Pharmacokinetic considerations for enhancing drug repurposing opportunities of anthelmintics: Niclosamide as a case study.

Recently, anthelmintics have showcased versatile therapeutic potential in addressing various diseases, positioning them as promising candidates for drug repurposing. However, challenges such as low bioavailability and a lack of a solid pharmacokinetic basis impede successful repurposing. To overcome these flaws, we aimed to investigate the key pharmacokinetic factors of anthelmintics mainly focusing on the absorption, distribution, and metabolism profiles by employing niclosamide (NIC) as a model drug. The intestinal permeability of NIC is significantly influenced by solubility and doesn't function as a substrate for efflux transporters. It showed high plasma protein binding. Also, the metabolism study indicated that NIC would have low metabolic stability by extensively undergoing the intestinal glucuronidation. Additionally, we investigated the CYP-mediated drug-drug interaction potential of NIC in both direct and time-dependent ways. NIC showed strong inhibitory effects on CYP1A2 and CYP2C8 and is not likely to become a time-dependent inhibitor. Our findings could contribute to the identification of essential factors in the pharmacokinetics of anthelmintics, potentially facilitating their repositioning.

The Next Generation COVID-19 Antiviral; Niclosamide-Based Inorganic Nanohybrid System Kills SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic is a serious global threat with surging new variants of concern. Although global vaccinations have slowed the pandemic, their longevity is still unknown. Therefore, new orally administrable antiviral agents are highly demanded. Among various repurposed drugs, niclosamide (NIC) is the most potential one for various viral diseases such as COVID-19, SARS (severe acute respiratory syndrome), MERS (middle east respiratory syndrome), influenza, RSV (respiratory syncytial virus), etc. Since NIC cannot be effectively absorbed, a required plasma concentration for antiviral potency is hard to maintain, thereby restricting its entry into the infected cells. Such a 60-year-old bioavailability challenging issue has been overcome by engineering with MgO and hydroxypropyl methylcellulose (HPMC), forming hydrophilic NIC-MgO-HPMC, with improved intestinal permeability without altering NIC metabolism as confirmed by parallel artificial membrane permeability assay. The inhibitory effect on SARS-CoV-2  replication is confirmed in the Syrian hamster model to reduce lung injury. Clinical studies reveal that the bioavailability of NIC hybrid drug can go 4 times higher than the intact NIC. The phase II clinical trial shows a dose-dependent bioavailability of NIC from hybrid drug  suggesting its potential applicability as a game changer in achieving the much-anticipated endemic phase.

NOAEL cancer therapy: a tumor targetable docetaxel-inorganic polymer nanohybrid prevents drug-induced neutropenia.

To date, cancer therapies largely consist of five pillars: surgery, radiation, chemotherapy, targeted therapy, and immunotherapy. Still, researchers are trying to innovate the current cancer therapies to pursue an ideal one without side effects. For developing such a therapy, we designed a chemically well-defined route to a PEG- and docetaxel (DTX)-conjugated inorganic polymer, polyphosphazene, named "polytaxel (PTX)" with a prolonged blood circulation time and tumor localization. Here, we conducted the proof-of-concept study of the ideal therapy in orthotopic and xenograft pancreatic cancer models. We found that the average tumor inhibition rates of PTX were similar to those of DTX without any DTX toxicity-related side effects, such as neutropenia and weight loss. In conclusion, PTX met the requirements of an ideal anticancer drug with high anticancer efficacy and 100% survival rate. PTX is expected to replace any existing anticancer therapies in clinical practice.

Polyphosphazene-Based Biomaterials for Biomedical Applications.

Recently, synthetic polymers have attracted great interest in the field of biomedical science. Among these, polyphosphazenes (PPZs) are regarded as one of the most promising materials, due to their structural flexibility and biodegradability compared to other materials. PPZs have been developed through numerous studies. In particular, multi-functionalized PPZs have been proven to be potential biomaterials in various forms, such as nanoparticles (NPs) and hydrogels, through the introduction of various functional groups. Thus, PPZs have been applied for the delivery of therapeutic molecules (low molecular weight drugs, genes and proteins), bioimaging, phototherapy, bone regeneration, dental liners, modifiers and medical devices. The main goal of the present review is to highlight the recent and the most notable existing PPZ-based biomaterials for aforementioned applications, with future perspectives in mind.

Multifunctional Polymeric Micelles for Cancer Therapy.

