Hybrid thermoresponsive nanoparticles containing drug nanocrystals for NIR-triggered remote release

The on-demand administration of anaesthetic drugs can be a promising alternative for chronic pain management. To further improve the efficacy of drug delivery vectors, high drug loadings combined with a spatiotemporal control on the release can not only relief the pain according to patient''s needs, but also improve the drawbacks of conventional burst release delivery systems. In this study, a hybrid nanomaterial was developed by loading bupivacaine nanocrystals (BNCs) into oligo(ethylene glycol) methyl ether methacrylate (OEGMA)-based thermoresponsive nanogels and coupling them to NIR-absorbing biodegradable copper sulphide nanoparticles (CuS NPs). Those CuS NPs were surface modified with polyelectrolytes using layer-by-layer techniques to be efficiently attached to the surface of nanogels by means of supramolecular interactions. The encapsulation of bupivacaine in the form of nanocrystals allowed to achieve CuS@BNC-nanogels having drug loadings as high as 65.5 wt%. The nanocrystals acted as longlasting drug reservoirs, leading to an elevated localized drug content, which was useful for their application in prolonged pain relief. The CuS@BNC-nanogels exhibited favorable photothermal transducing properties upon NIR-light irradiation. The photothermal effect granted by the CuS NPs triggered the nano-crystallized drug release to be boosted by the collapse of the thermoresponsive nanogels upon heating. Remote control was achieved for on-demand release at a specific time and place, indicating their potential use as an externally activated triggerable drug-delivery system. Furthermore, cell viability tests and flow cytometry analysis were performed showing satisfactory cytocompatibility in the dose-ranging study having a subcytotoxic concentration of 0.05 mg/mL for CuS@BNC-nanogels. This remotely activated nanoplatform is a promising strategy for long-lasting controlled analgesia and a potential alternative for clinical pain management. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND licens

Thin Films of Self-Assembled Quantum Dots, Surfactants and Polymers

[ES]El autoensamblaje se ha establecido como una técnica muy utilizada en la preparación de diferentes tipos de nanomateriales. En esta tesis se utilizan el tensioactivo geminal dibromuro de etil-bis (dimetil octadecil ammonio) (18-2-18), y el polímero poli(anhídrido maleico-alt-1-octadeceno) (PMAO), con el objetivo de controlar el autoensamblaje de Quantum Dots (QDs) de CdSe sobre sólidos. Se ha utilizado la técnica de Langmuir-Blodgett (LB) para la fabricación de las películas, y se han estudiado las propiedades de las mismas en la interfase aire-agua. Se diseñaron dos metodologías de deposición, la primera consiste en preparar una monocapa mixta formada por el polímero o el tensioactivo y los QDs que posteriormente se deposita sobre el sólido mediante la técnica de LB, co-spreading. La segunda, consistió en preparar una primera película LB del polímero o del tensioactivo sobre la que después se depositaron los QDs, bicapa. Se han utilizado diversas técnicas para la caracterización de las películas, como son Microscopía de Fuerza Atómica (AFM), Microscopía Electrónica de Barrido (SEM), Microscopía Electrónica de Transmisión (TEM) y Elipsometría. Con el objetivo de estudiar la emisión de fluorescencia de las películas de QDs y los procesos involucrados en su dinámica de fluorescencia, se utilizó la técnica de microscopía de tiempos de vida de fluorescencia (FLIM). Para estudiar el mecanismo, las fuerzas involucradas y los factores que afectan a la organización de los nanomateriales en la interfase, se abordó la investigación de las propiedades reológicas y estructurales, de las moléculas de PMAO y tensioactivo geminal que recubren el sustrato, y de la película de QDs con la técnica de Microbalanza de Cristal de Cuarzo (QCM), que ha permitido conocer también la cantidad de material adsorbido y su cinética de adsorción

