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COVID-19 is a pandemic disease caused by the SARS-CoV-2, which continues to cause global health and economic problems since emerging in China in late 2019. Until now, there are no standard antiviral treatments. Thus, several strategies were adopted to minimize virus transmission, such as social distancing, face covering protection and hand hygiene. Rhamnolipids are glycolipids produced formally by Pseudomonas aeruginosa and as biosurfactants, they were shown to have broad antimicrobial activity. In this study, we investigated the antimicrobial activity of rhamnolipids against selected multidrug resistant bacteria and SARS-CoV-2. Rhamnolipids were produced by growing Pseudomonas aeruginosa strain LeS3 in a new medium formulated from chicken carcass soup. The isolated rhamnolipids were characterized for their molecular composition, formulated into nano-micelles, and the antibacterial activity of the nano-micelles was demonstrated in vitro against both Gram-negative and Gram-positive drug resistant bacteria. In silico studies docking rhamnolipids to structural and non-structural proteins of SARS-CoV-2 was also performed. We demonstrated the efficient and specific interaction of rhamnolipids with the active sites of these proteins. Additionally, the computational studies suggested that rhamnolipids have membrane permeability activity. Thus, the obtained results indicate that SARS-CoV-2 could be another target of rhamnolipids and could find utility in the fight against COVID-19, a future perspective to be considered.

Graphical abstract, Viral infections represent 44% of newly emerging infections, and as is shown by the COVID-19 outbreak constitute a major risk to human health and wellbeing. Although there are many efficient antiviral agents, they still have drawbacks such as development of virus resistance and accumulation within off-target organs. Encapsulation of antiviral agents into nanoparticles (NPs) has been shown to improve bioavailability, control release, and reduce side effects. However, there is little quantitative understanding of how the uptake of NPs into virally infected cells compares to uninfected cells. In this work, the uptake of fluorescently labeled polymer NPs was investigated in several models of rhinovirus (RV) infected cells. Different multiplicities of RV infections (MOI) and timings of NPs uptake were also investigated. In some cases, RV infection resulted in a significant increase of NPs uptake, but this was not universally noted. For HeLa cells, RV-A16 and RV-A01 infection elevated NPs uptake upon increasing the incubation time, whereas at later timepoints (6 h) a reduced uptake was noted with RV-A01 infection (owing to decreased cell viability). Beas-2B cells exhibited more complex trends: decreases in NPs uptake (cf. uninfected cells) were observed at short incubation times following RV-A01 and RV-A16 infection. At later incubation times (4 h), we found a marked decrease of NPs uptake for RV-A01 infected cells but an increase in uptake with RV-A16 infected cells. Where increases in NPs uptake were found, they were very modest compared to results previously reported for a hepatitis C/ Huh7.5 cell line model. An increase in RV dose (MOI) was not associated with any notable change of NPs uptake. We argue that the diverse endocytic pathways among the different cell lines, together with changes in virus nature, size, and entry mechanism are responsible for these differences. These findings suggest that NPs entry into virally infected cells is a complex process, and further work is required to unravel the different factors which govern this. Undertaking this additional research will be crucial to develop potent nanomedicines for the delivery of antiviral agents.

Nucleoside analogues are active therapeutic agents for different types of diseases e.g. Cancer and virus infections. However, they are associated with several side effects due to off-target accumulation. Particulate delivery systems such as nanoparticles (NP) may be able to selectively target drug into affected organs and lower or omit off-target accumulation. Hydrophilic nucleoside analogues are poorly incorporated into NP. This work has used boronic compounds to synthesize more hydrophobic biodegradable pro-drugs of hydrophilic nucleosides to improve drug loading into NP. Ribavirin (RV) was used as a model hydrophilic nucleoside to test our hypothesis. RV is a broad antiviral agent, active against both RNA and DNA viruses. RV accumulates into Red Blood Cells (RBCs) causing haemolytic anaemia that restricts its therapeutic benefits. RBCs are reported to have no endocytic mechanisms. So, NP delivery should be advantageous. Two hydrophobic pro-drugs of RV were synthesized namely, ribavirin conjugated to phenylboronic acid and ribavirin conjugated to 4-butoxy-3, 5-dimethylphenylboronic acid and were encapsulated into polymer NP. It was shown that the pro-drugs were incorporated more effectively into polymer nanoparticles with a 1700 fold improved RV loading. Polymer NP had been prepared with biocompatible and biodegradable polymers, Poly(glycerol adipate) and its more hydrophobic derivatives.

