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Modern Brain Drug Delivery: Innovative or Obsolete?

Authored by Gwen Schway

Art by Michelle Choi


You may be familiar with various names of common therapeutics responsible for treating brain disorders such as Prozac which generic name is fluoxetine, Lexapro which generic name is escitalopram, Zoloft which generic name is sertraline, and so on. However, a lesser known fact is these therapeutics deliver a limited amount that can actually penetrate the blood brain barrier, which grants entry to the central nervous system. In fact, less than ten percent of small molecule therapeutics and less than one percent of large molecule therapeutics are able to penetrate this barrier [1]. The blood-brain barrier only allows drugs which are lipophilic, consist of positively-charged molecules, and have a molecular weight lower than 400 Da to penetrate [1]. This severely limits the range of drugs available to treat brain disorders. Larger molecules are unable to penetrate due to size while the membranes of cell molecules which are hydrophilic repel other hydrophilic molecules.


The question then arises: how do we get a drug into the brain without meeting these stringent criteria? The process is far from straightforward. Various methods have been explored such as osmotic disruption of the blood brain barrier [2], enhanced cellular transport [1], and nanoparticle delivery [3]. These are only a few of the methods that have been tested to allow drug delivery. Though efforts have been extensive, each strategy is associated with various limitations. Osmotic disruption of the blood-brain barrier is maximally invasive, enhanced cellular transport is associated with cell toxicity, while nanoparticle delivery is inefficient. How are we then able to contract diseases such as meningitis, AIDS, and leukemia, if it is such a difficult process? 


The answer lies within evolution. Meningitis, AIDS, and leukemia have evolved the ability to bypass the blood brain barrier. In order to expedite the natural process, we are able to use the method of directed evolution. During research, genes that express proteins by the name of LY6C1 and CA-IV proved to be crucial targets associated with penetration of the blood-brain barrier. Though CA-IV is not novel, there was no previous association with mechanisms necessary to the penetration of the blood-brain barrier. The team, understanding these evolutionary mechanisms, isolated LY6C1 and CA-IV, amplified, and ultimately subjected it to mutagenesis [4]. Using a cell culture screen, researchers tested each individual protein’s ability to infect vectors. Scientists use a simulator to observe how the proteins would interact with each vector. This allowed the discovery of which vectors and protein pairings were most optimal to allow crossing which has the potential to further advance clinically effective neurotherapeutics. 


Researchers are excited about the potential of discovering additional methods to cross the blood-brain barrier. In the future, LY6C1 and CA-IV may prove integral to expanding the quantity and range of neuropharmaceuticals available to treat brain disorders [4]. The blood-brain barrier is highly complex, varying over an organism’s lifetime. A greater comprehension of the mechanisms needed to cross the blood-brain barrier may enable personalized treatments across a wide array of populations [5]. This is undoubtedly a promising step to the advancement of delivering a wider range of neuropharmaceuticals.


Works Cited

  1. Pardridge, William M. “Drug and Gene Targeting to the Brain with Molecular Trojan Horses.” Nature News, Nature Publishing Group, 1 Feb. 2002, www.nature.com/articles/nrd725

  2. Rapport, Stanley I, et al. “Testing of a Hypothesis for Osmotic Opening of the Blood-Brain Barrier.” American Journal of Physiology, 1 Aug. 1972, www.journals.physiology.org/doi/abs/10.1152/ajplegacy.1972.223.2.323

  3. Allen, T.M., et al. “Strategy for Effective Brain Drug Delivery.” European Journal of Pharmaceutical Sciences, Elsevier, 16 May 2010, www.sciencedirect.com/science/article/abs/pii/S0928098710001818?via%3Dihub

  4. Shay, Timothy F, et al. “Primate-Conserved Carbonic Anhydrase IV and Murine-Restricted ... - Science.” Science Advances, 19 Apr. 2023, www.science.org/doi/10.1126/sciadv.adg6618

  5. Dajose, Lori. “A New Mechanism for Crossing the Blood–Brain Barrier.” California Institute of Technology, 19 Apr. 2023, www.caltech.edu/about/news/a-new-mechanism-for-crossing-the-bloodbrain-barrier

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