Polymeric micelles, nanosized assemblies of amphiphilic polymers with a core-shell architecture, have been used as carriers for various therapeutic compounds. They have gained attention due to specific properties such as their capacity to solubilize poorly water-soluble drugs, biocompatibility, and the ability to accumulate in tumor via enhanced permeability and retention (EPR). Moreover, additional functionality can be provided to the micelles by a further modification. For example, micelle surface modification with targeting ligands allows a specific targeting and enhanced tumor accumulation. The introduction of stimuli-sensitive groups leads to the drug's release in response to environment change. This review highlights the progress in the development of multifunctional polymeric micelles in the field of cancer therapy. This review will also cover some examples of multifunctional polymeric micelles that are applied for tumor imaging and theragnosis.

NICLOSAMIDE-EXFOLIATED ANIONIC CLAY NANOHYBRID REPURPOSED AS AN ANTIVIRAL DRUG FOR TACKLING COVID-19; ORAL FORMULATION WITH TWEEN 60/EUDRAGIT S100.

The ongoing pandemic, COVID-19 (SARS-CoV-2), has afflicted millions of people around the world, necessitating that the scientific community work, diligently and promptly, on suitable medicaments. Although vaccination programs have been run globally, the new variants of COVID-19 make it difficult to restrict the spread of the virus by vaccination alone. The combination of vaccination with anti-viral drug formulation is an ideal strategy for tackling the current pandemic situation. Drugs approved by the United States Food and Drug Administration (FDA), such as Remdesivir, have been found to be of little or no benefit. On the other hand, re-purposing of FDA-approved drugs, such as niclosamide (NIC), has offered promise but its applicability is limited due to its poor aqueous solubility and, therefore, low bioavailability. With advanced nano-pharmaceutical approaches, re-purposing this drug in a suitable drug-carrier for a better outcome may be possible. In the current study, an attempt was made to explore the loading of NIC into exfoliated layered double hydroxide nanoparticles (X-LDH NPs); prepared NIC-X-LDH NPs were further modified with eudragit S100 (ES100), an enteric coating polymer, to make the final product, ES100-NIC-X-LDH NPs, to improve absorption by the gastro/intestinal tract (GIT). Furthermore, Tween 60 was added as a coating on ES100-NIC-X-LDH NPs, not just to enhance its in vitro and in vivo stability, but also to enhance its mucoadhesive property, and to obtain, ultimately, better in vivo pharmacokinetic (PK) parameters upon oral administration. Release of NIC from Tween 60-ES100-NIC-X-LDH NPs was found to be greater under gastro/intestinal solution within a shorter period of time than the uncoated samples. The in vivo analysis revealed that Tween 60-ES100-NIC-X-LDH NPs were able to maintain a therapeutically relevant NIC plasma concentration in terms of PK parameters compared to the commercially available Yomesan®, proving that the new formulation might prove to be an effective oral drug-delivery system to deal with the SARS-CoV-2 viral infections. Further studies are required to ensure their safety and anti-viral efficacy. Supplementary Information: The online version contains supplementary material available at 10.1007/s42860-021-00153-6.

Niclosamide encapsulated in mesoporous silica and geopolymer: A potential oral formulation for COVID-19.

COVID-19 is a rapidly evolving emergency, for which there have been no specific medication found yet. Therefore, it is necessary to find a solution for this ongoing pandemic with the aid of advanced pharmaceutics. What is proposed as a solution is the repurposing of FDA approved drug such as niclosamide (NIC) having multiple pathways to inactivate the SARS-CoV-2, the specific virion that induces COVID-19. However, NIC is hardly soluble in an aqueous solution, thereby poor bioavailability, resulting in low drug efficacy. To overcome such a disadvantage, we propose here an oral formulation based on Tween 60 coated drug delivery system comprised of three different mesoporous silica biomaterials like MCM-41, SBA-15, and geopolymer encapsulated with NIC molecules. According to the release studies under a gastro/intestinal solution, the cumulative NIC release out of NIC-silica nanohybrids was found to be greatly enhanced to ~97% compared to the solubility of intact NIC (~40%) under the same condition. We also confirmed the therapeutically relevant bioavailability for NIC by performing pharmacokinetic (PK) study in rats with NIC-silica oral formulations. In addition, we discussed in detail how the PK parameters could be altered not only by the engineered porous structure and property, but also by interfacial interactions between ion-NIC dipole, NIC-NIC dipoles and/or pore wall-NIC van der Waals in the intra-pores of silica nanoparticles.

Injectable niclosamide nanohybrid as an anti-SARS-CoV-2 strategy.

