Nanomedicine "New Food for an Old Mouth": Novel Approaches for the Treatment of COVID-19

Coronavirus disease (COVID-19) is an infectious disease caused by coronavirus. Devel-oping specific drugs for inhibiting replication and viral entry is crucial. Several clinical trial studies are underway to evaluate the efficacy of anti-viral drugs for COVID-19 patients. Nanomedicine formulations can present a novel strategy for targeting the virus life cycle. Nano-drug delivery systems can modify the pharmacodynamics and pharmacokinetics properties of anti-viral drugs and reduce their adverse effects. Moreover, nanocarriers can directly exhibit anti-viral effects. A number of nanocarriers have been studied for this purpose, including liposomes, dendrimers, exosomes and decoy nanoparticles (NPs). Among them, decoy NPs have been considered more as nanodecoys can efficiently protect host cells from the infection of SARS-CoV-2. The aim of this review article is to highlight the probable nanomedicine therapeutic strategies to develop anti-viral drug delivery systems for the treatment of COVID-19.Copyright © 2023 Bentham Science Publishers.

Dendrimer-Mediated Delivery of DNA and RNA Vaccines.

DNA and RNA vaccines (nucleic acid-based vaccines) are a promising platform for vaccine development. The first mRNA vaccines (Moderna and Pfizer/BioNTech) were approved in 2020, and a DNA vaccine (Zydus Cadila, India), in 2021. They display unique benefits in the current COVID-19 pandemic. Nucleic acid-based vaccines have a number of advantages, such as safety, efficacy, and low cost. They are potentially faster to develop, cheaper to produce, and easier to store and transport. A crucial step in the technology of DNA or RNA vaccines is choosing an efficient delivery method. Nucleic acid delivery using liposomes is the most popular approach today, but this method has certain disadvantages. Therefore, studies are actively underway to develop various alternative delivery methods, among which synthetic cationic polymers such as dendrimers are very attractive. Dendrimers are three-dimensional nanostructures with a high degree of molecular homogeneity, adjustable size, multivalence, high surface functionality, and high aqueous solubility. The biosafety of some dendrimers has been evaluated in several clinical trials presented in this review. Due to these important and attractive properties, dendrimers are already being used to deliver a number of drugs and are being explored as promising carriers for nucleic acid-based vaccines. This review summarizes the literature data on the development of dendrimer-based delivery systems for DNA and mRNA vaccines.

Application of antiviral activity of polymer

The world facing public health crisis due to novel corona virus and it created awareness regarding the prevention of spread of viruses. Treatment and prevention modalities include vaccinations for modulating immunity and use of antiviral drugs. Biocompatible polymers show immense possibilities toward the development of antiviral therapeutics. Researchers have engineered such polymers with antiviral efficacy in fabricating face masks, personal protective equipment, gloves or surfaces, or as surface coating element which can destroy the adhered viruses or other microorganisms. Antiviral polymers have also been constructed for efficient viral prevention and antiviral drug carriers. Here, we summarized different kinds of polymers having antiviral activities. The antiviral polymers are extensively used in drug delivery, protective application, and in food packaging applications. The ongoing clinical research on these areas is presented in this chapter. © 2023 Elsevier Inc. All rights reserved.

Aptamer-Mediated Antiviral Approaches for SARS-CoV-2.

2020 and 2021 were disastrous years across the world, with the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) virus as a pandemic, which continues to be a top global health issue. There are still many countries and regions struggling to fight coronavirus disease 2019 (COVID-19), and, with the emergence of the various variants of the virus, we are still far from considering this global pandemic over. In addition to having good diagnostic tools and a variety of vaccines with high efficacy, it is of utmost importance to develop effective antiviral drugs or therapies to battle COVID-19. Aptamers known as the next-generation targeting elements can offer promising opportunities in developing antiviral drugs against SARS-CoV-2. This is owing to their high specificity and affinity, making them ideal for targeting ligands and neutralizers to impede both, viral entry and replication or even further enhance the anti-infection effects in the infected host cells. Also, aptamers are extremely attractive as they can be rapidly synthesized and scalable with a lower production cost. This work provides in-depth discussions on the potential of aptamers in therapeutic applications, their mode of action, and current progress on the use of aptamer-based therapies against SARS-CoV-2 and other viruses. The article also discusses the limitations associated with aptamer-based SARS-CoV-2-antiviral therapy with several proposed ideas to resolve them. Lastly, theranostic applications of aptamer nanoformulated dendrimers against viral infections are discussed.