Terapia fototérmica mediante un fotosensibilizador intracelular: La Croconaina

El mundo de la nanomedicina aplicada en el tratamiento de cáncer está creciendo muy rápidamente. De hecho, a lo largo de las últimas décadas se han diseñado muchas nanoterapias como alternativa o mejora de las terapias ya existentes contra el cáncer y contra las enfermedades infecciosas principalmente. Una de ellas, la terapia fototérmica, tiene como finalidad el aprovechar el calor emitido por algunos agentes fototérmicos al absorber luz en el infrarrojo cercano (NIR), para poder así destruir células cancerígenas por ablación térmica. Por otro lado, la croconaina es una molécula ya estudiada como agente fotosensibilizante por su dualidad estructural y de absorbancia frente a cambios de pH, presentando una importante absorción en 800 nm cuando se encuentra en medio ácido (pH 5). Esta característica resulta interesante para una terapia fototérmica más segura y efectiva que solo permite la inactivación de las células cuando se encuentra en su interior (ya que algunos compartimentos intracelulares, endosomas, son ácidos) pues el medio extracelular es ligeramente alcalino. En este trabajo se presenta la compleja síntesis de la croconaina incluida en un macrociclo para evitar su posterior agregación y posible quenching de absorbancia. Asimismo, se muestran nuevas encapsulaciones de croconaina que se han llevado a cabo tanto en nanopartículas poliméricas, mediante nanoprecipitación o doble emulsión, como en niosomas. Estas innovadoras encapsulaciones exhiben beneficios frente a los liposomas ya utilizados para encapsular dicha molécula, pues tienen una mayor estabilidad y reducidos costes. También se resalta la dificultad de lograr el comportamiento dual en medio ácido y alcalino de las nanopartículas cargadas de croconaina, debido a la baja difusión del medio en la nanopartícula, impidiendo su cambio de estructura, o bien de la posible baja concentración de molécula encapsulada dentro de las nanopartículas. Todas las síntesis químicas se han caracterizado mediante resonancia magnética nuclear (RMN), y todas las síntesis de nanopartículas se han caracterizado mediante técnicas de visualización ya sea mediante microscopía electrónica de barrido (SEM) o mediante microscopía electrónica de transmisión (TEM). Por otro lado, el comportamiento fototérmico de la croconaina y las nanopartículas se ha evaluado mediante ensayo espectroscópico de absorción UV/VIS y mediante la monitorización de la temperatura al irradiar las muestras con un láser de 808 nm. Finalmente, se ha comprobado la baja citotoxicidad de la molécula en cultivos celulares de monocitos, y su imposible aplicación, a las dosis estudiadas y con las irradiancias usadas, como agente de terapia fototérmica para la ablación de Estafilococos Aureus en infecciones a causa de la alta resistencia térmica de dicha cepa bacteriana

New insights in osteoarthritis diagnosis and treatment: Nano-strategies for an improved disease management

Osteoarthritis (OA) is a common chronic joint pathology that has become a predominant cause of disability worldwide. Even though the origin and evolution of OA rely on different factors that are not yet elucidated nor understood, the development of novel strategies to treat OA has emerged in the last years. Cartilage degradation is the main hallmark of the pathology though alterations in bone and synovial inflammation, among other comorbidities, are also involved during OA progression. From a molecular point of view, a vast amount of signaling pathways are implicated in the progression of the disease, opening up a wide plethora of targets to attenuate or even halt OA. The main purpose of this review is to shed light on the recent strategies published based on nanotechnology for the early diagnosis of the disease as well as the most promising nano-enabling therapeutic approaches validated in preclinical models. To address the clinical issue, the key pathways involved in OA initiation and progression are described as the main potential targets for OA prevention and early treatment. Furthermore, an overview of current therapeutic strategies is depicted. Finally, to solve the drawbacks of current treatments, nanobiomedicine has shown demonstrated benefits when using drug delivery systems compared with the administration of the equivalent doses of the free drugs and the potential of disease-modifying OA drugs when using nanosystems. We anticipate that the development of smart and specific bioresponsive and biocompatible nanosystems will provide a solid and promising basis for effective OA early diagnosis and treatment. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacemen

Langmuir‐Blodgett Methodology: A Versatile Technique to Build 2D Material Films

The Langmuir‐Blodgett (LB) methodology is based on the transfer process of a monolayer adsorbed at the water interface, Langmuir film, from the air‐water interface onto solids by vertical dipping of the substrate immersed on the subphase. The technique allows the continuous variation of material density, packing, and arrangement by compressing or expanding the film by using barriers. Consequently, it provides the possibility of preparing films with the control of interparticle distance necessary to exploit the two‐dimensional (2D) materials in technological applications. In this chapter, we present some examples of fabrication of thin films of 2D material using this methodology. We show some methodologies based on this technique to build thin films of graphene oxides, Quantum Dots (QDs), and silver nanowires

Diseño y desarrollo de un vehículo híbrido multipropósito y ligero para servicios urbanos

La necesidad de reducir las emisiones de CO2 ha obligado a los fabricantes de automóviles a mejorar el consumo de combustible de sus vehículos y a desarrollar arquitecturas híbridas de propulsión, tanto gasolina – eléctrico como con pila de combustible. Aunque la configuración de este tipo de vehículos híbridos puede ser similar a la de los tradicionales de motor térmico, nuevos componentes implican nuevas posibilidades de reconfigurar el sistema de propulsión, diferentes distribuciones de volúmenes y pesos, de manera que se puede mejorar su dinámica y sus prestaciones. El origen del proyecto presentado es la respuesta del INSIA a las necesidades de una empresa de equipamiento urbano de tener un vehículo híbrido para aplicaciones ligeras. Está diseñado para equipar diferentes configuraciones híbridas, tanto de gasolina como de pila de combustible y, por petición del cliente, dispone de paneles solares en el techo de la cabina y de la caja de carga