COVID-19 is a rapidly evolving emergency, which necessitates scientific community to come up with novel formulations that could find quick relief to the millions affected around the globe. Remdesivir being the only injectable drug by FDA for COVID-19, it initially showed promising results, however, later on failed to retain its claims, hence rejected by the WHO. Therefore, it is important to develop injectable formulation that are effective and affordable. Here in this work, we formulated poly ethylene glycol (PEG) coated bovine serum albumin (BSA) stabilized Niclosamide (NIC) nanoparticles (NPs) (∼BSA-NIC-PEG NPs) as an effective injectable formulation. Here, serum albumin mediated strategy was proposed as an effective strategy to specifically target SARS-CoV-2, the virus that causes COVID-19. The in-vitro results showed that the developed readily water dispersible formulation with a particle size <120 nm size were well stable even after 3 weeks. Even though the in-vitro studies showed promising results, the in-vivo pharmaco-kinetic (PK) study in rats demands the need of conducting further experiments to specifically target the SARS-CoV-2 in the virus infected model. We expect that this present formulation would be highly preferred for targeting hypoalbuminemia conditions, which was often reported in elderly COVID-19 patients. Such studies are on the way to summarize its potential applications in the near future.

Hydrotalcite-Niclosamide Nanohybrid as Oral Formulation towards SARS-CoV-2 Viral Infections.

COVID-19 has been affecting millions of individuals worldwide and, thus far, there is no accurate therapeutic strategy. This critical situation necessitates novel formulations for already existing, FDA approved, but poorly absorbable drug candidates, such as niclosamide (NIC), which is of great relevance. In this context, we have rationally designed NIC-loaded hydrotalcite composite nanohybrids, which were further coated with Tween 60 or hydroxypropyl methyl cellulose (HPMC), and characterized them in vitro. The optimized nanohybrids showed particle sizes <300 nm and were orally administrated to rats to determine whether they could retain an optimum plasma therapeutic concentration of NIC that would be effective for treating COVID-19. The pharmacokinetic (PK) results clearly indicated that hydrotalcite-based NIC formulations could be highly potential options for treating the ongoing pandemic and we are on our way to understanding the in vivo anti-viral efficacy sooner. It is worth mentioning that hydrotalcite-NIC nanohybrids maintained a therapeutic NIC level, even above the required IC50 value, after just a single administration in 8-12 h. In conclusion, we were very successfully able to develop a NIC oral formulation by immobilizing with hydrotalcite nanoparticles, which were further coated with Tween 60 or HPMC, in order to enhance their emulsification in the gastrointestinal tract.

A Novel Cell Penetrating Peptide for the Differentiation of Human Neural Stem Cells.

Retinoic acid (RA) is a bioactive lipid that has been shown to promote neural stem cell differentiation. However, the highly hydrophobic molecule needs to first solubilize and translocate across the cell membrane in order to exert a biological response. The cell entry of RA can be aided by cell penetrating peptides (CPPs), which are short amino acid sequences that are able to carry bioactive cargo past the cell membrane. In this work, a novel cell penetrating peptide was developed to deliver RA to human neural stem cells and, subsequently, promote neuronal differentiation. The novel CPP consists of a repeating sequence, whose number of repeats is proportional to the efficiency of cell penetration. Using fluorescence microscopy, the mode of translocation was determined to be related to an endocytic pathway. The levels of β-III tubulin (Tubb3) and microtubule associated protein 2 (MAP2) expression in neural stem cells treated with RA conjugated to the CPP were assessed by quantitative immunocytochemistry.

Novel lower critical solution temperature phase transition materials effectively control osmosis by mild temperature changes.

Osmosis can be controlled reversibly and effectively by mild temperature changes based on novel thermosensitive solutes with LCST transition. The nBu-TAEA thermosensitive solution can draw fresh water from seawater at temperatures less than the phase separation temperature, and the osmotic flow was reversed at higher temperatures.

Effect of deoxycholate conjugation on stability of pDNA/polyamidoamine-diethylentriamine (PAM-DET) polyplex against ionic strength.

Polyplexes formed from cationic polymer/pDNA have been known to be vulnerable to external ionic strength. To improve polyplex stability against ionic strength, we attempted the chemical conjugation of the hydrophobic deoxycholate (DC) moiety to the polyamidoamine-diethylenetriamine (PAM-DET) dendrimer. Dynamic light scattering studies showed that the tolerance of the resulting PAM-DET-DC against ionic strength is higher than that of PAM-DET. In addition, we confirmed that the stability of polyplex has a strong relationship with the degree of conjugation of the DC moiety to the PAM-DET dendrimer and the charge ratio of PAM-DET-DC. Furthermore, the transfection efficiency of the PAM-DET-DC polyplex is higher than that of PAM-DET but its cytotoxicity remains the same. Therefore, the chemical conjugation of DC is a safe and effective method for increasing the stability of supramolecules formed from electrostatic interaction.

