Thixotropic Hydrogels Based on Laponite® and Cucurbituril for Delivery of Lipophilic Drug Molecules.

Nowadays the use of hydrogels for biomedical purposes is increasing because of their interesting features that allow the development of targeted drug delivery systems. Herein, hydrogel based on Laponite® (Lap) clay mineral as gelator and cucurbit[6]uril (CB[6]) molecules were synthetized for the delivery of flufenamic acid (FFA) for potential topical application. Firstly, the interaction between CB[6] and FFA was assessed by UV-vis spectroscopic measurements and molecular modeling calculations. Then, the obtained complex was used as filler for Lap hydrogel (Lap/CB[6]/FFA). The properties of the hydrogel in terms of viscosity and, self-repair abilities were investigated; its morphology was imaged by scanning electron and polarized optical microscopies. Furthermore, the changes in the hydrodynamic radii and in the colloidal stability of CB[6]/Lap mixture were investigated in terms of translational diffusion from dynamic light scattering and ζ-potential measurements. Finally, the kinetic in vitro release of FFA, from Lap/CB[6]/FFA hydrogel, was studied in a medium mimicking the pH of skin and the obtained results were discussed both by an experimental point of view and by molecular modeling calculations.

Thixotropic Hydrogels Based on Laponite® and Cucurbituril for Delivery of Lipophilic Drug Molecules.

Invited for this month's cover are the collaborating groups of Prof. Serena Riela at University of Catania, Prof. César Viseras at University of Granada and Dr. Ignacio Sainz-Diaz at Instituto Andaluz de Ciencias de la Tierra. The cover picture shows the possible application of the developed system. In particular, flufenamic acid, anti-inflammatory and anti-pyretic drug, was complexed into cucurbituril cavity and the supramolecular system obtained was used as filler for laponite® hydrogel for its topical delivery. More information can be found in the Research Article by Viseras-Iborra, Riela, and co-workers.

Nanoformulations based on collagenases loaded into halloysite/Veegum® clay minerals for potential pharmaceutical applications.

The design and development of nanomaterials capable of penetrate cancer cells is fundamental when anticancer therapy is involved. The use of collagenase (Col) is useful since this enzyme can degrade collagen, mainly present in the tumor extracellular matrix. However, its use is often limited since collagenase suffers from inactivation and short half-life. Use of recombinant ultrapure collagenase or carrier systems for their delivery are among the strategies adopted to increase the enzyme stability. Herein, based on the more stability showed by recombinant enzymes and the possibility to use them in anticancer therapy, we propose a novel strategy to further increase their stability by using halloysite nanotubes (HNTs) as carrier. ColG and ColH were supramolecularly loaded onto HNTs and used as fillers for Veegum gels. The systems could be used for potential local administration of collagenases for solid tumor treatment. All techniques adopted for characterization showed that halloysite interacts with collagenases in different ways depending with the Col considered. Furthermore, the hydrogels showed a very slow release of the collagenases within 24 h. Finally, biological assays were performed by studying the digestion of a type-I collagen matrix highlighting that once released the Col still possessed some activity. Thus we developed carrier systems that could further increase the high recombinant collagenases stability, preventing their inactivation in future in vivo applications for potential local tumor treatment.

Biocomposite for Prolonged Release of Water-Soluble Drugs.

This study aimed to develop a prolonged-release system based on palygorskite and chitosan, which are natural ingredients widely available, affordable, and accessible. The chosen model drug was ethambutol (ETB), a tuberculostatic drug with high aqueous solubility and hygroscopicity, which is incompatible with other drugs used in tuberculosis therapy. The composites loaded with ETB were obtained using different proportions of palygorskite and chitosan through the spray drying technique. The main physicochemical properties of the microparticles were determined using XRD, FTIR, thermal analysis, and SEM. Additionally, the release profile and biocompatibility of the microparticles were evaluated. As a result, the chitosan-palygorskite composites loaded with the model drug appeared as spherical microparticles. The drug underwent amorphization within the microparticles, with an encapsulation efficiency greater than 84%. Furthermore, the microparticles exhibited prolonged release, particularly after the addition of palygorskite. They demonstrated biocompatibility in an in vitro model, and their release profile was influenced by the proportion of inputs in the formulation. Therefore, incorporating ETB into this system offers improved stability for the administered product in the initial tuberculosis pharmacotherapy dose, minimizing its contact with other tuberculostatic agents in the treatment, as well as reducing its hygroscopicity.

