The outbreak of COVID-19
Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously called 2019-nCoV). As on May 1st, COVID-19 has caused 2,33,388 deaths out of 32,56,846 confirmed cases in 210 countries and territories. The ripple effect of COVID-19 presents an unprecedented challenge to identify effective drugs for prevention and treatment. Although, the current scenario represents no such potential therapeutic outcomes in patients with either suspected or confirmed cases of COVID-19, clinicians and researchers in all over the world have been racing to get a better understanding about SARS-CoV-2 to develop new-age therapeutic strategies.
COVID-19 and Nanoparticles: The plausible interaction
As the need of the hour is to develop a smart therapeutic agent for SARS-CoV-2, the complete understanding on the structure of the virus and their action after entering in human systems is extremely important. The COVID-19 causative agent is severe acute respiratory syndrome (SARS) virus (SARS-CoV-2) which is more contagious than the previously reported SARS-COV which was observed in 2002. SARS-COV-2, a single stranded RNA-enveloped virus, targets host cells through the binding of the glycosylated spike (S) protein to a receptor protein named as angiotensin-converting enzyme 2 (ACE2) receptor located on the surface of host cells. It is already reported that a host type 2 transmembrane serine protease, TMPRSS2, facilitates its cell entry via the S protein. The interaction between viral S protein and ACE2 on the host cell surface is of significant interest since it initiates the infection process and it is found that the affinity of SARS-CoV-2 to ACE2 is 10-20 times higher than the SARS-CoV protein. So far, no evident treatment or vaccine has been developed for the treatment of COVID-19 except for some conventionally used drugs which are previously used to improve the immune system against malaria or rheumatoid arthritis called hydroxychloroquine or tocilizumab. Nanotechnology holds great promise serving as potential game changers in the field of various diseases, especially cancer. We may hope that engineered nanoparticles with its smart architecture may find a better solution towards this pandemic. Here, I would like to mention the quote of Professor Kostas Kostarelos, chair professor of nanomedicine at the university of Manchester that “viruses are the most beautiful, smart and capable nanoparticles”! Another professor Thomas Webster from Northeastern university mentioned that they are trying to develop iron based nanoformulations which may exhibit plausible interactions with spike (S) proteins due to similar size and architecture of SARS-CoV-2 with an average diameter 125 nm. They also added that these nanoformulations can be disrupted through applying infrared light treatment like in the treatment of in cancer. Unfortunately, there is still no active solution regarding the treatment of COVID-19.
Therapeutics of COVID-19: Does nanotechnology help in therapeutic development?
Various repurposed therapeutic agents are already studied in clinical trials for COVID-19 and they are in various formulations of Chloroquine, Hydroxychloroquine, Lopinavir-Ritonavir, Arbidol or Ribavirin, Tocilizumab. These drugs have shown potential results in other chronic inflammatory diseases including HIV, malaria and rheumatoid arthritis. They may appear to block viral entry into cells by inhibiting glycosylation of host receptors, endosomal acidification and inhibition of 3-chymotrypsin protease. These agents also have immunomodulatory effects through attenuation of cytokine production and inhibition of autophagy and lysosomal activity in host cells. The use of nanoparticles in the treatment of HIV has shown promising results where Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as a delivery system to Lopinavir/Ritonavir therapy. Ribavirin, the antiviral agent, has delivered with polymeric nanoparticles to treat Hepatitis C with satisfactory results. Ribavirin in combination with gold (Au) nanoparticles showed antiviral activity against measles virus. Various formulations of nanoparticles along with these drugs have been successfully tested in animal models mimicking infectious diseases. Recently, a group of researchers from Germany has shown that using their functionalized carbon nanoparticles; they inhibited the entry of SARS-CoV-2 into the host cells by interfering the function of S protein. Thus, nanoparticles could help us to win over the COVID-19 outbreak.