Unveiling the G4-PAMAM capacity to bind and protect Ang-(1-7) bioactive peptide by molecular dynamics simulations.

Angiotensin-(1-7) re-balance the Renin-Angiotensin system affected during several pathologies, including the new COVID-19; cardiovascular diseases; and cancer. However, one of the limiting factors for its therapeutic use is its short half-life, which might be overcome with the use of dendrimers as nanoprotectors. In this work, we addressed the following issues: (1) the capacity of our computational protocol to reproduce the experimental structural features of the (hydroxyl/amino)-terminated PAMAM dendrimers as well as the Angiotensin-(1-7) peptide; (2) the coupling of Angiotensin-(1-7) to (hydroxyl/amino)-terminated PAMAM dendrimers in order to gain insight into the structural basis of its molecular binding; (3) the capacity of the dendrimers to protect Angiotensin-(1-7); and (4) the effect of pH changes on the peptide binding and covering. Our Molecular-Dynamics/Metadynamics-based computational protocol well modeled the structural experimental features reported in the literature and our double-docking approach was able to provide reasonable initial structures for stable complexes. At neutral pH, PAMAM dendrimers with both terminal types were able to interact stably with 3 Angiotensin-(1-7) peptides through ASP1, TYR4 and PRO7 key amino acids. In general, they bind on the surface in the case of the hydroxyl-terminated compact dendrimer and in the internal zone in the case of the amino-terminated open dendrimer. At acidic pH, PAMAM dendrimers with both terminal groups are still able to interact with peptides either internalized or in its periphery, however, the number of contacts, the percentage of coverage and the number of hydrogen bonds are lesser than at neutral pH, suggesting a state for peptide release. In summary, amino-terminated PAMAM dendrimer showed slightly better features to bind, load and protect Angiotensin-(1-7) peptides.

The Role of Nanotechnology in Antiviral Regime: An Overview

Nanomedicine or nanotechnology exhibits outstanding features to challenge severe health issues including pathogenic viral infections, the most culpable invaders in the present situation. The perpetual mutational pattern in viruses topped with raising resistance to drug epitomizes the current situation as a trigger to explore nanotech platforms in antiviral therapies. Referring to novel physicochemical features of nanomaterials associated with effective drug delivery, it is viewed as an ideal strategy for treatment of viral infections. The coronavirus induced pathogenesis, including MERS, SARS and SARS-CoV-2 infections, has triggered alarming and highly dangerous precedents against existence of humans. Applications of nanotechnology can serve a new direction for disinfection or treatment of viruses. Presently, various types of nanomaterials, such as nanogels, nanospheres, nanocapsules, liposomes, nanoparticles and many others, that have been investigated in vivo and in vitro for successful drug delivery, vaccination, diagnostic assay and device development with anticipation to be translated in advanced clinical practices, need a collective relook. This paper intents to contribute insightful critique of current studies on the efficacy of nanoplatforms as drug transporter, diagnostic tool and vaccine candidate against pathogenic viruses counting the highly pathogenic and incurable "coronaviruses".

PAMAM-calix-dendrimers: Synthesis and Thiacalixarene Conformation Effect on DNA Binding.

A convenient method for the synthesis of the first generation PAMAM dendrimers based on the thiacalix[4]arene has been developed for the first time. Three new PAMAM-calix-dendrimers with the macrocyclic core in cone, partial cone, and 1,3-alternate conformations were obtained with high yields. The interaction of the obtained compounds with salmon sperm DNA resulted in the formation of the associates of the size up to 200 nm, as shown by the UV-Vis spectroscopy, DLS, and TEM. It was demonstrated by the CD method that the structure of the DNA did not undergo significant changes upon binding. The PAMAM-calix-dendrimer based on the macrocycle in cone conformation stabilized DNA and prevented its degradation.

