Freezing-Tolerant Supramolecular Adhesives from Tannic Acid-Based Low-Transition-Temperature Mixtures.

Natural polyphenols like tannic acid (TA) have recently emerged as multifunctional building blocks for designing advanced materials. Herein, we show the benefits of having TA in a dynamic liquid state using low-transition-temperature mixtures (LTTMs) for developing freezing-tolerant glues. TA was combined with betaine or choline chloride to create LTTMs, which direct the self-assembly of guanosine into supramolecular viscoelastic materials with high adhesion. Molecular dynamics simulations showed that the structural properties of the material are linked to strong hydrogen bonding in TA-betaine and TA-choline chloride mixtures. Notably, long-term and repeatable adhesion was achieved even at -196 °C due to the binding ability of TA's catechol and gallol units and the mixtures' glass transition temperature. Additionally, the adhesives demonstrated injectability and low toxicity against fibroblasts in vitro. These traits reveal the potential of these systems as bioadhesives for tissue repair, opening new avenues for creating multifunctional soft materials with bioactive properties.

Nano-in-nano enteric protein delivery system: coaxial Eudragit® L100-55 fibers containing poly(N-vinylcaprolactam) nanogels.

Oral protein delivery holds significant promise as an effective therapeutic strategy for treating a wide range of diseases. However, effective absorption of proteins faces challenges due to biological barriers such as harsh conditions of the stomach and the low permeability of mucous membranes. To address these challenges, this article presents a novel nano-in-nano platform designed for enteric protein delivery. This platform, obtained by electrospinning, involves a coaxial arrangement comprising poly(N-vinylcaprolactam) nanogels (NGs) enclosed within nanofibers of Eudragit® L100-55 (EU), a pH-responsive polymer. The pH-selective solubility of EU ensures the protection of NGs during their passage through the stomach, where the fibers remain intact at low pH, and releases them in the intestine where EU dissolves. The switchable characteristic of this nano-in-nano platform is confirmed by using NGs loaded with a model protein (ovalbumin), which is selectively released when the intestinal pH is achieved. The versatility of this nano-in-nano delivery platform is demonstrated by the ability to modify the fibers dissolution profile simply by adjusting the concentration of EU used in the electrospinning process. Furthermore, by tuning the properties of NGs, the potential applications of this platform can be further extended, paving the way for diverse therapeutic possibilities.

Exploiting cyanine dye J-aggregates/monomer equilibrium in hydrophobic protein pockets for efficient multi-step phototherapy: an innovative concept for smart nanotheranostics.

After several decades of development in the field of near-infrared (NIR) dyes for photothermal therapy (PTT), indocyanine green (ICG) still remains the only FDA-approved NIR contrast agent. However, upon NIR light irradiation ICG can react with molecular oxygen to form reactive oxygen species and degrade the ICG core, losing the convenient dye properties. In this work, we introduce a new approach for expanding the application of ICG in nanotheranostics, which relies on the confinement of self-organized J-type aggregates in hydrophobic protein domains acting as monomer depots. Upon the fast photobleaching, while the dye is irradiated, this strategy permits the equilibrium-driven monomer replacement after each irradiation cycle that radically increases the systems' effectivity and applicability. Gadolinium-doped casein micelles were designed to prove this novel concept at the same time as endowing the nanosystems with further magnetic resonance imaging (MRI) ability for dual-modal imaging-guided PTT. By teaching a new trick to a very old dog, the clinical prospect of ICG will undoubtedly be boosted laying the foundation for novel therapeutics. It is anticipated that future research could be expanded to other relevant J-aggregates-forming cyanine dyes or nanocrystal formulations of poorly water-soluble photosensitizers.

Thermally self-assembled biodegradable poly(casein-g-N-isopropylacrylamide) unimers and their application in drug delivery for cancer therapy.

