A functionalized cell membrane biomimetic nanoformulation based on layered double hydroxide for combined tumor chemotherapy and sonodynamic therapy.

The development of nanoformulations with simple compositions that can exert targeted combination therapy still remains a great challenge in the area of precision cancer nanomedicine. Herein, we report the design of a multifunctional nanoplatform based on methotrexate (MTX)-loaded layered double hydroxide (LDH) coated with chlorin e6 (Ce6)-modified MCF-7 cell membranes (CMM) for combined chemo/sonodynamic therapy of breast cancer. LDH nanoparticles were in situ loaded with MTX via coprecipitation, and coated with CMM that were finally functionalized with phospholipid-modified Ce6. The created nanoformulation of LDH-MTX@CMM-Ce6 displays good colloidal stability under physiological conditions and can release MTX in a pH-dependent manner. We show that the formulation can homologously target breast cancer cells, and induce their significant apoptosis through arresting the cell cycle via cooperative MTX-based chemotherapy and ultrasound (US)-activated sonodynamic therapy. The assistance of US can not only trigger sonosensitizer Ce6 to produce reactive oxygen species, but also enhance the cellular uptake of LDH-MTX@CMM-Ce6 via an acoustic cavitation effect. Upon intravenous injection and US irradiation, LDH-MTX@CMM-Ce6 displays an admirable antitumor performance towards a xenografted breast tumor mouse model. Furthermore, the modification of Ce6 on the CMM endows the LDH-based nanoplatform with fluorescence imaging capability. The developed LDH-based nanoformulation here provides a general intelligent cancer nanomedicine platform with simple composition and homologous targeting specificity for combined chemo/sonodynamic therapy and fluorescence imaging of tumors.

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.

Multifunctional Layered Double Hydroxides for Drug Delivery and Imaging.

Two-dimensional nanomaterials, particularly layered double hydroxides (LDHs), have been widely applied in the biomedical field owing to their biocompatibility, biodegradability, controllable drug release/loading ability, and enhanced cellular permeability. Since the first study analyzing intercalative LDHs in 1999, numerous studies have investigated their biomedical applications, including drug delivery and imaging; recent research has focused on the design and development of multifunctional LDHs. This review summarizes the synthetic strategies and in-vivo and in-vitro therapeutic actions and targeting properties of single-function LDH-based nanohybrids and recently reported (from 2019 to 2023) multifunctional systems developed for drug delivery and/or bio-imaging.

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.

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.

Effects of Nanofillers Based on Cetyltrimethylammonium-Modified Clays in a Polypropylene Nanocomposite.

Nanocomposites of hydrophobic organo-clay/polypropylene (organo-clay/PP) were efficiently developed through a solution-blending technique. For this, we utilized various smectite clays as host agents; namely, Na-montmorillonite (Mt, ~1000 nm), Na-fluorine mica (Mica, ~1500 nm), and Na-hectorite (Ht, ~60 nm) with varied sizes, layer charges, and aspect ratios. Such clays were functionalized with cetyltrimethylammonium (CTA) bromide via an intercalation technique to obtain hydrophobic organic clays. The as-made clay particles were further mixed with a PP/xylene solution; the latter was removed to obtain the final product of the CTA-clay/PP nanocomposite. An X-ray diffraction (XRD) analysis confirmed that there were no characteristic (001) diffraction peaks for CTA-Mica in the PP nanocomposites containing CTA-Mica, assuring the fact that the Mica layers could be completely exfoliated and thereby homogenously composited within the PP. On the other hand, the CTA-Mt and CTA-Ht incorporated composites had broader (001) peaks, which might have been due to the partial exfoliation of CTA-Mt and CTA-Ht in the composites. Among the three CTA-clay/PP nanocomposites, the CTA-Mica nanohybrid showed an enhanced thermal stability by ~42 °C compared to the intact host polymer matrix. We also noted that when the CTA-Mica content was ~9 mass % in the nanocomposites, the Young's modulus was drastically maximized to 69%. Our preliminary results therefore validated that out of the three tested clay-PP nanocomposites, the CTA-Mica nanofiller served as the best one to improve both the thermal and mechanical properties of the PP nanocomposites.

Bio-Inorganic Layered Double Hydroxide Nanohybrids in Photochemotherapy: A Mini Review.

Clay-based bio-inorganic nanohybrids, such as layered double hydroxides (LDH), have been extensively researched in the various fields of biomedicine, particularly for drug delivery and bio-imaging applications. Recent trends indicate that such two-dimensional LDH can be hybridized with a variety of photo-active biomolecules to selectively achieve anti-cancer benefits through numerous photo/chemotherapies (PCT), including photothermal therapy, photodynamic therapy, and magnetic hyperthermia, a combination of therapies to achieve the best treatment regimen for patients that cannot be treated either by surgery or radiation alone. Among the novel two-dimensional clay-based bio-inorganic nanohybrids, LDH could enhance the photo-stability and drug release controllability of the PCT agents, which would, in turn, improve the overall phototherapeutic performance. This review article highlights the most recent advances in LDH-based two-dimensional clay-bio-inorganic nanohybrids for the aforementioned applications.

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.

Dilute lattice doping of 64Cu into 2D-nanoplates: its impact on radio-labeling efficiency and stability for target selective PET imaging.

A quintinite nanoplate (64Cu-QT-NP) isomorphically substituted with 64Cu, as the positron emission tomography (PET) imaging material, was prepared via two-step processes. A 64Cu labeling efficiency of 99% was realized, for the first time, by immobilizing the 64Cu radioisotope directly in the octahedral site of the 2-dimensional (2D) quintinite lattice. Furthermore, the 64Cu labeling stability of 64Cu-QT-NPs was also achieved to be more than ∼99% in various solutions such as saline, phosphate-buffered saline (PBS), and other biological media (mouse and human serums). In an in vivo xenograft mouse model, the passive targeting behavior of 64Cu-QT-NPs into tumor tissue based on the enhanced permeability and retention (EPR) effect was also demonstrated by parenteral administration, and successfully visualized using a PET scanner. For enhancing the tumor tissue selectivity, bovine serum albumin (BSA) was coated on 64Cu-QT-NPs to form 64Cu-QT-NPs/BSA, resulting in better colloidal stability and longer blood circulation time, which was eventually evidenced by the 2-fold higher tumor uptake rate when intravenousely injected in an animal model. It is, therefore, concluded that the present 64Cu-QT-NPs/BSA with tumor tissue selectivity could be an advanced nano-device for radio-imaging and diagnosis as well.

The emergence of nanoporous materials in lung cancer therapy.

Lung cancer is one of the most common cancers, affecting more than 2.1 million people across the globe every year. A very high occurrence and mortality rate of lung cancer have prompted active research in this area with both conventional and novel forms of therapies including the use of nanomaterials based drug delivery agents. Specifically, the unique physico-chemical and biological properties of porous nanomaterials have gained significant momentum as drug delivery agents for delivering a combination of drugs or merging diagnosis with targeted therapy for cancer treatment. This review focuses on the emergence of nano-porous materials for drug delivery in lung cancer. The review analyses the currently used nanoporous materials, including inorganic, organic and hybrid porous materials for delivering drugs for various types of therapies, including chemo, radio and phototherapy. It also analyses the selected research on stimuli-responsive nanoporous materials for drug delivery in lung cancer before summarizing the various findings and projecting the future of emerging trends. This review provides a strong foundation for the current status of the research on nanoporous materials, their limitations and the potential for improving their design to overcome the unique challenges of delivering drugs for the treatment of lung cancer.

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.