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. 

If you’d like to learn more about nanotechnology, please subscribe to our newsletter and stay tuned for upcoming posts.

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

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Vaccination is one of the strongest tools with regards to fighting infectious diseases. Vaccination is a method of introducing immunization in an individual. It greatly reduces the burden of infectious diseases as it reduces symptomatic disease development as well as prevent further transmission of the vira [1]. This reduces the burden of disease on the national health care systems.

Immune System Response

In all simplicity, immunization is a stimulation of the immune system. This stimulation induces the production of antibodies that can neutralize the stimulus [2]. A vaccine utilizes the immunization that happens when the immune system is exposed to new antigens. However, the infectious agent is replaced with a modified agent that poses as the infectious agent. The modification ensures that no harm or disease is developed. 

The immune stimulation is begun by introducing a modified pathogen (disease inducing organism) to the immune system. This can be done by e.g. injecting an inactivated virus. Different proteins are present on the surface of the pathogen. These allow the pathogen to e.g. adhere to cells in the body and infect the cells [3]. 

Some of these surface proteins are unique for the pathogen in question. These are known as antigens. [4]. These are the particles that the immune system will react to by producing antibodies that are specific to each type of antigen. Each antibody enables the immune system to quickly identify and neutralize any organism that contains the specific antigen on its surface [5].

However, the immune system needs time to react and develop specific antibodies when first exposed to a new antigen. This delay is where the live pathogen has time to multiply and cause symptomatic disease [4]. However, no or only mild disease development occurs if the immune response is triggered by an attenuated or inactivated pathogen as part of a vaccine. If the immune system encounters the antigen again, it is able to immediately confine and destroy the invading organism [6, 7]. This means that any subsequent infection with the same pathogen will result in no or a mild, short course of the disease.

Active Immunization and Vaccine Development

Active immunization has been applied for multiple centuries with the first examples documented in China in the 16th century during a smallpox outbreak [8]. Active immunization at that time was the deliberate exposure of a disease to an individual without modification of the infectious agent. The goal was to induce a mild disease progression while, simultaneously, activating the immune system. This would immunize the subject and prevent smallpox from developing due to any future exposure [8].

A second breakthrough in active immunization arose in the 18th century where vaccines with live, attenuated organisms saw first light [8]. This later progressed into vaccine development based on virus or cell cultures with inactivated disease vectors [8]. 

One of the latest technological approaches to vaccine development is the use of genetic engineering. Genetic manipulation enables the expression of surface proteins from any pathogen, e.g. a virus [2]. The proteins will activate the immune system and immunization process when injected into an individual. The use of genetic engineering thus enables vaccination without introducing the actual pathogen to the vaccine recipient.

mRNA Vaccine Used Against COVID-19

The target antigens of COVID-19 are 180-200 kDa, which corresponds approximately to a size of 5 nm [9]. This means that nanotechnology is needed in order to design a vaccine against COVID-19.

A radically new approach to vaccination has been developed recently. It relies on genetic engineering of mRNA and does not entail introducing any proteins or attenuated pathogens into the body [10]. This means that the vaccine does not cause any disease during the immunization process [11]. This type of vaccine was one of the first COVID-19 vaccine types to be approved for use.

The vaccine consists of a DNA-sequence that encodes the antigen or antigens that are unique to the target pathogen. However, the sequence is injected in the form of mRNA (messenger RNA) which prevents the sequence from permanently integrating itself into the genome of the individual [11,12]. Instead, it only acts as a transient carrier of the genetic information and will degrade over time.

The mRNA in the vaccine enables in situ production of the antigen. This means that the antigen for which the immune response is desired is produced directly in the body of the vaccinated individual. The produced antigen will then trigger the same immune response as if the individual had been exposed to the actual pathogen [11,12]. 

This means that no pathogen – either attenuated or inactivated will ever have entered the body. Instead, the natural protein production environment in our body is used to build the immunization that enables protection against e.g. COVID-19. This also removes the potential side effects of mild symptoms during the immunization process.

If you’d like to learn more about nanotechnology, please subscribe to our newsletter and stay tuned for upcoming posts.