COVID-19, is a disease resulting from the SARS-CoV-2 global pandemic. Due to the current global emergency and the length of time required to develop specific antiviral agent(s) and a vaccine for SARS-CoV-2, the world health organization (WHO) adopted the strategy of repurposing existing medications to treat COVID-19. Iron oxide nanoparticles (IONPs) were previously approved by the US food and drug administration (FDA) for anemia treatment and studies have also demonstrated its antiviral activity in vitro. Therefore, we performed a docking study to explore the interaction of IONPs (Fe2O3 and Fe3O4) with the spike protein receptor binding domain (S1-RBD) of SARS-CoV-2 that is required for virus attachment to the host cell receptors. A similar docking analysis was also performed with hepatitis C virus (HCV) glycoproteins E1 and E2. These studies revealed that both Fe2O3 and Fe3O4 interacted efficiently with the SARS-CoV-2 S1-RBD and to HCV glycoproteins, E1 and E2. Fe3O4 formed a more stable complex with S1-RBD whereas Fe2O3 favored HCV E1 and E2. These interactions of IONPs are expected to be associated with viral proteins conformational changes and hence, viral inactivation. Therefore, we recommend FDA-approved-IONPs to proceed for COVID-19 treatment clinical trials., Graphical abstract Image, graphical abstract

Layered gadolinium hydroxides (LGdH) have significant potential in simultaneous drug delivery and magnetic resonance imaging (MRI). In this work, we synthesized LGdH nanocomposites surface functionalised with SiO2 nanodots (LGdH@SiO2). We find these to have good dispersibility in cell culture medium, and a reduced tendency to aggregate compared to their uncoated analogue. Under the optimal reaction conditions, SiO2 nanodots were evenly spread across the surface of the LGdH particles. We further intercalated ibuprofen (Ibu) and 5-fluorouracil (5FU) into LGdH@SiO2, and explored the use of the resultant composites for drug delivery in vitro. While the SiO2 coating could effectively reduce aggregation of the Ibu intercalate prepared by ion exchange from the parent LGdH, it was noted to increase aggregation in the case of the 5FU-loaded systems produced by coprecipitation. With a SiO2 coating, 5FU release from the composite was almost zero-order at pH 7.4. The LGdH-5FU@SiO2 composites can effectively inhibit the growth of A549 ​cells (a human adenocarcinoma cell line). In contrast, the Ibu-loaded materials are highly biocompatible. After SiO2 modification, LGdH-5FU@SiO2 retains the same proton relaxivity properties as LGdH-5FU, while LGdH-Ibu@SiO2 becomes suitable for use as a negative contrast agent in MRI.

Ribavirin is an antiviral agent, has a broad-spectrum activity against many RNA and DNA viruses and could be used for treatment of myriad types of viral infections. The conventional therapy of ribavirin is accompanied by dose dependant haemolytic anaemia due to its accumulation into Red Blood Cells (RBCs) that limits its dose, and hence, treatment outcome. It is known from the literature that RBCs have no endocytic mechanisms. Although, recent publications showed some data of nanoparticle (NP) uptake by RBCs, it is still a matter of debate and needs further investigation. In addition, according to our knowledge, No one has tried to quantitate how much NP might be taken up by RBCs and correlate that to the possibility of NP use as a delivery system for ribavirin. This work is a continuation of our previous work trying to figure out the advantages that might be offered by polymer NP to deliver ribavirin to treat viral infections. In this work, we used fluorescently labelled polymer nanoparticle, Rhodamine B isothiocyanate poly (glycerol-adipate) nanoparticle [RBITC-PGA NP] to track and quantitate the amount of NP that might be taken up by RBCs versus Huh7.5, human hepatoma cells as a model of endocytic cells to ascertain the advantages offered by polymer NP to increase safety of ribavirin to improve the treatment outcome of viral infections. Spectro-photofluorometry and flow cytometry showed a negligible amount of NP taken up by RBCs compared to Huh7.5 cells, and therefore, polymer NP could be considered as a promising delivery system for ribavirin and its use could be associated with a better management of viral infections (e.g. Hepatitis C) due to a lower possibility of ribavirin accumulation into RBCs. However, future studies using polymer nanoparticles with a sufficient drug loading and retention of ribavirin will be necessary to confirm these results experimentally and clinically.

The formation of nanoscale fibers from pH-sensitive polymers is a route which has been widely explored for targeted drug delivery. In particular, the Eudragit L100 and S100 families of polymers have received significant attention for this purpose. However, while in some cases it is shown that making drug-loaded Eudragit polymers effectively prevents drug release in low-pH media where the polymer is insoluble, this is not always the case, and other studies have reported significant amounts of drug release at acidic pHs. In this study, we sought to gain insight into the factors influencing the release of active ingredients from Eudragit S100 (ES100) fibers. A family of materials was prepared loaded with the model active ingredients (AIs) benzoic acid, 1-naphthoic acid, 1-naphthylamine, and 9-anthracene carboxylic acid. Analogous systems were prepared with an AI-loaded core and an ES100 sheath. The resultant fibers were smooth and cylindrical in the majority of cases, and X-ray diffraction and differential scanning calorimetry showed them to comprise amorphous solid dispersions. When AI release from the monolithic fibers was probed, it was found that there was significant release at pH 1 in all cases except with 9-anthracene carboxylic acid. Analysis of the results indicated that both the molecular weight of the AI and its acidity/basicity are important in controlling release, with lower molecular weight AIs and basic species released more quickly. The same release trends are seen with the core/shell fibers, but AI release at pH 1 is attenuated. The most significant change between the monolithic and core/shell systems was observed in the case of 1-naphthylamine. Mathematical equations were devised to connect molecular properties and AI release under acidic conditions.