In this work, we report the synthesis of graft copolymers based on casein and N-isopropylacrylamide, which can self-assemble into biodegradable micelles of approximately 80 nm at physiological conditions. The obtained copolymers were degraded by trypsin, an enzyme that is overexpressed in several malignant tumors. Moreover, graft copolymers were able to load doxorubicin (Dox) by ionic interaction with the casein component. In vitro release experiments showed that the in situ assembled micelles can maintain the cargo at plasma conditions but release Dox immediately after their exposition at pH 5.0 and trypsin. Cellular uptake and cytotoxicity assays revealed the efficient delivery to the nucleus and antiproliferative efficacy of Dox in the breast cancer cell line MDA231. Both delivery and therapeutic activity were enhanced in presence of trypsin. Overall, the prepared micelles hold a great potential for their utilization as dual responsive trypsin/pH drug delivery system.

Influence of Alkyl Chains of Modified Polysuccinimide-Based Polycationic Polymers on Polyplex Formation and Transfection.

The development of polymers with low toxicity and efficient gene delivery remains a significant barrier of nonviral gene therapy. Modification and tuning of chemical structures of carriers is an attractive strategy for efficient nucleic acid delivery. Here, polyplexes consisting of plasmid DNA (pDNA) and dodecylated or non-dodecylated polysuccinimide (PSI)-based polycations are designed, and their transfection ability into HeLa cells is investigated by green fluorescent protein (GFP) expressing cells quantification. All cationic polymers show lower cytotoxicity than those of branched polyethyleneimine (bPEI). PSI and bPEI-based polyplexes have comparable physicochemical properties such as size and charge. Interestingly, a strong interaction between dodecylated polycations and pDNA caused by the hydrophobic moiety is observed in dodecylated PSI derivatives. Moreover, the decrease of GFP expression is associated with lower dissociation of pDNA from polyplexes according to the heparin displacement assay. Besides, a hydrophobization of PSI cationic derivatives with dodecyl side chains can modulate the integrity of polyplexes by hydrophobic interactions, increasing the binding between the polymer and the DNA. These results provide useful information for designing polyplexes with lower toxicity and greater stability and transfection performance.

Crossing biological barriers with nanogels to improve drug delivery performance.

The current limitations in the use of nanocarriers to treat constantly evolving diseases call for the design of novel and smarter drug delivery systems (DDS). Nanogels (NGs) are three-dimensional crosslinked polymers with dimensions on the nanoscale and with a great potential for use in the biomedical field. Particular interest focuses on their application as DDS to minimize severe toxic effects and increase the therapeutic index of drugs. They have recently gained attention, since they can include responsive modalities within their structure, which enable them to excerpt a therapeutic function on demand. Their bigger sizes and controlled architecture and functionality, when compared to non-crosslinked polymers, make them particularly interesting to explore novel modalities to cross biological barriers. The present review summarizes the most significant developments of NGs as smart carriers, with focus on smart modalities to cross biological barriers such as cellular membrane, tumor stroma, mucose, skin, and blood brain barrier. We discuss the properties of each barrier and highlight the importance that the NG design has on their capability to overcome them and deliver the cargo at the site of action.