Ion pairs of risedronate for transdermal delivery and enhanced permeation rate on hairless mouse skin.

Ion-paired solutions of risedronate (RIS) with L-arginine (ARG), L-lysine (LYS), and diethylenetriamine (DETA) were tested in vitro for their potential to enhance the penetration of RIS across the skin of hairless mouse. The xylene solubilities of RIS paired with ARG, LYS, and DETA in molar ratios of 1:2, 1:2, and 1:1 were 8.9%, 12.0%, and 2.1%, respectively, in comparison with the solubility in deionized water, but non-ion-paired RIS was not detected in xylene. In vitro permeation tests were performed on the skin of hairless mice, and the results indicated that ion-paired RIS could penetrate mice skin about 36 times more effectively than RIS alone. The cumulative amount of ion paired RIS after 24 h resulted in 475.18±94.19 µg/cm(2) and 511.21±106.52 µg/cm(2) at molar ratio of 1:2 and 1:1. The cumulative amount of RIS alone was as low as 14.13±5.49 µg/cm(2) in 24h. The hairless mice showed no skin irritation after a single administration of RIS alone and ion-paired RIS (1:2 molar ratio with ARG, and 1:1 molar ratio with DETA). In this study, we found that RIS can be delivered transdermally, and the ion-paired system in an aqueous solution showed an enhanced flux through the skin barrier.

Biodegradable branched poly(ethylenimine sulfide) for gene delivery.

We synthesized biodegradable b-PEIS (branched poly(ethylenimine sulfide)) by crosslinking linear PEIS. We controlled the degree of crosslinking and molecular weight by adjusting the amount of the crosslinker, bisepoxide. The b-PEIS was readily degradable under reductive conditions (5mm glutathione solution) and the degradation time was dependent on the degree of crosslinking. We controlled the molecular weights of the b-PEIS by regulating the amount of crosslinker and thus, the degree of crosslinking. Our titration data showed that there was almost no loss in buffering ability before or after bisepoxide crosslinking. We verified the degradation of this polymer by MALLS and gel electrophoresis, and confirmed that there was a high transfection efficiency and low cytotoxicity based on cellular data. Intracellular trafficking was observed by image restoration microscopy, demonstrating that b-PEIS does not accumulate in the cell interior.

A new biodegradable crosslinked polyethylene oxide sulfide (PEOS) hydrogel for controlled drug release.

We developed a polyethylene glycol (PEG)-based biodegradable hydrogel through disulfide crosslinking of polyethylene oxide sulfide (PEOS). The crosslinking rate was highly dependent on temperature, and incubation at about 40-50 degrees C was required for efficient crosslinking. The crosslinked PEOS hydrogel showed glutathione-dependent dissolution and corresponding controlled release of a model drug-fluorescein isothiocyanate (FITC)-labeled dextran-because the disulfide bond, the main linker, is selectively degraded in response to the high concentration of glutathione. The temperature-sensitive crosslinking and the hydrogel formation have the potential for use as an injectable biogel precursor, which was confirmed by in situ gel formation in mice.

Visualization of the degradation of a disulfide polymer, linear poly(ethylenimine sulfide), for gene delivery.

Polyethylenimine (PEI) shows high transfection efficiency and cytoxicity due to its high amine density. The new disulfide cationic polymer, linear poly(ethylenimine sulfide) (l-PEIS), was synthesized for efficient and safe gene delivery. As the amine density of l-PEIS increased, the transfection efficiency also increased. l-PEIS-6 and l-PEIS-8 show transfection efficiencies that are similar to that of PEI. However, cytotoxicity of l-PEIS was not observed due to the biodegradable disulfide bond. The disulfide bonds are stable in the oxidative extracellular condition and can be degraded rapidly in the reductive intracellular condition. The degradation of l-PEIS in HeLa cells was visualized by fluorescence microscopy using the probe-probe dequenching effect of BODIPY-FL fluorescence dye. l-PEIS was degraded completely within 3 h.

Poly(ethylene oxide sulfide): new poly(ethylene glycol) derivatives degradable in reductive conditions.

Poly(ethylene oxide sulfide) (PEOS), polymers consisting of an internal ethylene oxide oligomer and disulfide linkage, were synthesized and characterized. The degree of polymerization was dependent upon temperature, dimethyl sulfoxide condition, and monomer hydrophobicity. The stability of PEOS was measured by the size exclusion chromatography method after the incubation both with and without 5 mM glutathione. The disulfide bond was stable in the extracellular condition but completely degraded in 2 h in the reductive cytosolic condition. Hydrophilic PEOS polymers showed no cytotoxicity on the HepG2 cell line. On the basis of these properties, PEOS can be applied in many drug delivery fields.