Bibliography

[1] World Health Organization (WHO). “Vaccination greatly reduces disease, disability, death and inequity worldwide.” Bulletin of the World Health Organization, WHO, 2008, Accessed, January 2021, at https://www.who.int/bulletin/volumes/86/2/07-040089/en/.

[2] Murray, Kenneth, et al. “Genetic engineering applied to the development of vaccines.” Philosophical Transactions of the Royal Society of London, B. Biological Sciences, vol. 324, no. 1224, 1989, pp. 461-476.

[3] Science Direct. “Surface Proteins.” Science Direct Topics, Science Direct, 2020, Accessed, January 2021, at https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/surface-proteins.

[4] The Immunisation Advisory Centre. “The immune system and immunisation.” Immunisation, January 2020, accessed, January 2021, at https://www.immune.org.nz/immunisation/immune-system-vaccination.

[5] Britannica. Antibody, accessed, January 2021, at https://www.britannica.com/science/antibody.

[6] Siegrist, Claire-Anne. “Vaccine immunology.” Vaccines, 5 ed., Saunders, 2008, pp. 17-36.

[7] World Health Organization(WHO). “DNA Vaccines.” who.int, WHO, 2007, Accessed, January 2021, at https://www.who.int/teams/health-product-and-policy-standards/standards-and-specifications/vaccines-quality/dna.

[8] Plotkin, Stanley A. History of Vaccine Development. Springer Science & Business Media, 2011.

[9] Huang, Yuan, et al. “Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19.” Acta Pharmacologica Sinica, vol 41, no 9, 2020, pp. 1141-1149.

[10] Bert Hubert, Reverse Engineering the source code of the BioNTech/Pfizer SARS-CoV-2 Vaccine, December 2020, accessed, January 2021, at https://berthub.eu/articles/posts/reverse-engineering-source-code-of-the-biontech-pfizer-vaccine/

[11] Okay, Sezer, et al. “Nanoparticle-based delivery platforms for mRNA vaccine development.” AIMS Biophysics, vol. 7, no. 4, 2020, pp. 323-338.

[12] Schlake, Thomas, et al. “Developing mRNA-vaccine technologies.” RNA Biology, vol. 9, no. 11, 2012, pp. 1319-1330.

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Nanotechnology has multiple research areas that can be utilized in this scientific and technological fight against COVID-19: prevention of dissemination and early diagnosis [1].

Preventing Dissemination

COVID-19 is a respiratory virus infection that is transmitted by contact, droplets and passive carriers such as utensils, light switches or handles that share multiple users [2,3]. The immune system is the primary line of defense for most people, but this is not sufficient for people with compromised immune systems [4]. They instead require e.g. hand sanitizers or face masks as a source of protection.

Chemical disinfectants that can be bought in regular stores can be used for disinfection and sterilization. However, they have limited effect over time and pose a potential risk to public health and the environment [4]. A different method has been proposed: metallic nanoparticles [5,6,7]. 

Metallic nanoparticles are particles of a given metal whose size is on the submicron scale. That is, their diameter is smaller than 0.001 mm (0.00004 inches). This means that their size is comparable to that of a virus particle [8,9]. The interaction between a virus and the nanoparticle depends on which metal is used. One mechanism of action is inactivation of the virus particle before it enters the cells of the human body. The nanoparticle can also stop the viral particle from entering the cell completely [9,10]. This role as an antiviral “doorman” can be due to the binding competition between the virus particle and the nanoparticle – if the nanoparticle binds first, the virus will no longer be able to bind and infect a cell.

The nanoparticles can be incorporated into face masks or can be used for disinfecting air and surfaces to limit the spread of the disease [4]. However, their toxicity must be considered as they can possibly affect human health in larger doses [5].

Diagnosis on the Nanoscale

It is also important to be able to rapidly and accurately diagnose COVID-19. Control measures such as isolation and infection tracking can be initiated and implemented earlier in each case if the detection and diagnosis process is fast. Nanotechnology in the form of nanomaterials can help increase the accuracy and decrease the testing time for a diagnostic process [6].