Exploiting the interaction between halloysite and charged PNAs for their controlled release.

The design and development of nanomaterials that could be used in nanomedicine are of fundamental importance to obtain smart nanosystems for the treatment of several diseases. Halloysite, because of its interesting features, represents a suitable nanomaterial for the delivery of different biologically active species. Among them, peptide nucleic acids (PNAs) have attracted considerable attention in recent decades for their potential applications in both molecular antisense diagnosis and as therapeutic agents, although up to now, the actual clinical applications have been very limited. Herein we report a systematic study on the supramolecular interaction of three differently charged PNAs with halloysite. Understanding the interaction mode of charged molecules with the clay surfaces represents a key factor for the future design and development of halloysite based materials which could be used for the delivery and subsequent intracellular release of PNA molecules. Thus, three different PNA tetramers, chosen as models, were synthesized and loaded onto the clay. The obtained nanomaterials were characterized using spectroscopic studies and thermogravimetric analysis, and their morphologies were studied using high angle annular dark field transmission electron microscopy (HAADF/STEM) coupled with Energy Dispersive X-ray spectroscopy (EDX). The aqueous mobility of the three different nanomaterials was investigated by dynamic light scattering (DLS) and ζ-potential measurements. The release of PNA tetramers from the nanomaterials was investigated at two different pH values, mimicking physiological conditions. Finally, to better understand the stability of the synthesized PNAs and their interactions with HNTs, molecular modelling calculations were also performed. The obtained results showed that PNA tetramers interact in different ways with HNT surfaces according to their charge which influences their kinetic release in media mimicking physiological conditions.

Aloe vera and copaiba oleoresin-loaded chitosan films for wound dressings: microbial permeation, cytotoxicity, and in vivo proof of concept.

Chitosan films are commonly used for wound dressing, provided that this polymer has healing, mucoadhesiveness and antimicrobial properties. These properties can be further reinforced by the combination of chitosan with polysaccharides and glycoproteins present in aloe vera, together with copaiba oleoresin's pharmacological activity attributed to sesquiterpenes. In this work, we developed chitosan films containing either aloe vera, copaiba oil or both, by casting technique, and evaluated their microbial permeation, antimicrobial activity, cytotoxicity, and in vivo healing potential in female adult rats. None of the developed chitosan films promoted microbial permeation, while the cytotoxicity in Balb/c 3 T3 clone A31 cell line revealed no toxicity of films produced with 2 % of chitosan and up to 1 % of aloe vera and copaiba oleoresin. Films obtained with either 0.5 % chitosan or 0.5 % copaiba oleoresin induced cell proliferation which anticipate their potential for closure of wound and for the healing process. The in vivo results confirmed that tested films (0.5 % copaiba-loaded chitosan film and 0.5 % aloe vera-loaded chitosan film) were superior to a commercial dressing film. For all tested groups, a fully formed epithelium was seen, while neoformation of vessels seemed to be greater in formulations-treated groups than those treated with the control. Our work confirms the added value of combining chitosan with aloe vera and copaiba oil in the healing process of wounds.

Exploring the cellular uptake of hectorite clay mineral and its drug carrier capabilities.

In the last years, the use of clay minerals for pharmaceutical purposes has increased due to their interesting properties. Hectorite (Ht) is a clay belonging to the smectite group which has attracted attention for applications in biology, tissue engineering and as drug carrier and delivery system. However, the mechanisms involved in Ht cellular uptake and transport into cells, are still unclear. Herein, we used a labeled Ht (Ht/1Cl) to study both the cellular uptake, by confocal laser scanning microscopy, and internalization pathways involved in the cellular uptake, by various endocytosis-inhibiting studies and fluorescence microscopy. These studies highlighted that Ht can penetrate the cellular membrane, localizing mainly in the cytoplasm. The main intracellular transport mechanisms are the ATP-dependent ones and those where filaments and microtubules are involved. Finally, as proof of concept for the potential of Ht as carrier system, we envisaged the covalent grafting of the anticancer molecule methotrexate (MTX), chosen as model, to obtain the Ht-MTX nanomaterial. The covalent linkage was confirmed by several techniques and the morphology of the obtained nanomaterial was imaged by SEM and TEM investigations. The kinetic release of the drug from the Ht-MTX nanomaterial in physiological conditions was studied as well. Furthermore, cytotoxic studies on different cell lines, namely, HL-60, HL-60R, MCF-7, 5637, UMUC3 and RT112 showed that Ht could be a promising material for anticancer therapy.

