Drug delivery to the brain is the process of passingtherapeutically active molecules across theblood–brain barrier into thebrain. This is a complex process that must take into account the complex anatomy of the brain as well as the restrictions imposed by the special junctions of the blood–brain barrier.
The blood–brain barrier is formed by specialtight junctions betweenendothelial cells lining brain blood vessels. Blood vessels of all tissues contain this monolayer ofendothelial cells, however only brainendothelial cells have tight junctions preventing passive diffusion of most substances into thebrain tissue.[1] The structure of these tight junctions was first determined in the 1960s by Tom Reese, Morris Kranovsky, and Milton Brightman. Furthermore,astrocytic "end feet", the terminal regions of the astrocytic processes, surround the outside of braincapillaryendothelial cells".[1] Theastrocytes areglial cells restricted to thebrain andspinal cord and help maintain blood-brain barrier properties in brainendothelial cells.[1]
The primary function of the blood-brain barrier is to protect the brain and keep it isolated from harmful toxins that are potentially in theblood stream. It accomplishes this because of its structure, as is usual in the body that structure defines its function. Thetight junctions between theendothelial cells prevent large molecules and manyions from passing between the junction spaces. This forces molecules to go through the endothelial cells to enter thebrain tissue, meaning that they must pass through thecell membranes of theendothelial cells.[2]Because of this, the only molecules that can easily transverse the blood–brain barrier are verylipid-soluble ones. These are not the only molecules that can transverse the blood–brain barrier;glucose,oxygen andcarbon dioxide are notlipid-soluble but areactively transported across the barrier, to support the normal cellular function of thebrain.[3] The fact that molecules have to fully transverse theendothelial cells makes them a perfect barricade to unspecified particles from entering the brain, working to protect the brain at all costs. Also, because most molecules are transported across the barrier, it does a very effective job of maintaininghomeostasis for the most vital organ of the human body.[1]
Because of the difficulty fordrugs to pass through the blood–brain barrier, a study was conducted to determine the factors that influence a compound’s ability to transverse the blood–brain barrier. In this study, they examined several different factors to investigatediffusion across the blood–brain barrier. They usedlipophilicity,Gibbs Adsorption Isotherm, a Co CMC Plot, and the surface area of the drug to water and air. They began by looking at compounds whose blood–brainpermeability was known and labeled them either CNS+ or CNS- for compounds that easily transverse the barrier and those that did not.[4] They then set out to analyze the above factors to determine what is necessary to transverse the blood–brain barrier. What they found was a little surprising;lipophilicity is not the leading characteristic for a drug to pass through the barrier. This is surprising because one would think that the most effective way to make a drug move through alipophilic barrier is to increase itslipophilicity, it turns out that it is a complex function of all of these characteristics that makes a drug able to pass through the blood–brain barrier. The study found that barrierpermittivity is "based on the measurement of the surface activity and as such takes into account the molecular properties of bothhydrophobic and charged residues of the molecule of interest."[4] They found that there is not a simple answer to what compounds transverse the blood–brain barrier and what does not. Rather, it is based on the complex analysis of the surface activity of the molecule as well asrelative size.
Other problems persist besides just simply getting through the blood–brain barrier. The first of these is that a lot of times, even if a compound transverses the barrier, it does not do it in a way that thedrug is in a therapeutically relevant concentration.[5] This can have many causes, the most simple being that the way the drug was produced only allows a small amount to pass through the barrier. Another cause of this would be the binding to otherproteins in the body rendering the drug ineffective to either be therapeutically active or able to pass through the barrier with the adheredprotein.[6] Another problem that must be accounted for is the presence ofenzymes in thebrain tissue that could render the drug inactive. The drug may be able to pass through the membrane fine, but will be deconstructed once it is inside the brain tissue rendering it useless. All of these are problems that must be addressed and accounted for in trying to deliver effective drug solutions to the brain tissue.[5]
A group from theUniversity of Oxford led by Prof. Matthew Wood claims that exosomes can cross the blood–brain barrier and deliversiRNAs, antisense oligonucleotides, chemotherapeutic agents and proteins specifically to neurons after inject them systemically (in blood). Because these exosomes are able to cross the blood–brain barrier, this protocol could solve the issue of poor delivery of medications to the central nervous system and cure Alzheimer's, Parkinson's Disease and brain cancer, among other diseases. The laboratory has been recently awarded a major new €30 million project leading experts from 14 academic institutions, two biotechnology companies and seven pharmaceutical companies to translate the concept to the clinic.[7][8][9][10]
