Synbiotic of Pediococcus acidilactici and Inulin Ameliorates Dextran Sulfate Sodium-Induced Acute Ulcerative Colitis in Mice.

Colitis is a major gastrointestinal disease that threatens human health. In this study, a synbiotic composed of inulin and Pediococcus acidilactici (P. acidilactici) was investigated for its ability to alleviate dextran sulfate sodium (DSS)-induced colitis. The results revealed that the synbiotic, composed of inulin and P. acidilactici, attenuated the body weight loss and disease activity index (DAI) score in mice with DSS-mediated colitis. Determination of biochemical indicators found that the synbiotic increased anti-oxidation and alleviated inflammation in mice. Additionally, histopathological examination revealed that colonic goblet cell loss and severe mucosal damage in the model group were significantly reversed by the combination of inulin and P. acidilactici. Moreover, synbiotic treatment significantly reduced the levels of IL-1ß, TNF-α, and IL-6 in the serum of mice. Thus, a synbiotic composed of inulin and P. acidilactici has preventive and therapeutic effects on DSSinduced colitis in mice.

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.

Curcumin in exfoliated layered double hydroxide nanoparticles: Pre-clinical evaluation as lung cancer nanomedicine.

Rationally designed ∼ 100 nm sized curcumin (CRC) loaded exfoliated layered double hydroxide nanoparticles (X-LDH/CRC-NPs) have been tested for its suitability as nanomedicine in non-small cell lung cancer (NSCLC) cell lines (A549 and NCI-H460) resulting enhanced apoptosis. Preclinical evaluation on A549 tumor bearing nude mouse model confirmed that such a well-designed X-LDH/CRC NPs would be highly advantageous for treating lung cancers.

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.

pH-Responsive Inorganic/Organic Nanohybrids System for Controlled Nicotinic Acid Drug Release.

Although nicotinic acid (NA) has several clinical benefits, its potency cannot be fully utilized due to several undesirable side effects, including cutaneous flushing, GIT-associated symptoms, etc. To overcome such issues and improve the NA efficacy, a new inorganic-organic nanohybrids system was rationally designed. For making such a hybrid system, NA was intercalated into LDH through a coprecipitation technique and then coated with Eudragit® S100 to make the final drug delivery system called Eudragit® S100-coated NA-LDH. The as-made drug delivery system not only improved the NA release profile but also exhibited good bio-compatibility as tested on L929 cells. Such an inorganic-organic nanohybrid drug delivery agent is expected to reduce the undesirable side effects associated with NA and hopefully improve the pharmacological effects without inducing any undesirable toxicity.

Artesunate drug-loaded 2D nano-shuttle landing on RBCs infected with malaria parasites.

Artesunic acid (AS0), a derivative of artemisinin, is recommended for the treatment of severe and complicated malaria, but its use is limited because of limitations such as a short half-life, non-specific targeting capability, low bioavailability, etc. To overcome these issues, a novel 2D inorganic delivery shuttle system for an AS0 drug to target the malarial host, red blood cells (RBCs), is explored by immobilizing AS0 into 2D metal hydroxides to form AS- (artesunate, the deprotonated form of artesunic acid) nanohybrid drugs. Haemolysis assay showed that the AS- nanohybrids not only are haemo-compatible but also target RBCs due to the electrostatic interaction and hydrogen bonding between RBCs and AS- nanohybrids. As clearly demonstrated by the subsequent parasite lactate dehydrogenase assay, the antimalarial effect of the AS- nanohybrids is determined to be 6 times more effective than that of intact AS0 against malaria. Therefore, the AS- nanohybrids with haemo-compatible 2D inorganic carriers could be the promising drug delivery systems for targeting the malarial host, RBCs.

Monolayer Graphitic Carbon Nitride as Metal-Free Catalyst with Enhanced Performance in Photo- and Electro-Catalysis.

