the fact that certain neurotransmitters have the chemical “passport” required to gain access throughout the brain. “NTs are endogenous chemicals that enable neurotransmission,” they continued. “Notably, some NTs have been demonstrated to cross the BBB.” By attaching a lipid molecule to the neurotransmitter, the team developed what they termed NT-lipidoid constructs that can be doped into lipid nanoparticles (LNPs)—tiny lipid bubbles that can encapsulate molecules such as therapeutic drugs. The LNPs can be injected intravenously, and carry the drugs to the blood-brain barrier, while the NT-lipidoid helps the LNPs to carry the drugs across the barrier. The LNPs can then fuse with neurons and other cells in the brain to deliver their therapeutic payload.
Using LNPs with the NT-lipidoids, the researchers successfully delivered into the brain of a mouse three different types of otherwise BBB-impermeable cargo: a small molecule antifungal drug, amphotericin B; macromolecules including a tau antisense oligonucleotide that inhibits the production of tau protein connected to Alzheimer’s disease; and the gene editing protein GFP-Cre. The researchers observed the effect of diminished tau protein, as well as direct evidence of the gene editing protein entering neurons. In fact, the researchers suggest, their studies resulted in the first demonstration of genome editing within neurons delivered via intravenous injection.
The Tufts researchers found that addition of NT-lipidoid can render many varieties of LNPs permeable to the blood-brain barrier. That gives scientists the option to optimize the LNPs for lipid length and ratios so they can be designed to package drugs of different types, from small molecules to DNA to large enzyme complexes, and then provide the same blood-brain barrier permeability to the LNPs by addition of the NT-lipidoid.
A successful transfer of Cre-recombinase packaged in an NT-lipidoid-doped lipid nanoparticle is demonstrated when the Cre-recombinase activates the expression of the tdTomato fluorescent protein in the cells of the mutant mice. Transfected neurons located throughout the brain (cerebellum shown here) light up in red (scale bar 100 μm) Inset: TEM image of lipid nanoparticles containing Cre-recombinase (scale bar 0.1 μm). [Qiaobing Xu, Tufts University]
“It is particularly notable that, while each delivery application used a different BBB-impermeable LNP carrier, we simply doped with the same NT1-lipidoid for each application,” they wrote. “This demonstrates a unique simplicity and flexibility of this system. We would theorize that simply adding NT1-lipidoid to any LNP system may provide that system with a similar BBB permeability, provided appropriate optimization. This may prove to be a very powerful and versatile platform for therapeutic drug delivery to the brain.”
While the Tufts team also acknowledged that more studies and clinical trials will be needed to determine the utility and safety of the technology in humans, they suggest that the delivery method could be a significant advance as a general application method for central nervous system drug delivery. “In summary, we developed a new, simple, universal, and effective brain delivery system, which may find wide applications in treating CNS diseases or providing a tool to study the brain function.”
Co-first author Feihe Ma, PhD, a post-doctoral scholar in the Xu lab, added, “It’s simple, effective, and potentially broadly applicable—we can modify the container for the drug, and by adding the NT-lipidoid, it’s like attaching an address label for delivery into the brain.” Co-first author Liu Yang, a graduate student in the Xu lab, said, “We envision that a wide range of neurological therapeutics could eventually be tried that were previously thought to be impractical due to limitations in delivery.”
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This research opens the door to easy access to a human brain and manipulate cells and even DNA (editing) via the human neurological network, at will...it mimics your neurons so it has full access to your cells with nanobots already there to assist in cellular manipulation and operations
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, not to mention something that makes everything in history like the whole of WW2 look like nothing, that's what we could be looking at, that they have planed for us all. most people would take no regard to such as I am pointing out, but that's what they would of said about the 6 million Jews back in the early 1940's Awe C'mon man ! 