This is the process of disguising medically active molecules withlipophilic molecules that allow it to better sneak through the blood–brain barrier. Drugs can be disguised using morelipophilic elements or structures. This form of the drug will be inactive because of thelipophilic molecules but then would be activated, by eitherenzyme degradation or some other mechanism for removal of thelipophilic disguise to release the drug into its active form. There are still some major drawbacks to these pro-drugs. The first of which is that the pro-drug may be able to pass through the barrier and then also re-pass through the barrier without ever releasing the drug in its active form. The second is the sheer size of these types of molecules makes it still difficult to pass through the blood–brain barrier.[11]
Similar to the idea of pro-drugs, another way of masking the drugschemical composition is by masking apeptide’s characteristics by combining with other molecular groups that are more likely to pass through the blood–brain barrier. An example of this is using acholesteryl molecule instead ofcholesterol that serves to conceal thewater soluble characteristics of the drug. This type of masking as well as aiding in traversing the blood–brain barrier. It also can work to mask the drug peptide from peptide-degrading enzymes in the brain[7] Also a "targetor" molecule could be attached to the drug that helps it pass through the barrier and then once inside the brain, is degraded in such a way that the drug cannot pass back through the brain. Once the drug cannot pass back through the barrier the drug can be concentrated and made effective for therapeutic use.[7] However drawbacks to this exist as well. Once the drug is in the brain there is a point where it needs to be degraded to preventoverdose to thebrain tissue. Also if the drug cannot pass back through the blood–brain barrier, it compounds the issues of dosage and intense monitoring would be required. For this to be effective there must be a mechanism for the removal of the active form of the drug from the brain tissue.[7]
These are drug compounds that increase the permeability of the blood–brain barrier.[12] By decreasing the restrictiveness of the barrier, it is much easier to get a molecule to pass through it. These drugs increase thepermeability of the blood–brain barrier temporarily by increasing theosmotic pressure in theblood which loosens thetight junctions between theendothelial cells. By loosening thetight junctions normal injection of drugs through an [IV] can take place and be effective to enter the brain.[8] This must be done in a very controlled environment because of the risk associated with these drugs. Firstly, the brain can be flooded with molecules that are floating through theblood stream that are usually blocked by the barrier. Secondly, when thetight junctions loosen, thehomeostasis of the brain can also be thrown off which can result inseizures and the compromised function of the brain.[8]
The most promising drug delivery system is usingnanoparticle delivery systems, these are systems where the drug is bound to a nanoparticle capable of traversing the blood–brain barrier. The most promising compound for the nanoparticles isHuman Serum Albumin (HSA). The main benefits of this is that particles made of HSA are well tolerated without serious side effects as well as thealbumin functional groups can be utilized for surface modification that allows for specific cell uptake.[5] Thesenanoparticles have been shown to transverse the blood–brain barrier carrying host drugs. To enhance the effectiveness of nanoparticles, scientists are attempting to coat thenanoparticles to make them more effective to cross the blood–brain barrier. Studies have shown that "the overcoating of the [nanoparticles] with polysorbate 80 yielded doxorubicin concentrations in the brain of up to 6 μg/g after i.v. injection of 5 mg/kg" as compared to no detectable increase in an injection of the drug alone or the uncoated nanoparticle.[13] This is very new science and technology so the real effectiveness of this process has not been fully understood. However young the research is, the results are promising pointing tonanotechnology as the way forward in treating a variety ofbrain diseases.
Microbubbles are small "bubbles" ofmono-lipids that are able to pass through the blood–brain barrier. They form alipophilic bubble that can easily move through the barrier.[14] One barrier to this however is that thesemicrobubbles are rather large, which prevents their diffusion into the brain. This is counteracted by a focusedultrasound. Theultrasound increases thepermeability of the blood–brain barrier by causing interference in thetight junctions in localized areas. This combined with themicrobubbles allows for a very specific area ofdiffusion for themicrobubbles, because they can only diffuse where theultrasound is disrupting the barrier.[10] Thehypothesis and usefulness of these is the possibility of loading amicrobubble with an active drug to diffuse through the barrier and target a specific area.[10] There are several important factors in making this a viable solution fordrug delivery. The first is that the loadedmicrobubble must not be substantially greater than the unloaded bubble. This ensures that thediffusion will be similar and theultrasound disruption will be enough to inducediffusion. A second factor that must be determined is the stability of the loaded micro-bubble. This means is the drug fully retained in the bubble or is there leakage. Lastly, it must be determined how the drug is to be released from themicrobubble once it passes through the blood–brain barrier. Studies have shown the effectiveness of this method for getting drugs to specific sites in the brain in animal models.[10]