A nanomaterial is any material that exists on the nanoscale. That means that their defining characteristics also depend on their small size. These properties can be e.g. increased strength or reactivity when compared to the same material at a much larger scale [11]. This means that a sphere of gold or silver can be used for different purposes when it is very small (e.g. a nanoparticle) compared to a larger sphere.

Many nanomaterials are already used for virus detection [6]. Nanomaterials can help early detection as they can facilitate the detection of a target (here – an indicator of COVID-19) even if it is present in much smaller concentrations, i.e. at an earlier time in the infection cycle. The implementation of nanomaterials also requires a smaller sample – and possibly less invasive testing. One advantage of nanomaterials is that they can be designed to have specific desired properties such as optical (interaction with light) or magnetic properties. This means that the materials for diagnosis can be designed to promote a faster and more precise diagnosis [6].

Summary

Nanotechnology can aid the fight against the COVID-19 global pandemic. One aspect is to limit the spread of the disease. This can both be with regards to faster diagnosis (and thus earlier onset of control measures) and more efficient protection measures such as face masks or disinfectants. This means that nanotechnology can help limit the dissemination process and lead to less frequent COVID-19 cases. While it might not completely prohibit the virus from spreading, it can slow the disease down while therapeutic measures and vaccines are being developed.

If you’d like to learn more about nanotechnology, please subscribe to our newsletter and stay tuned for upcoming posts.

Note: Featured image by Fusion Medical Animation on Unsplash

References

[1] Nanotechnology versus coronavirus. Nature Nanotechnology. 15, 617 (2020). https://doi.org/10.1038/s41565-020-0757-7

[2] Subbarao, Kanta, and Siddhartha Mahanty. “Respiratory virus infections: Understanding COVID-19.” Immunity (2020). DOI: https://doi.org/10.1016/j.immuni.2020.05.004

[3] World Health Organization. “Coronavirus disease (COVID-19): Similarities and differences with influenza”. (2020). https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-and-answers-hub/q-a-detail/q-a-similarities-and-differences-covid-19-and-influenza 

[4] Talebian, Sepehr, et al. “Nanotechnology-based disinfectants and sensors for SARS-CoV-2.” Nature nanotechnology 15.8 (2020): 618-621. DOI: https://doi.org/10.1038/s41565-020-0751-0 

[5] Rai, Mahendra, et al. “Metal nanoparticles: The protective nanoshield against virus infection.” Critical reviews in microbiology 42.1 (2016): 46-56. DOI: https://doi.org/10.3109/1040841X.2013.879849 

[6] Campos, Estefânia VR, et al. “How can nanotechnology help to combat COVID-19? Opportunities and urgent need.” Journal of Nanobiotechnology 18.1 (2020): 1-23. DOI: https://doi.org/10.1186/s12951-020-00685-4 

[7] Aderibigbe, Blessing Atim. “Metal-based nanoparticles for the treatment of infectious diseases.” Molecules 22.8 (2017): 1370. DOI: https://dx.doi.org/10.3390%2Fmolecules22081370 

[8] Cuffari, Benedette. “The Size of SARS-CoV-2 Compared to Other Things”. (2020). https://www.news-medical.net/health/The-Size-of-SARS-CoV-2-Compared-to-Other-Things.aspx 

[9] Maduray, Kaminee, and Raveen Parboosing. “Metal Nanoparticles: a Promising Treatment for Viral and Arboviral Infections.” Biological trace element research (2020): 1-18. DOI: https://dx.doi.org/10.1007%2Fs12011-020-02414-2 

[10] Brandelli, Adriano, Ana Carolina Ritter, and Flávio Fonseca Veras. “Antimicrobial activities of metal nanoparticles.” Metal Nanoparticles in Pharma. Springer, Cham, 2017. 337-363. DOI: https://doi.org/10.1007/978-3-319-63790-7_15 

[11] Schwirn, Kathrin, Lars Tietjen, and Inga Beer. “Why are nanomaterials different and how can they be appropriately regulated under REACH?.” Environmental Sciences Europe 26.1 (2014): 4. DOI: https://doi.org/10.1186/2190-4715-26-4 

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