Encapsulation of Large-Size Plasmids in PLGA Nanoparticles for Gene Editing: Comparison of Three Different Synthesis Methods

The development of new gene-editing technologies has fostered the need for efficient and safe vectors capable of encapsulating large nucleic acids. In this work we evaluate the synthesis of large-size plasmid-loaded PLGA nanoparticles by double emulsion (considering batch ultrasound and microfluidics-assisted methodologies) and magnetic stirring-based nanoprecipitation synthesis methods. For this purpose, we characterized the nanoparticles and compared the results between the different synthesis processes in terms of encapsulation efficiency, morphology, particle size, polydispersity, zeta potential and structural integrity of loaded pDNA. Our results demonstrate particular sensibility of large pDNA for shear and mechanical stress degradation during double emulsion, the nanoprecipitation method being the only one that preserved plasmid integrity. However, plasmid-loaded PLGA nanoparticles synthesized by nanoprecipitation did not show cell expression in vitro, possibly due to the slow release profile observed in our experimental conditions. Strong electrostatic interactions between the large plasmid and the cationic PLGA used for this synthesis may underlie this release kinetics. Overall, none of the methods evaluated satisfied all the requirements for an efficient non-viral vector when applied to large-size plasmid encapsulation. Further optimization or alternative synthesis methods are thus in current need to adapt PLGA nanoparticles as delivery vectors for gene editing therapeutic technologies

Diseño de encuestas de evaluación de la percepción del alumno sobre la utilidad de las diferentes actividades formativas en la adquisición de competencias

Memoria ID12-0195. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2012-2013

Nanoengineering palladium plasmonic Nanosheets inside polymer nanospheres for photothermal therapy and targeted drug delivery

The incorporation of plasmonic nanoconstructs in biodegradable polymeric nanoparticles (NPs), together with therapeutic drugs in a controlled procedure is of interest for different applications in Nanomedicine. Advanced hybrid nanomaterials can be engineered by combining the in situ formation of plasmonic palladium nanosheets (NSs) and the proper ionic nature of the encapsulated drug. This study presents a new procedure to synthesize hybrid nanostructures by a Pickering double emulsion. Anisotropic palladium (Pd) NSs with unique near-infrared (NIR)-optical properties can be assembled within a poly lactic-co-glycolic acid matrix of REF: RTI2018-099019-A-I00. R.A. acknowledges funding from the Spanish MICINN (project grant PID2019-104739GB-100/AEI/10.13039/501100011033), from the Government of Aragon (project DGA E13-20R), and from the European Union H2020 program “ESTEEM3” (No. 823717).Peer reviewe

Light activated pulsatile drug delivery for prolonged peripheral nerve block

Regional anesthesia is widely used in peripheral nerve block and in neuraxial anesthesia to reduce anesthetics systemic side effects and shorten recovery times. However, when applied as a single injection (e.g., peripheral nerve block) it is limited by the duration of its effect. Herein, we develop a thermoresponsive nanogel based on poly(oligoethylene glycol methacrylate) containing the long-lasting anesthetic bupivacaine, which can be externally activated by using near-infrared light due to the photothermal properties of hollow gold nanoparticles embedded in the nanogel which facilitate its phase transition, triggering drug release at a controlled temperature above body temperature. Bupivacaine in vitro release can be repeatedly triggered to achieve a controlled pulsatile release of the drug due to the reversible nature of the thermosensitive nanogel, achieving a spatio-temporal control of the release. In vivo sciatic nerve block demonstrates that whereas the administered dose of free bupivacaine produces sensory block and impaired motor function for 2 h, the equivalent bupivacaine dose included in the developed release system can significantly prolong its neurobehavioral anesthetic effect for over 6 h. This release system can also be reactivated multiple times by subsequent irradiation cycles without observing detrimental toxicity in the infiltrated tissues.Financial support from the ERC Consolidator Grant program (ERC-2013-CoG-614715, NANOHEDONISM) is gratefully acknowledge. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III with the assistance of the European Regional Development Fund. We acknowledge the LMA-INA (University of Zaragoza, Spain), the Histopathology Unit from CNIO (Spain), and Cell Culture, Cell Separation and Flow Cytometry, Animal Care and Pathological Anatomy Core Units from IACS/IIS Aragon for their instruments and expertise. We would like to thank Dr. Elena Tapia, Dr. Jorge Palacio, Dr. Cristina Pastor and Dr. Eduardo Romanos for helpful advice in the in vivo studies. S.G-S. and G.L. acknowledge the support from the FPI program (BES-2015-073735 and PRE2018-085769, Spanish Ministry of Science, Innovation and Universities). G.M. gratefully acknowledges the support from the Miguel Servet Program (MS19/00092; Instituto de Salud Carlos III).Peer reviewe