Polyamidoamine-Remdesivir Conjugate: Physical Stability and Cellular Uptake Enhancement

Nucleoside analogue antiviral remdesivir works by inhibiting the RNA-dependent RNA polymerase enzyme and terminating the viral replication. Currently, remdesivir is under a clinical trial for its activity against SARS-CoV-2. In the blood, remdesivir will undergo an enzymatic reaction to become monophosphate analogue form which is difficult to penetrate into the cell membrane. PAMAM (polyamidoamine) dendrimer is a good carrier to encapsulate remdesivir as a water-insoluble drug (0,339 mg/mL). Entrapment of remdesivir in the PAMAM cavity avoided remdesivir molecules to not undergo the enzymatic reactions. This study aimed to synthesize, characterize and evaluate cellular uptake of PAMAM-Remdesivir conjugate. PAMAM-Remdesivir was prepared with various stirring times (3, 6, 12, 24, and 48 hours). The conjugates were characterized to observe the size and particle distribution using Particle Size Analyzer, encapsulating efficiency using UV-Vis Spectroscopy, interaction between PAMAM and remdesivir particle using Fourier Transform Infrared Spectroscopy and cellular uptake of PAMAM-RDV using Fluorescence Microscope. The optimized stirring time of PAMAM-Remdesivir conjugate was 24 hours wich resulted the particles charge of + 23,07 mV of zeta potential, 1008 nm of particle size, 0,730 of PDI, and 69% entrapment efficiency. In addition, the FTIR analysis showed that remdesivir molecules successfully conjugated to PAMAM. Thus, through strring optimization time, the remdesivir molecules were successfully entrapped to PAMAM cavity. The cellular uptake in Vero Cell of PAMAM-RDV conjugated fluorescein isothiocyanate was observed with fluorescence microscope and had a stronger intensity than remdesivir only solution.

A Fast and Convenient Synthesis of New Water-Soluble, Polyanionic Dendrimers.

Reasonably simple, efficient, and possessing aspects of generality, the methodology for the synthesis of new, water-soluble, dendrimeric polyesters with great potential applications as antiviral drugs in their own right is described. The essential aspect of the presented approach is a quite unique, immediate access to the polyanionic material at each generation during divergent synthesis. Six target polyanionic dendrimers (generations 1, 2, and 3) have been synthesized. The key monomers applied in this project were 1,3,5-benzenetricarboxylic acid derivatives, which also worked as direct precursors of the charged dendrimer surface.

Protective Effects of Astodrimer Sodium 1% Nasal Spray Formulation against SARS-CoV-2 Nasal Challenge in K18-hACE2 Mice.

Strategies to combat COVID-19 require multiple ways to protect vulnerable people from infection. SARS-CoV-2 is an airborne pathogen and the nasal cavity is a primary target of infection. The K18-hACE2 mouse model was used to investigate the anti-SARS-CoV-2 efficacy of astodrimer sodium formulated in a mucoadhesive nasal spray. Animals received astodrimer sodium 1% nasal spray or PBS intranasally, or intranasally and intratracheally, for 7 days, and they were infected intranasally with SARS-CoV-2 after the first product administration on Day 0. Another group was infected intranasally with SARS-CoV-2 that had been pre-incubated with astodrimer sodium 1% nasal spray or PBS for 60 min before the neutralisation of test product activity. Astodrimer sodium 1% significantly reduced the viral genome copies (>99.9%) and the infectious virus (~95%) in the lung and trachea vs. PBS. The pre-incubation of SARS-CoV-2 with astodrimer sodium 1% resulted in a significant reduction in the viral genome copies (>99.9%) and the infectious virus (>99%) in the lung and trachea, and the infectious virus was not detected in the brain or liver. Astodrimer sodium 1% resulted in a significant reduction of viral genome copies in nasal secretions vs. PBS on Day 7 post-infection. A reduction in the viral shedding from the nasal cavity may result in lower virus transmission rates. Viraemia was low or undetectable in animals treated with astodrimer sodium 1% or infected with treated virus, correlating with the lack of detectable viral replication in the liver. Similarly, low virus replication in the nasal cavity after treatment with astodrimer sodium 1% potentially protected the brain from infection. Astodrimer sodium 1% significantly reduced the pro-inflammatory cytokines IL-6, IL-1α, IL-1ß, TNFα and TGFß and the chemokine MCP-1 in the serum, lung and trachea vs. PBS. Astodrimer sodium 1% nasal spray blocked or reduced SARS-CoV-2 replication and its sequelae in K18-hACE2 mice. These data indicate a potential role for the product in preventing SARS-CoV-2 infection or for reducing the severity of COVID-19.

