According to the Global Burden of Disease Study in 2017 Neurological disorders are an increasing health burden worldwide. However the current standard drugs used can often only relieve symptoms, and their ability to reach the brain is limited due to the protective properties of the blood-brain barrier, BBB [1].
The BBB’s neurophysiological purpose is to keep harmful substances at bay and to control the highly specialized environment that neurons require to function properly. For this reason, the endothelial cells of the cerebral microvessels that constitute the door into the brain are highly selective to which metabolites they transport into the brain [2]. These unique properties make the brain very different from other organs, and therefore, by exploring how the underlying transport mechanisms through the BBB work it can potentially revolutionize the treatment of neurological disorders.
Illustration by Armin Kübelbeck, showing the different types of transportation through the blood-brain barrier. https://commons.wikimedia.org/wiki/File:Blood-brain_barrier_transport_ca.png
So how can you use nanotechnology to effectively deliver medicine to the central nervous system, CNS?
The reason why researchers are interested in using nanomaterials to deliver drugs to the brain, is due to their small size and because they can be functionalized to be more site-specific. Nanomaterials is a very broad term that covers nanocarriers, which can function as transport vehicles for substances such as drugs. There exist many different kinds of nanocarriers such as polymers, liposomes, quantum dots, metallic nanoparticles etc. So let’s take a look at the research that has been conducted in recent years to understand how the drug-delivery problem has been approached using some of these different nanomaterials.
Liu R. et al investigated whether nanoparticles could be used to treat Alzheimer’s disease in mice. There are several physical changes in the brain related to the pathology of Alzheimer’s disease. One of them is an increase in production and deposition of plaques that consists of peptides. It is also suggested that neuronal support cells called microglia play a role in the pathology of the disease due to an increase in neuroinflammatory responses which can harm the neuronal cells. In this study, the aim was to reduce the harmful peptides and normalize the function of microglia. The nanoparticles used consisted of four different components:
(1) A zwitterionic polymer, which increases the cell uptake into the microglia and protects the nanoparticles from being destroyed by the disposal system of the cell (called lysosomes). (2) A sugar analogue which increases the permeability of the nanoparticle through the BBB by targeting specific receptors. (3) Zinc oxide which is encapsuled inside the nanoparticle together with (4) fingolimod. The fingolimod is a drug that can reduce inflammation inside the microglia while zinc oxide is used to further normalize these cells. The resulting size of the nanoparticle is around 100 nm in diameter. The effects of the nanoparticles were tested in mice. After four weeks of treatment, the results showed an increase in the removal of harmful peptides related to Alzheimer’s disease and a normalization of dysfunctional microglia. The treated mice showed an improvement in both spatial learning and memory [3].
Illustration from article by Liu, R. et al., showing the components of the nanoparticle and its final structure and mechanism. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974948/
Kim D. et al. investigated whether graphene Quantum dots (GQD) can prevent the accumulation of alpha-synuclein proteins that aggregate forming fibrils in neurons which is seen in Parkinson’s disease, a devastating progressive nervous system disorder that currently cannot be cured [4].
Quantum dots are very small semiconductor crystals that can obtain many different properties depending on the material it is made of and its size and shape. Carbon based quantum dots such as the GQD’s are less toxic and more biocompatible compared to quantum dots made with heavy metals. Quantum dots can serve as a nanocarrier of medicine through modifications and functionalizations [5]. The pathophysiology of Parkinson’s disease is not completely understood but consists among others of: mitochondrial dysfunction and degeneration of dopamine neurons. Using an in vitro BBB model the researchers showed that the GQD’s could permeate the BBB due to their small size. The GQD’s were able to bind to the alpha-synuclein and stop them from aggregating and they could also break down the already existing fibrils. Moreover, seven days of treatment in mice models with the GQD’s resulted in neuroprotective effects preventing dopamine neuronal death, synaptic loss and improved dysfunctional mitochondria. The treated mice showed improvement in their motor skills, and after six months of GQD injections no long-term toxicity was observed in vitro or in vivo [4].
