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Exosomes as Drug Delivery Vehicles for Parkinson’s Disease Therapy
Diane Youngstrom
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Exosomes are the epitome of “small but mighty.” They have the potential to revolutionize drug delivery by allowing impermeable compounds to cross the blood brain barrier (BBB).
Exosomes are effective drug carriers because they are exceedingly small – nanosized, in fact (see Figure 1) – and because they have multiple adhesive proteins on their surface that facilitate their specialization in cell-to-cell communication by binding to their targets. In addition, exosomes have plenty of interior space to house compounds of interest.1 Dr. Batrakova – a research associate professor at the Eshelman School of Pharmacy – and her collaborators have used exosome-based drug formulations to treat cancer, HIV, infectious diseases, inflammatory disorders, and neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease. According to Dr. Batrakova, crossing the BBB is one of the foremost obstacles in drug delivery because “the brain is like a sanctuary.” 2 Pathogens in the bloodstream are thwarted by the BBB due to its high selectivity for what it allows to pass into the brain. While the selective nature of the BBB protects a healthy brain, it also prevents drugs from helping a sick brain. Thus, developing innovative mechanisms to cross the BBB is crucial for the advancement of treatments for neurodegenerative diseases and other pathologies. Exosomes are an exciting frontier in drug delivery. Similar to how Uber Eats uses an address to deliver food to a customer, exosomes provide a biological address to deliver drugs to specific locations in the brain and body. Exosomes have a natural lipid bilayer with many adhesive proteins on their surface, which facilitate the binding of exosomes to their target cells, as well as a roomy interior that can be packed with drug therapies to be carried across the BBB. 3 Exosome treatments are based on the natural communication mechanisms of our body used to deliver proteins or genes to
Dr. Elena Batrakova
other cells and organs. Batrakova’s lab decided to “use macrophages as smart vehicles because if you load them with nanoparticles they know where to go”. 2 Macrophages are a type of white blood cell that devour foreign materials to protect the body, and are instrumental to natural immune responses. Equipping macrophages with exosomes harnesses the body’s immune system and bolsters the body’s ability to fight diseases. The exosomes from macrophages travel to sites of inflammation, unzipping the tight barriers of the BBB (see Figure 2). Because exosomes are naturally produced by many cells in the body, they are better than previous methods at interacting with target cells for more selective drug delivery. The unique proteins and lipids on the surface membrane of exosomes allow them to communicate with neighboring cells and cells in distant systems. In addition, exosomes are less likely to be filtered out by the liver and spleen because immune cells – such as macrophages – recognize them as non-pathogenic, which leads to decreased exosome degradation. Therefore, more of the drug injected via exosomes will be available for combating disease. In general, increasing bioavailability inherently lowers the cost of treatment, and reduces the risk of side effects, because less of the compound is required. After researchers determined the superiority of
Figure 1: Exosome size compared to the average cell, bacteria, and virus. Figure courtesy of Nina Koliha
exosomes over many polymer-based formulations, the next step was to ascertain the best method for administration. When thinking of drugs, the first thought that pops up is typically pills. However, oral delivery is surprisingly inefficient. 2-3% of drugs taken orally are able to survive the acidity of the stomach and the filtration of the liver to even make it into the bloodstream, let alone into the brain. 2 Intranasal delivery and intravenous administration are far superior to oral administration because more of the drug can be absorbed into the blood and brain, which is why Dr. Batrakova uses intranasal injections in many of her ongoing projects. Investigating alternative injection mechanisms is an overarching goal of the lab. Dr. Batrakova and her lab are developing exosome treatments for Parkinson’s disease along with many other diseases. Dopamine is important for reward, motivation, and movement. Damage to dopamine neurons due to inflammatory responses and oxidative stress causes the symptoms of Parkinson’s disease (see Figure 3). 4 There are no current treatments that have successfully stopped or reversed the progression of Parkinson’s disease, in part because promising therapies have not been able to cross the BBB. Dr. Batrakova began her investigation by delivering catalase to in vivo mouse models via exoCAT, the exosomal-based formulation of catalase. Catalase is a powerful antioxidant that can protect the endangered dopamine neurons, but it has to get past the BBB. Once the exosomes are filled with drugs, they are re-injected into the mouse. A similar method would be used in clinical trials: white blood cells would be isolated from a patient’s blood, exosomes secreted from macrophages would be extracted and loaded with the therapeutic drug, and the loaded exosomes would be re-administered back into the patient (see Figure 2). Dr. Batrakova is eager to replicate her success with exosomes in another animal model as a step closer to clinical trials. Imagine being able to treat diseases ranging from cancer to Parkinson’s to HIV with a drug-filled particle one million times smaller than a grain of sand. Dr. Batrakova’s research aims to contribute to the discovery and development of exosome-based treatments for Parkinson’s disease, Alzheimer’s disease, breast cancer, and many other diseases. The solution to these conditions is inevitably complex, but exosomes are a valuable piece of the larger puzzle.
Figure 2: The flow of exosome production and readministration. Figure courtesy of Dr. Batrakova et al.
References
1. Batrakova, E. V.; Soo Kim, M. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release. 2015, 219, 396-405. 2. Interview with Elena Batrakova, Ph.D. 09/17/2019. 3. Soo Kim, M. S.; Haney, M.; Zhao, Y.; Yuan, D.; Deygen, I.; Klyachko, N. L.; Kabanov, A. V.; Batrakova, E. V. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomedicine 2018, 14, 195-204. 4. Haney, M. J.;, Klyachko, N. L.;, Zhao, Y.;, Gupta, R.;, Plotnikova, E. G.;, He, Z.; Patel, T.; Piroyan, A.; Sokolsky, M.; Kabanov, A. V.; et al., Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015, 207, 18-30.