HIGHLIGHTS: The g-C3N4 monolayer in the perfect 2D limit was successfully realized, for the first time, by the well-defined chemical strategy based on the bottom-up process. The most striking evidence was made from Cs-high resolution transmission electron microscopy measurements by observing directly the atomic structure of g-C3N4 unit cell, which was again supported by the corresponding high resolution transmission electron microscopy image simulation results. We demonstrated that the newly prepared g-C3N4 monolayer showed outstanding photocatalytic activity for H2O2 generation as well as excellent electrocatalytic activity for oxygen reduction reaction. The exfoliation of bulk graphitic carbon nitride (g-C3N4) into monolayer has been intensively studied to induce maximum surface area for fundamental studies, but ended in failure to realize chemically and physically well-defined monolayer of g-C3N4 mostly due to the difficulty in reducing the layer thickness down to an atomic level. It has, therefore, remained as a challenging issue in two-dimensional (2D) chemistry and physics communities. In this study, an "atomic monolayer of g-C3N4 with perfect two-dimensional limit" was successfully prepared by the chemically well-defined two-step routes. The atomically resolved monolayer of g-C3N4 was also confirmed by spectroscopic and microscopic analyses. In addition, the experimental Cs-HRTEM image was collected, for the first time, which was in excellent agreement with the theoretically simulated; the evidence of monolayer of g-C3N4 in the perfect 2D limit becomes now clear from the HRTEM image of orderly hexagonal symmetry with a cavity formed by encirclement of three adjacent heptazine units. Compared to bulk g-C3N4, the present g-C3N4 monolayer showed significantly higher photocatalytic generation of H2O2 and H2, and electrocatalytic oxygen reduction reaction. In addition, its photocatalytic efficiency for H2O2 production was found to be the best for any known g-C3N4 nanomaterials, underscoring the remarkable advantage of monolayer formation in optimizing the catalyst performance of g-C3N4.

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.

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.

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.

Bovine Serum Albumin-Coated Niclosamide-Zein Nanoparticles as Potential Injectable Medicine against COVID-19.

(1) Background: COVID-19 has affected millions of people worldwide, but countries with high experimental anti-SARS-CoV-2 vaccination rates among the general population respectively show progress in achieving general herd immunity in the population (a combination of natural and vaccine-induced acquired immunity), resulting in a significant reduction in both newly detected infections and mortality rates. However, the longevity of the vaccines' ability to provide protection against the ongoing pandemic is still unclear. Therefore, it is of utmost importance to have new medications to fight against the pandemic at the earliest point possible. Recently, it has been found that repurposing already existing drugs could, in fact, be an ideal strategy to formulate effective medication for COVID-19. Though there are many FDA-approved drugs, it has been found that niclosamide (NIC), an anthelmintic drug, has significantly high potential against the SARS-CoV-2 virus. (2) Methods: Here we deployed a simple self-assembling technique through which Zein nanoparticles were successfully used to encapsulate NIC, which was then coated with bovine serum albumin (BSA) in order to improve the drugs' stability, injectablity, and selectivity towards the virus-infected cells. (3) Results: The particle size for the BSA-stabilized Zein-NIC nanohybrid was found to be less than 200 nm, with excellent colloidal stability and sustained drug release properties. In addition, the nanohybrid showed enhanced drug release behavior under serum conditions, indicating that such a hybrid drug delivery system could be highly beneficial for treating COVID-19 patients suffering from high endothelial glycocalyx damage followed by a cytokine storm related to the severe inflammations.

Inorganic-inorganic nanohybrids for drug delivery, imaging and photo-therapy: recent developments and future scope.

Advanced nanotechnology has been emerging rapidly in terms of novel hybrid nanomaterials that have found various applications in day-to-day life for the betterment of the public. Specifically, gold, iron, silica, hydroxy apatite, and layered double hydroxide based nanohybrids have shown tremendous progress in biomedical applications, including bio-imaging, therapeutic delivery and photothermal/dynamic therapy. Moreover, recent progress in up-conversion nanohybrid materials is also notable because they have excellent NIR imaging capability along with therapeutic benefits which would be useful for treating deep-rooted tumor tissues. Our present review highlights recent developments in inorganic-inorganic nanohybrids, and their applications in bio-imaging, drug delivery, and photo-therapy. In addition, their future scope is also discussed in detail.

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.

Niclosamide-Clay Intercalate Coated with Nonionic Polymer for Enhanced Bioavailability toward COVID-19 Treatment.