Cerámicas: una actualización / Ceramics: an update / Cerâmica: uma atualização

Las cerámicas dentales utilizadas para restaurar y reemplazar tejido dental perdido de los dientes o las piezas dentales mismas, han sufrido una enorme transformación desde que aparecieron las primeras porcelanas hace ya varias décadas. Con las feldespáticas se podían hacer dientes, coronas y puentes pero, necesitaban un soporte de metal para que no sufran fracturas con los esfuerzos masticatorios, y por ello no tenían una apa-riencia vital. Hoy en día, han aparecido muchas otras cerámicas con diferentes y mejoradas características mecánicas y ópticas, lo que ha permitido que los odontólogos puedan por primera vez ofrecer a sus pacientes dientes artificiales con sorprendente naturalidad. Objetivo: Describir la clasificación actual, las características mecánicas y ópticas, así como la microestructura y los usos clínicos de las diferentes cerámicas dentales utilizadas hoy en día. Materiales y métodos: Revisión de la literatura acerca del tema, en tres de los más importantes buscadores de internet (Pubmed,Cochrane,Web of Science). Limitando su busca a artículos en inglés y publicados en los journals de investigación de materiales dentales con calificación Q1 y Q2. Resul-tados: Se revisaron 69 artículos publicados entre 1975 y 2019 los cuales aportaron una fuente interesante de información que permitió desarrollar el conocimiento acerca de la clasificación, microestructura, propiedades mecánicas y ópticas, usos clínicos y forma de procesamiento de las cerámicas. Conclusiones: Actualmente los odontólogos tienen a disposición una amplia variedad de materiales cerámicos con diferentes composicio-nes y características únicas que son necesarias conocer al momento de escoger la cerámica específica para cada necesidad de los pacientes.

The dental ceramics used to restore and replace lost tooth tissue or the teeth have undergone a huge trans-formation since the first porcelains appeared several decades ago. With the feldspathic teeth, crowns and bridges could be made but, they needed a metal support so that they did not suffer fractures with the mastica-tory efforts, and therefore they did not have a vital appearance. Today, many other ceramics with different and improved mechanical and optical characteristics have appeared, which has allowed dentists to offer artificial teeth to their patients for the first time with surprising naturalness. Objective: Describe the current classifica-tion, mechanical and optical characteristics, as well as the microstructure and clinical uses of the different dental ceramics used today. Materials and methods: Review about the literature on the subject, in three of the most important internet search engines (Pubmed, Cochrane, Web of Science). Limiting your search to articles in English and published in the journals of research of dental materials with qualification Q1 and Q2. Results:69 articles published between 1975 and 2019 were reviewed, which provided an interesting source of informa-tion that allowed the development of knowledge about classification, microstructure, mechanical and optical properties, clinical uses and method of processing ceramics. Conclusions: Currently, dentists have available a wide variety of ceramic materials with different compositions and unique characteristics that are necessary to know when choosing the specific ceramic for each patient need.

A cerâmica dentária usada para restaurar e substituir o tecido dentário perdido ou as próprias peças dentárias sofreram uma enorme transformação desde que as primeiras porcelanas surgiram várias décadas atrás. Com os materiais feldespáticos, podiam ser feitas coroas e pontes, mas eles precisavam de um suporte de metal para não sofrer fraturas com os esforços mastigatórios e, portanto, não tinham uma aparência de vitalidade. Hoje, outras cerâmicas com características mecânicas e ópticas diferentes e aprimoradas surgiram, o que permitiu aos dentistas oferecer dentes artificiais a seus pacientes pela primeira vez com uma naturalidade surpreendente. Objetivo: Descrever a classificação atual, características mecânicas e ópticas, bem como a microestrutura e os usos clínicos das diferentes cerâmicas odontológicas utilizadas atualmente. Materiais e métodos: Revisão da literatura sobre o assunto, em três dos mais importantes mecanismos de busca na In-ternet (Pubmed, Cochrane, Web of Science). Limitando a sua pesquisa a artigos em inglês e publicados nas revistas científicas de materiais dentários com qualificação Q1 e Q2. Resultados: Foram revisados 69 artigos publicados entre 1975 e 2019, que forneceram uma fonte interessante de informações que permitiram desen-volver conhecimento sobre a classificação, microestrutura, propriedades mecânicas e ópticas, usos clínicos e forma de processamento da cerâmica. Conclusões: Atualmente, os dentistas têm disponível uma ampla variedade de materiais cerâmicos com composição diferente e características únicas que são necessárias conhecer ao escolher a cerâmica específica para cada necessidade do paciente.

Effect of Delivery Platforms Structure on the Epidermal Antigen Transport for Topical Vaccination.