3. A Japanese research group investigated whether nanocarriers and macromolecules could cross the BBB by attaching cyclic peptides (a chain of amino acids that is circular in shape) to nanoparticles and a larger molecule called phage M13. Liposomes were used as nanocarriers, which were coated with the cyclic peptide. They used in vitro rat, monkey and human cell lines as BBB models to control the permeation of the nanocarrier and phage M13. In all models, they saw an increase in BBB permeability for both the nanocarrier and the phage M13 in vivo.
The researchers point out the importance of using human cell lines and/or cell lines from several different species in order to increase the translation of research into clinical application [6].
As we can see from the mentioned research, the use of nanotechnology in medicine shows promising results for permeating the BBB and alleviating neurodegenerative diseases by functionalizing the nanocarriers to target specific brain sites. But even though nanocarriers have shown effectiveness in both preclinical and clinical studies, there is still a long way until they can be translated to the bedside and directly benefit patients [7]. A main concern regarding nanomaterials is their potential risks of harming the body. Therefore in order to bring nanomedicine closer to clinical practices, several aspects must be investigated to make nanomedicine safer for the body. There is a need of creating standardized nanotoxological studies and strict monitorization, to better understand potential adverse effects such as oxidative stress, accumulation, immune responses and neuronal death[8].
Moreover, the surface modifications made to nanomaterials must be carefully considered to make treatment as effective as possible. Luckily there is an increased interest in developing more biocompatible nanomaterials amongst researchers [9]. In summary the prospects for nano-neuromedicine are promising but contain challenges regarding ensuring safety and the need for further development and advancement of the current methods to benefit patients in the (hopefully) near future.
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References
[1] Cascione, M., Matteis, V. D., Leporatti, S. & Rinaldi, R. 2020. The New Frontiers in Neurodegenerative Diseases Treatment: Liposomal-based Strategies, Frontiers in Bioengineering and Biotechnology, vol 8, pp. 1-17. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649361/
[2] Kandel, E. R. et al. 2012, Principles of Neural Science, pp. 1565-1578.
[3] Liu, R. et al., 2020. An “Amyloid-β Cleaner” For the Treatment of Alzheimer’s Disease by Normalizing Microglial Dysfunction, Advanced Science, vol. 7, Issue 2, pp. 1-12. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974948/
[4] Kim, D., 2018, Graphene quantum dots prevent α-synucleinopathy in Parkinson’s Disease, Nature nanotechnology, vol. 13, pp. 812-818. Available at: https://www.nature.com/articles/s41565-018-0179-y
[5] Matea, C. T., 2017, Quantum dots in imaging, drug delivery and sensor applications, International Journal of Nanomedicine, vol 12, pp. 5421-5431. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546783/
[6] Yamaguchi, S., 2020, Novel cyclic peptides facilitating transcellular blood-brain barrier transport of macromolecules in vitro and in vivo, Journal of Controlled Release, vol. 321, pp. 744-755. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0168365920301401?via%3Dihub
[7] Naqvi, S., Panghal, A. & Flora, S. J. S., 2020, Nanotechnology: A promising Approach for Delivery of Neuroprotective Drugs, Frontiers in Neuroscience, vol. 14, s. 1-26. Available at: https://www.frontiersin.org/articles/10.3389/fnins.2020.00494/full#T1
[8] Teleanu, D. M., 2020, Impact on Nanoparticles on Brain Health: An Up to Date Overview, Journal of Clinical Medicine, vol. 7, Issue 7, pp. 1-14.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306759/
[9] Hanif, M., 2020, Nanomedicine-based immunotherapy for central nervous system disorders, Acta Pharmacological Sinica, vol. 41, pp. 936-953. Available at:
https://www.nature.com/articles/s41401-020-0429-z#Sec12