Niclosamide (NIC), a conventional anthelmintic agent, is emerging as a repurposed drug for COVID-19 treatment. However, the clinical efficacy is very limited due to its low oral bioavailability resulting from its poor aqueous solubility. In the present study, a new hybrid drug delivery system made of NIC, montmorillonite (MMT), and Tween 60 is proposed to overcome this obstacle. At first, NIC molecules were immobilized into the interlayer space of cationic clay, MMT, to form NIC-MMT hybrids, which could enhance the solubility of NIC, and then the polymer surfactant, Tween 60, was further coated on the external surface of NIC-MMT to improve the release rate and the solubility of NIC and eventually the bioavailability under gastrointestinal condition when orally administered. Finally, we have performed an in vivo pharmacokinetic study to compare the oral bioavailability of NIC for the Tween 60-coated NIC-MMT hybrid with Yomesan®, which is a commercially available NIC. Exceptionally, the Tween 60-coated NIC-MMT hybrid showed higher systemic exposure of NIC than Yomesan®. Therefore, the present NIC-MMT-Tween 60 hybrid can be a potent NIC drug formulation with enhanced solubility and bioavailability in vivo for treating Covid-19.

Implantable multireservoir device with stimulus-responsive membrane for on-demand and pulsatile delivery of growth hormone.

Implantable devices for on-demand and pulsatile drug delivery have attracted considerable attention; however, many devices in clinical use are embedded with the electronic units and battery inside, hence making them large and heavy for implantation. Therefore, we propose an implantable device with multiple drug reservoirs capped with a stimulus-responsive membrane (SRM) for on-demand and pulsatile drug delivery. The SRM is made of thermosensitive POSS(MEO2MA-co-OEGMA) and photothermal nanoparticles of reduced graphene oxide (rGO), and each of the drug reservoirs is filled with the same amount of human growth hormone (hGH). Therefore, with noninvasive near-infrared (NIR) irradiation from the outside skin, the rGO nanoparticles generate heat to rupture the SRM in the implanted device, which can open a single selected drug reservoir to release hGH. Therefore, the device herein is shown to release hGH reproducibly only at the times of NIR irradiation without drug leakage during no irradiation. When implanted in rats with growth hormone deficiency and irradiated with an NIR light from the outside skin, the device exhibits profiles of hGH and IGF1 plasma concentrations, as well as body weight change, similar to those in animals treated with conventional s.c. hGH injections.

Alendronate-Anionic Clay Nanohybrid for Enhanced Osteogenic Proliferation and Differentiation.

BACKGROUND: Alendronate (AL), a drug for inhibiting osteoclast-mediated bone-resorption, was intercalated into an inorganic drug delivery nanovehicle, layered double hydroxide (LDH), to form a new nanohybrid, AL-LDH, with 1:1 heterostructure along the crystallographic C-axis. Based on the intercalation reaction strategy, the present AL-LDH drug delivery system (DDS) was realized with an enhanced drug efficacy of AL, which was confirmed by the improved proliferation and osteogenic differentiation of osteoblast-like cells (MG63). METHODS: The AL-LDH nanohybrid was synthesized by conventional ion-exchange reaction and characterized by powder X-ray diffraction (PXRD), high-resolution transmission electron microscopy (HR-TEM), and Fourier transform infrared (FT-IR) spectroscopy. Additionally, in vitro efficacy tests, such as cell proliferation and alkaline phosphatase (ALP) activity, were analyzed. RESULTS: The AL was successfully intercalated into LDH via ion-exchange reaction, and thus prepared AL-LDH DDS was X-ray single phasic and chemically well defined. The accumulated AL content in MG63 cells treated with the AL-LDH DDS nanoparticles was determined to be 10.6-fold higher than that within those treated with the intact AL after incubation for 1 hour, suggesting that intercellular permeation of AL was facilitated thanks to the hybridization with drug delivery vehicle, LDH. Furthermore, both in vitro proliferation level and ALP activity of MG63 treated with the present hybrid drug, AL-LDH, were found to be much more enhanced than those treated with the intact AL. This is surely due to the fact that LDH could deliver AL drug very efficiently, although LDH itself does not show any effect on proliferation and osteogenic differentiation of MG63 cells. CONCLUSION: The present AL-LDH could be considered as a promising DDS for improving efficacy of AL.

Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.