Transdermal immunization is highly attractive because of the skin's accessibility and unique immunological characteristics. However, it remains a relatively unexplored route of administration because of the great difficulty of transporting antigens past the outermost layer of skin, the stratum corneum. In this article, the abilities of three poly( N-vinylcaprolactam) (PVCL)-based thermoresponsive assemblies-PVCL hydrogels and nanogels plus novel film forming PVCL/acrylic nanogels-to act as protein delivery systems were investigated. Similar thermal responses were observed in all systems, with transition temperatures close to 32 °C, close to that of the skin surface. The investigated dermal delivery systems showed no evidence of cytotoxicity in human fibroblasts and were able to load and release ovalbumin (OVA), a well-studied antigen, in a temperature-dependent manner in vitro. The penetration of OVA into ex vivo human skin following topical application was evaluated, where enhanced skin delivery was seen for the OVA-loaded PVCL systems relative to administration of the protein alone. The distinct protein release and skin penetration profiles observed for the different PVCL assemblies were here discussed on the basis of their structural differences.

Optimizing Circulating Tumor Cells' Capture Efficiency of Magnetic Nanogels by Transferrin Decoration.

Magnetic nanogels (MNGs) are designed to have all the required features for their use as highly efficient trapping materials in the challenging task of selectively capturing circulating tumor cells (CTCs) from the bloodstream. Advantageously, the discrimination of CTCs from hematological cells, which is a key factor in the capturing process, can be optimized by finely tuning the polymers used to link the targeting moiety to the MNG. We describe herein the relationship between the capturing efficiency of CTCs with overexpressed transferrin receptors and the different strategies on the polymer used as linker to decorate these MNGs with transferrin (Tf). Heterobifunctional polyethylene glycol (PEG) linkers with different molecular weights were coupled to Tf in different ratios. Optimal values over 80% CTC capture efficiency were obtained when 3 PEG linkers with a length of 8 ethylene glycol (EG) units were used, which reveals the important role of the linker in the design of a CTC-sorting system.

Acid-sensitive lipidated doxorubicin prodrug entrapped in nanoemulsion impairs lung tumor metastasis in a breast cancer model.

AIM: To develop an acid-sensitive lipidated, doxorubicin (Dox) prodrug (C16-Dox) to be entrapped in lipid nanoemulsion (NE-C16-Dox) as a nanocarrier to treat breast cancer models (in vitro and in vivo). RESULTS: We report the efficacy of NE-C16-Dox in in vitro experiments, as well as the improved chemotherapeutic index and tumor-control efficacy compared with treatment with free Dox in an in vivo murine 4T1 breast cancer model. In addition, NE-C16-Dox allowed the use of a higher dose of Dox, acceptable biocompatibility and a significant reduction in lung metastasis. CONCLUSION: Taken together, these results indicate that NE-C16-Dox is promising for breast cancer treatment, thus creating possibilities to translate these nanotechnology concepts to clinical applications.

Formation and characterization of Langmuir and Langmuir-Blodgett films of Newkome-type dendrons in presence and absence of a therapeutic compound, for the development of surface mediated drug delivery systems.

Organic macromolecules with dendrimeric architectures are polymeric materials potentially useful as nanocarriers for therapeutic drugs. In this work, we evaluate a series of Newkome-type dendrons in Langmuir and Langmuir-Blodgett films as platforms capable of interacting with a potential antitumoral agent. The nanocomposite is proposed as model for the development of surface mediated drug delivery systems. We were successful in the formation and characterization of pure (dendrons) and composite (drug-dendron) stable and reproducible monolayers, and their transfer to solid substrates. A detailed study of topographic characteristics of the generated surfaces by atomic force microscopy was conducted. Furthermore, we probed dendron monolayer films as anchorage surfaces for mammalian cells. Normal cell attachment and proliferation on the surfaces were observed. No evident cytotoxic effects were detected, demonstrating the adequate biocompatibility of the surfaces.

Chitosan-g-oligo(epsilon-caprolactone) polymeric micelles: microwave-assisted synthesis and physicochemical and cytocompatibility characterization.