Twenty Years of Research on Cyclodextrin Conjugates with PAMAM Dendrimers.

Recently, the number of gene and oligonucleotide drugs are increasing. Of various drug delivery systems (DDSs) for gene and oligonucleotide drugs, few examples of the clinical application of polymer as drug carriers are known, despite development of the novel polymers has been progressing. Cyclodextrin (CD) conjugates with starburst polyamidoamine (PAMAM) dendrimer (CDEs), as a new type of polymer-based carriers, were first published in 2001. After that, galactose-, lactose-, mannose-, fucose-, folate-, and polyethyleneglycol (PEG)-appended CDEs have been prepared for passive and active targeting for gene, oligonucleotide, and low-molecular-weight drugs. PEG-appended CDE formed polypsuedorotaxanes with α-CD and γ-CD, which are useful for a sustained release system of gene and oligonucleotide drugs. Interestingly, CDEs were found to have anti-inflammatory effects and anti-amyloid effects themselves, which have potential as active pharmaceutical ingredients. Most recently, CDE is reported to be a useful Cas9-RNA ribonucleoproteins (Cas9 RNP) carrier that induces genome editing in the neuron and brain. In this review, the history and progression of CDEs are overviewed.

Virucidal and antiviral activity of astodrimer sodium against SARS-CoV-2 in vitro.

An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral and virucidal (irreversible) activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 and Calu-3 cells, with 50% effective concentrations (EC50) for i) reducing virus-induced cytopathic effect of 0.002-0.012 mg/mL in Vero E6 cells, and ii) infectious virus release by plaque assay of 0.019-0.032 mg/mL in Vero E6 cells and 0.030-0.037 mg/mL in Calu-3 cells. The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also virucidal, irreversibly reducing SARS-CoV-2 infectivity by >99.9% (>3 log10) within 1 min of exposure, and up to >99.999% (>5 log10) shown at astodrimer sodium concentrations of 10-30 mg/mL in Vero E6 and Calu-3 cell lines. Astodrimer sodium also inhibited infection in a primary human airway epithelial cell line. The data were similar for all investigations and were consistent with the potent antiviral and virucidal activity of astodrimer sodium being due to irreversible inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial attachment of the virus to the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a topically administered agent for SARS-CoV-2 therapeutic applications.

Peptides and Dendrimers: How to Combat Viral and Bacterial Infections.

The alarming growth of antimicrobial resistance and recent viral pandemic events have enhanced the need for novel approaches through innovative agents that are mainly able to attach to the external layers of bacteria and viruses, causing permanent damage. Antimicrobial molecules are potent broad-spectrum agents with a high potential as novel therapeutics. In this context, antimicrobial peptides, cell penetrating peptides, and antiviral peptides play a major role, and have been suggested as promising solutions. Furthermore, dendrimers are to be considered as suitable macromolecules for the development of advanced nanosystems that are able to complement the typical properties of dendrimers with those of peptides. This review focuses on the description of nanoplatforms constructed with peptides and dendrimers, and their applications.