Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19

Abstract

There is urgent therapeutic need for COVID-19, a disease for which there are currently no widely effective approved treatments and the emergency use authorized drugs do not result in significant and widespread patient improvement. The food and drug administration-approved drug ivermectin has long been shown to be both antihelmintic agent and a potent inhibitor of viruses such as Yellow Fever Virus. In this study, we highlight the potential of ivermectin packaged in an orally administrable nanoparticle that could serve as a vehicle to deliver a more potent therapeutic antiviral dose and demonstrate its efficacy to decrease expression of viral spike protein and its receptor angiotensin-converting enzyme 2 (ACE2), both of which are keys to lowering disease transmission rates. We also report that the targeted nanoparticle delivered ivermectin is able to inhibit the nuclear transport activities mediated through proteins such as importin α/β1 heterodimer as a possible mechanism of action. This study sheds light on ivermectin-loaded, orally administrable, biodegradable nanoparticles to be a potential treatment option for the novel coronavirus through a multilevel inhibition. As both ACE2 targeting and the presence of spike protein are features shared among this class of virus, this platform technology has the potential to serve as a therapeutic tool not only for COVID-19 but for other coronavirus strains as well.

Recent Advances on Nanomaterials to COVID‐19 Management: A Systematic Review on Antiviral/Virucidal Agents and Mechanisms of SARS‐CoV‐2 Inhibition/Inactivation

“…[45] We collected data from several nanostructures' types studied against the coronavirus cited above as nanotubes, nanorods, nanoparticles, nanostars, nanowires, nanocrystals, nanosheets, nanogels, nanospheres, nanocapsules, nanoclusters, and nanostructured lipid carriers (NLCs). Of these, were identified the following nanotechnology-based approaches: bioconjugated carboxyl quantum dots (QDs); [74] silver nanomaterials; [58,60,69,80,96,97] synthetic virus-like particles (sVLPs); [77] gold nanoparticles; [59,77] biopolymeric/biodegradable polymeric nanoparticles and hydrogels (e.g., chitosan, collagen, poly(ethylene glycol) (PEG), poly lactic-co-glycolic acid (PLGA), and poly(hydroxyethyl) methacrylate); [61,62,63,79,[85][86][87]91,93] carbon quantum dots (CQDs) [71] and cationic carbon dots based on curcumin (CCM-CDs); [68] glutathione(GSH)-capped silver-sulfide nanoclusters (GSHcapped Ag 2 S NCs); [64] gold nanorod-based heptad repeat 1 (HR1) peptide; [72] antigen and adjuvant-loaded hollow polymeric nanoparticles; [73] bovine serum albumin (BSA)-coated tellurium nanoparticles (Te/BSA NPs) with a unique triangular star shape (Te/BSA nanostars); [65] GSH-modified zinc-sulfide nanoparticles (ZnS NPs); [66] glycyrrhizic-acid-based carbon dots (Gly-CDs); [67] multi-walled carbon nanotubes (MWCNTs) with target functions; [83] metal-decorated single-wall carbon nanotubes (SWCNTs); [100] NLCs; [88] graphene oxide; [60,82,92] iron oxide nanoparticles (IONPs), [75] functionalized graphene sheets;…”

“…[88,103,104] Ivermectin is a clinically approved antiviral drug and was repurposed against SARS-CoV-2, using orally administering PLGAgrafted-PEG-maleimide nanoparticles, an amphiphilic and biodegradable block copolymer system, which was capable of delivering a more potent therapeutic dose. [87] The system demonstrated potential for the therapeutic drug to COVID-19 by multisite inhibition into decreasing the viral uptake and transmission by i) inhibition of viral spike protein level and its entry rate by downregulation of ACE2 expression, and ii) possibly, inhibition of nuclear transport activities mediated by proteins (e.g., importin α/β1 heterodimer). [87] A recent study hypothesized that excessive neutrophil extracellular traps (NETs) and extracellular DNAs (eDNAs) could activate NETosis, neutrophil-specific programmed cell death might be associated with COVID-19 pathogenesis.…”

“…[87] The system demonstrated potential for the therapeutic drug to COVID-19 by multisite inhibition into decreasing the viral uptake and transmission by i) inhibition of viral spike protein level and its entry rate by downregulation of ACE2 expression, and ii) possibly, inhibition of nuclear transport activities mediated by proteins (e.g., importin α/β1 heterodimer). [87] A recent study hypothesized that excessive neutrophil extracellular traps (NETs) and extracellular DNAs (eDNAs) could activate NETosis, neutrophil-specific programmed cell death might be associated with COVID-19 pathogenesis. [85,105] Nowadays, there are no FDA-approved antiviral medications that can effectively suppress the SARS-CoV-2-mediated neutrophil activities, cytokine storm, acute respiratory distress syndrome (ARDS), and sepsis, thus, promoting widespread patient improvement.…”

“…[85,86] Therefore, different strategies using polymeric nanoparticles to deliver antiviral agents have been evaluated to drug repurpose. [85][86][87] An in vivo study with a septic mouse model showed the potential of bioinspired DNase-I-coated melanin-like nanospheres using PEG to reduce neutrophil counts and modulate sepsis-associated NETosis dysregulation in the plasma of COVID-19 patients alleviating inflammation and mortality. [85] Further research showed an exogenous administration of a long-acting DNase-1, a recombinant DNase-1-coated polydopamine-PEG nanoparticulated, can reduce SARS-CoV-2-mediated neutrophil activities and cytokine storm as a potential treatment to COVID-19-related illnesses.…”

COVID-19 and Ivermectin: Potential threats associated with human use

“…Nanomaterial-Ivermectin composites have been shown to enhance protective efficacy and long term stability in the blood against Zika virus in vitro [59] . Recently, a study concluded the stability of non-immunogenic nanoparticles combined with ivermectin, tagged with immunoglobulin fragment (orally fed) as the treatment and prevention against SARS-CoV-2 [60] . However, the in vivo safety and biodegradability of nanomaterials after being exposed to lung epithelia warrant more research focus.…”