With the aim to produce mucoadhesive polymeric micelles for drug administration by mucosal routes, chitosan-g-oligo(epsilon-caprolactone) copolymers were synthesized by the microwave-assisted ring-opening polymerization of epsilon-caprolactone using chitosan as the macroinitiator and methanesulfonic acid as the solvent, catalyst and protecting group of the amine moieties. The reaction was conducted under very mild conditions and was completed within 10 min with a monomer conversion above 90%. The grafting of oligo(epsilon-caprolactone) blocks to the free hydroxyl groups of chitosan was confirmed by ATR/FT-IR, 1H- and 13C-NMR, WAXD and thermal analysis (TGA/DSC). The molecular weight of the synthetic hybrid copolymers was determined by GPC and MALDI-ToF mass spectrometry. Polymeric micelles obtained by the solvent diffusion/evaporation method showed a spherical shape (TEM and AFM) with sizes between 111 and 154 nm and highly positive zeta potential (>+50 mV) (DLS). In addition, they displayed good cell compatibility in the human lung adenocarcinoma epithelial line, A549, and were readily up-taken by the cervical cancer cell line, HeLa. Results from the encapsulation of the antituberculosis drug, rifampicin, showed that the micelles had better performance than other nanocarriers previously investigated (e.g., cyclodextrins). Moreover, the micelles conserved the mucoadhesiveness displayed by pristine chitosan and are expected to transiently open tight cell junctions and lead to more prolonged residence times in mucosal tissues and greater drug bioavailability.

New dendronized polymers from acrylate Behera amine and their ability to produce visco-elastic structured fluids when mixed with CTAT worm-like micelles.

Two new water soluble dendronized polymers (PLn) from acrylate Behera amine monomer of different molecular weights were successfully synthesized. The polymers were characterized by FTIR, NMR, GPC and DLS. Both GPC and DLS results indicated that these PLn have a remarkable tendency to form aggregates in solution that lead to apparent molecular weights that are much higher than their theoretical values, as well as large diameters in solution. However, the addition of any PLn to water did not cause any increase in viscosity up to concentrations of 1000 ppm. The possible interactions of PLn with the cationic surfactant CTAT were explored by solution rheometry. A synergistic viscosity enhancement was found by adding small amounts of dendronized PLn polymers to a CTAT solution composed of entangled worm-like micelles. The highest association tendency with CTAT was found for PL1 at the maximum polymer concentration before phase separation (i.e., 100 ppm). The solution viscosity at low-shear rates could be increased by an order of magnitude upon addition of 100 ppm of PL1 to a 20mM CTAT solution. For this mixture, the fluid obtained was highly structured and exhibited only shear thinning behavior from the smallest shear rates employed. These PL1/CTAT mixtures exhibited an improved elastic character (as determined by dynamic rheometry) that translated in a much longer value of the cross-over relaxation time and a pronounced thixotropic behavior which are indicative of a strong intermolecular interaction. In the case of the polymer with a higher theoretical molecular weight, PL2, its association with CTAT leads to an extraordinary doubling of solution viscosity with just 0.25 ppm polymer addition to a 20mM CTAT solution. However, such synergistic viscosity enhancement saturated at rather low concentrations (25 ppm) indicating an apparent lower solubility as compared to PL1, a fact that may be related to its higher molecular weight.

Synthesis of amphiphilic dendrons and their interactions in aqueous solutions with cetyltrimethylammonium p-toluenesulfonate (CTAT).