Plant Polysaccharides in Engineered Pharmaceutical Gels.

Hydrogels are a great ally in the pharmaceutical and biomedical areas. They have a three-dimensional polymeric structure that allows the swelling of aqueous fluids, acting as an absorbent, or encapsulating bioactive agents for controlled drug release. Interestingly, plants are a source of biogels, specifically polysaccharides, composed of sugar monomers. The crosslinking of these polymeric chains forms an architecture similar to the extracellular matrix, enhancing the biocompatibility of such materials. Moreover, the rich hydroxyl monomers promote a hydrophilic behavior for these plant-derived polysaccharide gels, enabling their biodegradability and antimicrobial effects. From an economic point of view, such biogels help the circular economy, as a green material can be obtained with a low cost of production. As regards the bio aspect, it is astonishingly attractive since the raw materials (polysaccharides from plants-cellulose, hemicelluloses, lignin, inulin, pectin, starch, guar, and cashew gums, etc.) might be produced sustainably. Such properties make viable the applications of these biogels in contact with the human body, especially incorporating drugs for controlled release. In this context, this review describes some sources of plant-derived polysaccharide gels, their biological function, main methods for extraction, remarkable applications, and properties in the health field.

Clays as Vehicles for Drug Photostability.

Clay minerals are often used due to their high adsorption capacity, which has sparked interest in their biological applications to stabilize drugs and pharmaceutical products. This research aims to summarize information about the stability of drugs, cosmetics, dermocosmetics, and pharmaceutical compounds incorporated in the structure of different clay minerals. The databases used to search the articles were Web of Science, Scopus, PubMed, and Science Direct. Photostabilization of these compounds is reviewed and its importance demonstrated. For biological applications, the increase in solubility and bioavailability of clay minerals has proven useful for them as drug carriers. While their natural abundance, low toxicity, and accessible cost have contributed to classical applications of clay minerals, a wide range of interesting new applications may be facilitated, mainly through incorporating different organic molecules. The search for new functional materials is promising to challenge research on clay minerals in biological or biotechnological approaches.

A Novel Deep Neural Network Technique for Drug-Target Interaction.

Drug discovery (DD) is a time-consuming and expensive process. Thus, the industry employs strategies such as drug repositioning and drug repurposing, which allows the application of already approved drugs to treat a different disease, as occurred in the first months of 2020, during the COVID-19 pandemic. The prediction of drug-target interactions is an essential part of the DD process because it can accelerate it and reduce the required costs. DTI prediction performed in silico have used approaches based on molecular docking simulations, including similarity-based and network- and graph-based ones. This paper presents MPS2IT-DTI, a DTI prediction model obtained from research conducted in the following steps: the definition of a new method for encoding molecule and protein sequences onto images; the definition of a deep-learning approach based on a convolutional neural network in order to create a new method for DTI prediction. Training results conducted with the Davis and KIBA datasets show that MPS2IT-DTI is viable compared to other state-of-the-art (SOTA) approaches in terms of performance and complexity of the neural network model. With the Davis dataset, we obtained 0.876 for the concordance index and 0.276 for the MSE; with the KIBA dataset, we obtained 0.836 and 0.226 for the concordance index and the MSE, respectively. Moreover, the MPS2IT-DTI model represents molecule and protein sequences as images, instead of treating them as an NLP task, and as such, does not employ an embedding layer, which is present in other models.

Lipid Nanomaterials for Targeted Delivery of Dermocosmetic Ingredients: Advances in Photoprotection and Skin Anti-Aging.