Figure 1: Schematic represents virus-induced host immune system response and viral processing within target cells. Proposed targets of select repurposed and investigational products are noted. ACE2, angiotensin-converting enzyme 2; S protein, spike protein; and TMPRSS2, type 2 transmembrane serine protease. (Picture taken from Reference 1)
‘Cytokine Storm’ of COVID-19: Can nanotechnology be the game changer?
Immunomodulatory therapy is very popular in various chronic inflammatory diseases and is related to the innate immunity of our body which is the first line of defence. The patients of COVID-19 also had the same aberrant inflammatory cytokine storm as observed in SARS referring to an excessive inflammatory response flaring out of control and the immune system
awry. Interleukin 6 or IL-6 is an important cytokine in the storm which links innate to acquired immune response to any pathogenic organisms. It sends out warning signal to entire body in the form of pathogen recognition receptor (PRR) to other immune cells like monocytes and macrophages. Aberrant inflammatory response can be detected with large amount of IL-6 release from inflammatory cytokines. Targeted IL-6 which has been used in different other benign disease like Rheumatoid arthritis (RA) may potentially be effective and safe way to modulate immune response and cytokine storm in COVID-19. Thus, monoclonal antibodies directed against key inflammatory cytokines represent a potential class of immunomodulatory therapies for COVID-19. Tocilizumab is the first marketed IL-6 blocking monoclonal antibody through targeting IL-6 receptors and has proved its safety and effectiveness in therapy for rheumatoid arthritis by reducing the inflammatory response. Surface engineered nanoparticles with their stealthy nature have shown promising response as delivery agents of anti-inflammatory agents to supress cytokine storm in various infectious disease models. Regarding this one report from PostTech Pohang showed that gold nanoparticles in form of hyaluronate-gold nanoparticle-Tocilizumab (anti-IL-6 antibody) complex had promising results in treatment of RA with significantly decreased cytokine (IL-6) expression and had prolonged immunosuppressive effects though studied in mice model. Thus, these gold nanoparticles in combination with Tocilizumab can be targeted to COVID-19 patients and may be an effective therapeutic strategy to fight the deadly virus. However, regarding the treatment of inflammatory responses in COVID-19 patients, it is an awful truth that there is still no available therapy that can be able to fight this cytokine storm in COVID-19. To overcome these problems, research group of Dr Patrick Couvreur from University of Paris-Sud designed a “multi-drug nano particles” by the intelligent combination of adenosine and the antioxidant alpha-tocopherol and their results in mice showed that typical “cytokine storm” of COVID-19 was reduced by the subsequent increase in anti-inflammatory responses. Thus, combination of smart nanoparticles with monoclonal antibodies like tocilizumab or nanoformulations of antioxidants can be the potential game changers towards killing the virions of COVID-19, because they can battle against the “cytokine storm” of the patients with minimum side effects.
A ray of hope
COVID-19 pandemic represents the greatest global public health crisis of this generation. With its outbreak, we all have realized that the development in research sectors and healthcare industries will be of utmost importance to get a corona free world. In this deadly hour, we, the chemists, the material scientists, the biologists should contribute in a collective way to win over such avengers and together we are hopeful to overcome this dusky phase of our life.
- Treatments for Coronavirus Disease 2019 (COVID-19) A Review. J. M. Sanders, M.L. Monogue, T.Z. Jodlowski, J. B. Cutrell, JAMA. Published online April 13. 2020.
- Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. European Journal of Pharmaceutical Sciences. 2011, 42, 11.
- The effect of lopinavir/ritonavir and lopinavir/ritonavir loaded PLGA nanoparticles on experimental toxoplasmosis. F. Abou-El-Naga, E.D. El Kerdany, R.F. Mady, T.I. Shalaby E.M. Zaytoun. Parasitol Int. 2017, 66, 735.
- Hyaluronate-Gold Nanoparticle/Tocilizumab Complex for the Treatment of Rheumatoid Arthritis. Lee, M.Y.Lee, S. H. Bhang, B.S. Kim, Y. S. Kim, J.H. Ju, K.S. Kim, S.K. Hahn. ACS Nano. 2014, 8, 4790.
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