In this work, we report synthesis and rheology of an interesting structured fluid based on the self-assembly of amphiphilic dendrons and wormlike micelles. Two amphiphilic dendrons were synthesized by the combination of aliphatic chains and polar dendritic heads. They showed different degrees of hydrophobicity and formed micelles in aqueous solution at critical micelle concentrations (CMC) of 25 and 125 ppm. The dendrons were soluble in water up to a concentration of approximately 1200 ppm, and produced no measurable increase in the viscosity of the solvent. The rheology of solutions of mixtures of each dendron with cetyltrimethylammonium p-toluenesulfonate (CTAT, a cationic surfactant) was characterized in simple shear flow. In the concentration range in which CTAT forms semidilute solutions of wormlike micelles, dendron addition produced a substantial synergy in zero-shear rate viscosity. Parallel-plate oscillatory shear measurements demonstrated that the CTAT/dendron mixtures are significantly more elastic than CTAT solutions. The viscosity synergy occurs at dendron concentrations lower than their CMC, and it is stronger for the more hydrophobic dendron. This suggests that the interactions between dendrons and wormlike micelles are basically hydrophobic, which implies attachment of dendron micelles to wormlike CTAT micelles in a manner similar to micellization of surfactants on polyelectrolytes.

Schizophrenia treatment in the developing world: an interregional and multinational cost-effectiveness analysis.

OBJECTIVE: Schizophrenia is a highly disabling disease and is costly to treat. We set out to establish what are the most cost-effective interventions applicable to developing regions and countries. METHODS: Analysis was undertaken at the level of three WHO subregions spanning the Americas, Africa and South-East Asia, and subsequently in three member states (Chile, Nigeria and Sri Lanka). A state transition model was used to estimate the population-level health impact of older and newer antipsychotic drugs, alone or in combination with psychosocial intervention. Total population-level costs (in international dollars or local currencies) and effectiveness (measured in disability-adjusted life years averted) were combined to form cost-effectiveness ratios. FINDINGS: The most cost-effective interventions were those using older antipsychotic drugs combined with psychosocial treatment, delivered via a community-based service model (I$ 2350-7158 per disability-adjusted life year averted across the three subregions, I$ 1670-3400 following country-level contextualisation within each of these subregions). The relative cost-effectiveness of interventions making use of newer, "atypical" antipsychotic drugs is estimated to be much less favourable. CONCLUSION: By moving to a community-based service model and selecting efficient treatment options, the cost of substantially increasing treatment coverage is not high (less than I$ 1 investment per capita). Taken together with other priority-setting criteria such as disease severity, vulnerability and human rights protection, this study suggests that a great deal more could be done for persons and families living under the spectre of this disorder.

Electrochemical study of a dendritic family at the water/1,2-dichloroethane interface.

The transfer of six dendritric molecules, DMs, across the water/1,2-dichloroethane interface was investigated using cyclic voltammetry. From the variation of peak potential with pH, two different mechanisms of transfer were postulated depending on the nature of the molecules. Voltammetric parameters were employed to evaluate the hydrophilic/hydrophobic character and calculate the acid dissociation constant of these molecules. The results were explained taking into account the nature and multiplicity of functional surface groups.

Estudio geotécnico de la cuenca de la ciudad de La Paz y la aplicación en pantallas de retención tipo "pilar empotrado"

El sitio de La Paz presenta graves problemas fisicos que son particularmente debido a los riesgos naturales que limitan las posibilidades de extension de la urbanizacion. Por otra parte, el crecimiento de La Paz tropieza con condiciones muy desfavorables pendientes fuertes, relieve entrecortado, erosión torrencial muy activa. Sin pretender ser el unico, el presente trabajo propone un sistema de contención llamado "pilar empotrado" que por sus bondades resulta un método eficaz para paliar los problemas de rehabilitación urbana de la ciudad. En los primeros capitulos se hace hincapie acerca de la geología y geotecnia del sitio de La Paz, debido a la gran diversidad de los suelos de la cuenca y en especial de sus discimiles propiedades físico-mecánicas. En los capitulos cuatro y cinco se hace un análisis de la teoría de empujes desde los métodos clásicos a los experimentales mas modernos. Y en los últimos capitulos se analiza los costos comparativos con una pantalla de retención de Ho Ao y se comprueba que el sistema puede ser ventajoso.