Despite the health benefits of the sun, overexposure to solar radiation without proper precautions can cause irreversible damage to exposed skin. In the search for balance between the risks and benefits of exposure to solar radiation in human health, a technological alternative was found, the incorporation of photoprotective products in lipid nanoparticulate systems for topical application. These nanometric systems have demonstrated several advantages when used as adjuvants in photoprotection compared to chemical and/or physical sunscreens alone. The increase in the sun protection factor (SPF), photostability and UV action spectrum are parameters that have benefited from the application of these systems in order to increase the effectiveness and safety of photoprotective formulations containing organic and/or inorganic sunscreens.

Annatto Oil Loaded Nanostructured Lipid Carriers: A Potential New Treatment for Cutaneous Leishmaniasis.

Annatto (Bixa orellana L.) is extensively used as food pigment worldwide. Recently, several studies have found it to have healing and antioxidant properties, as well as effective action against leishmaniasis. Therefore, the purpose of this study was to incorporate the oil obtained from annatto seeds into a nanostructured lipid carrier (NLC) and evaluate its physicochemical properties and biological activity against Leishmania major. Nanoparticles were prepared by the fusion-emulsification and ultrasonication method, with the components Synperonic™ PE (PL) as the surfactant, cetyl palmitate (CP) or myristyl myristate (MM) as solid lipids, annatto oil (AO) (2% and 4%, w/w) as liquid lipid and active ingredient, and ultra-pure water. Physicochemical and biological characterizations were carried out to describe the NLCs, including particle size, polydispersity index (PDI), and zeta potential (ZP) by dynamic light scattering (DLS), encapsulation efficiency (EE%), thermal behavior, X-ray diffraction (XRD), transmission electron microscopy (TEM), Electron Paramagnetic Resonance (EPR), cytotoxicity on BALB/c 3T3 fibroblasts and immortalized human keratinocyte cells, and anti-leishmaniasis activity in vitro. Nanoparticles presented an average diameter of ~200 nm (confirmed by TEM results), a PDI of less than 0.30, ZP between -12.6 and -31.2 mV, and more than 50% of AO encapsulated in NLCs. Thermal analyses demonstrated that the systems were stable at high temperatures with a decrease in crystalline structure due to the presence of AOs (confirmed by XRD). In vitro, the anti-leishmania test displayed good activity in encapsulating AO against L. major. The results indicate that the oily fraction of Bixa orellana L. in NLC systems should be evaluated as a potential therapeutic agent against leishmaniasis.

New Trends in Drug Delivery Systems for Veterinary Applications.

BACKGROUND: The veterinary pharmaceutical industry has shown significant growth in recent decades. Several factors contribute to this increase as the demand for the improvement of the quality of life of both domestic and wild animals, together with the need to improve the quality, productivity, and safety of foodstuffs of animal origin. METHODS: The goal of this work was to identify the most suitable medicines for animals that focus on drug delivery routes as those for humans, although they may have different devices, such as collars and ear tags. RESULTS: Recent advances in drug delivery systems for veterinary use are discussed, both from academic research and the global market. The administration routes commonly used for veterinary medicines are also explored, while special attention is given to the latest technological trends to improve the drug performance, reducing the number of doses, animal stress, and side effects. CONCLUSION: Drug delivery system in veterinary decreased the number of doses, side effects, and animal stress that are a small fraction of the benefits of veterinary drug delivery systems and represent a significant increase in profit for the industry; also, it demands investments in research regarding the quality, safety, and efficacy of the drug and the drug delivery systems.

Natural Inorganic Ingredients in Wound Healing.

BACKGROUND: One of the major clinical challenges is to achieve a rapid and efficient treatment of complex chronic wounds. Nowadays, most wound dressings currently available are unable to find a solution to the challenges of resistance to bacterial infection, protein adsorption and increased levels of exudates. Natural inorganic ingredients (clay minerals, metal cations, zeolites, etc.) could be the key to solve the problem satisfactorily. Some of these materials have shown biocompatibility and ability to enhance cell adhesion, proliferation and cellular differentiation and uptake. Besides, some natural inorganic ingredients effectively retain drugs, allowing the design of drug delivery matrices. OBJECTIVE: Possibilities of natural inorganic ingredients in wound healing treatments have been reviewed, the following sections have been included: 1. Introduction 2. Functions of Inorganic Ingredients in wound healing 2.1. Antimicrobial effects 2.2. Hemostatic effects 3. Clay minerals for wound healing 3.1. Clay minerals 3.2. Clay mineral semisolid formulations 3.3. Clay/polymer composites and nanocomposites 3.4. Clay minerals in wound dressings 4. Other inorganic materials for wound healing 4.1. Zeolites 4.2. Silica and other silicates 4.3. Other minerals 4.4. Transition metals 5. Conclusion. Conclusion: Inorganic ingredients possess useful features for the development of chronic wounds advanced treatments. They improve physical (mechanical resistance and water vapor transmission), chemical (release of drugs, hemostasis and/or adsorption of exudates and moisture) and biological (antimicrobial effects and improvement of healing) properties of wound dressings. In summary, inorganic ingredients have proved to be a promising and easily accessible products in the treatment of wounds and, more importantly, chronic wounds.

Innovative nanocompounds for cutaneous administration of classical antifungal drugs: a systematic review.

Nanomedicine manipulates materials at atomic, molecular, and supramolecular scale, with at least one dimension within the nanometer range, for biomedical applications. The resulting nanoparticles have been consistently shown beneficial effects for antifungal drugs delivery, overcoming the problems of low bioavailability and high toxicity of these drugs. Due to their unique features, namely the small mean particle size, nanoparticles contribute to the enhanced drug absorption and uptake by the target cells, potentiating the therapeutic drug effect. The topical route is desirable due to the adverse effects arising from oral administration. This review provides a comprehensive analysis of the use of nano compounds for the current treatment of topical fungal infections. A special emphasis is given to the employment of lipid nanoparticles, due to their recognized efficacy, versatility, and biocompatibility, attracting the major attention as novel topical nanocompounds used for the administration of antifungal drugs.

Activity enhancement of selective antitumoral selenodiazoles formulated with poloxamine micelles.

Selenium (Se) incorporated into organic frameworks has demonstrated anticancer activity against several cancer types. One of the drawbacks of most of these constructs is their poor solubility and bioavailability, which can be overcome with the use of suitable nanocarriers. We have synthesized a series of 5-substituted amide selenodiazoles, based on the parent structure of ebselen, an organoselenium drug with proven cytoprotective activity, and solubilized them in polymeric micelles of poloxamines, poly(ethylene oxide)-poly(propylene oxide) X-shaped tetrablock-copolymers. Scattering methods (SANS and DLS) were employed to characterize the micellar nanocarriers. MTT biological evaluation highlights the selectivity of the Se-compounds towards cancer cells, with MCF-7 standing as the most responsive line. The alkylation of the heterocycle with a 12-carbon hydrophobic tail displays the highest activity, showing a 100-fold increase with respect to ebselen. This compound also exhibits the greatest increase in solubility in poloxamine micelles, overall resulting in a one-fold increase in activity with respect to the non-formulated form, making it a hit compound for further optimization.

Physicochemical characterization of surfactant incorporating vesicles that incorporate colloidal magnetite.

Drug administration through the transdermal route has optimized for the comfort of patients and easy application. However, the main limitation of transdermal drug delivery is the impermeability of the human skin. Recent advances on improvement of drug transport through the skin include elastic liposomes as a penetration enhancer. Entrapment of ferrofluids in the core of liposomes produces magnetoliposomes, which can be driven by a high-gradient magnetic field. The association of both strategies could enhance the penetration of elastic liposomes. This work relies on the preparation and characterization of elastic-magnetic liposomes designed to permeate through the skin. The incorporation of colloidal magnetite and the elastic component, octaethylene glycol laurate (PEG-8-L), in the structure of liposomes were evaluated. The capability of the elastic magnetoliposomes for permeation through nanopores of two stacked polycarbonate membranes was compared to conventional and elastic liposomes. Magnetite incorporation was dependent on vesicle diameter and size distribution as well as PEG-8-L incorporation into liposomes, demonstrating the capability of the fluid bilayer to accommodate the surfactant without disruption. On the contrary, PEG-8-L incorporation into magnetoliposomes promoted a decrease of average diameter and a lower PEG-8-L incorporation percentage as a result of reduction on the fluidity of the bilayer imparted by iron incorporation into the lipid structure. Elastic liposomes demonstrated an enhancement of the deformation capability, as compared with conventional liposomes. Conventional and elastic magnetoliposomes presented a reduced capability for deformation and permeation.