Design and synthesis of new dendrons for biomedical applications

Dendrons are excellent multifunctional platforms for many different applications. In particular, the development of multivalent molecular nanostructures, with a well-defined size and shape, has an enormous interest in the field of biomedicine1. Great efforts are being made in the design of new dendritic structures since their precise structure, multivalency and the possibility of functionalizing their terminal groups makes them a useful tool for certain applications. Recently, a new type of dendrimer (dendron) was designed and synthesized based on the iterative coupling of 2,2-Bis (AminoAlkyl) Propanamide units (BAPAD)2,3. This represents a versatile model when incorporating certain functionalities in its structure. However, the synthesis of these new dendritics structures was addressed using 3,3'-dichloropivalic acid as the starting substrate, which translated in the superficial amino groups of these new macromolecule being in relative positions 1,3. For certain applications, where the functionalization of the dendritics structures on its surface requires the introduction of relatively bulky groups, this may result in a problem of reactivity given the steric congestion. Here, we present the design and synthesis of new dendrons where the surface amino groups are in relative positions 1,7. Formally, it involves the preparation of dendrons with longer arms that can minimize the problems of steric congestion. These dendrons can be designed to modify surfaces superficially thanks to the versatility of the carboxylic acid which can be modified to introtoduce in the focal poin diferent functional groups (azido, amido, thiol, etc…).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Managing with (fluorescent)-biomimetic dendrimers

Dendrimers that are modified through their peripheral groups have been employed for many biomedical purposes. Diagnosis via specific interactions with target proteins is one of the objectives that has been given more attention. In this way, we have been developing different methodologies for the detection of immunoglobulins, as an in vitro method for the diagnosis of allergic reactions to drugs [1], [2]. Specific cell interactions of surfaces grafted dendrimers have been applied to the study of cell adhesion. We have studied also the application of dendrimer-based uneven nanopatterns to evaluate the local RGD surface density effects on cell adhesion, as bioactive substrates to evaluate the impact of the RGD local surface density on the chondrogenic induction of adult human mesenchymal stem cells [3], [4], [5]. Although the use of PAMAM dendrimer has allowed us to develop useful methods for this purpose, for certain objectives we have required the development of new dendrimeric models. We have developed a new approach for the production of allaliphatic polyamide dendrimers (BAPAD) by iterative 3,3′-diaminopivalic acid connections as building blocks for dendrimer construction. These dendrimers were studied in explicit solvent by atomistic forcefield-based molecular dynamics to characterize structural properties such as shape, radius and monomer distribution [6]. Fluorescent labeling of these biomimetic dendrimers has been used as a tool to study their interaction with cells.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Diseño y síntesis de nuevos dendrímeros y dendrones. Aplicaciones en regeneración tisular

Los dendrímeros han generado un enorme interés debido a su particular estructura ramificada y su multivalencia. La extensa investigación que se ha llevado a cabo sobre este tipo de macromoléculas ha demostrado la naturaleza multidisciplinar de las mismas, describiéndose sus aplicaciones en química, física, biología, medicina o en la mejora de nuevos materiales. En particular, el desarrollo de nanoestructuras moleculares multivalentes, con tamaño y forma bien definida, tiene un enorme interés en el campo de la biomedicina. El empleo de estos sistemas como plataformas multifuncionales en el estudio de las reacciones adversas a fármacos RAF (alergia a antibióticos betalactámicos en particular) ha quedado ampliamente demostrado. La síntesis de una serie de Antígenos Dendriméricos (DeAn) y su anclaje sobre distintas superficies, ha permitido avanzar en el estudio del diagnóstico clínico de la alergia a antibióticos betalactámicos mediante la técnica de Radio Allergo Sorbent Test (RAST). Recientemente, se han iniciado trabajos enfocados hacia la aplicación de estas macromoléculas en otra área de la biomedicina. En particular, se han realizado estudios sobre los procesos de adhesión celular enfocados al empleo de células madres mesenquimales (MSC) en regeneración tisular. La incorporación de patrones de reconocimiento celular basados en el péptido RGD (Arginina-Glicina-Ácido aspártico) a estructuras dendriméricas provoca un aumento de la adhesión celular in vitro, observando no sólo un aumento de la adhesión de las células a la superficie sino que la eficacia de esta adhesión está relacionada con la forma en que el dendrímero presenta el tripéptido a la célula. El empleo de plataformas sólidas que contengan las estructuras dendriméricas funcionalizadas puede ser crucial para determinadas aplicaciones en regeneración tisular.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Diseño y síntesis de nuevos dendrímeros

Los dendrímeros son excelentes plataformas multifuncionales para una gran cantidad de diferentes aplicaciones. En particular, el desarrollo de nanoestructuras moleculares multivalentes, con tamaño y forma bien definida, tiene un enorme interés en el campo de la biomedicina.1 Actualmente resulta necesario poder obtener dendrímeros multifuncionales, con estructuras muy precisas, diseñados específicamente para determinadas aplicaciones. Con las herramientas adecuadas se pueden incluir en la estructura del dendrímero los grupos requeridos en posiciones específicas del mismo. Recientemente se diseñó y sintetizó un nuevo tipo de dendrímero (dendrón) basado en el acoplamiento iterativo de unidades de 2,2-Bis(aminoalquil)propanamidas (BAPAD).2,3 Este representa un modelo versátil a la hora de incorporar determinadas funcionalidades en su estructura. Sin embargo, la síntesis de este nuevo dendrímero se abordó utilizando como sustrato de partida el ácido 3,3´-dicloropiválico. Los grupos amino superficiales de esta nueva macromolécula se encuentran en posiciones relativas 1,3, lo que para determinadas aplicaciones, donde la funcionalización del dendrímero en su superficie requiere introducir grupos relativamente voluminosos, supone un problema de reactividad dado la congestión estérica que se provoca. Se presenta el diseño y la síntesis de nuevos dendrímeros donde los grupos amino superficiales, necesarios para determinadas aplicaciones, queden en posiciones relativas 1,7. Formalmente implica la preparación de dendrímeros con brazos más largos que podrán minimizar los problemas de congestión estérica.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Slightly congested amino terminal dendrimers. The synthesis of amide-based stable structures on a large scale

Nowadays, amino terminal dendrimers are appealing materials for biological applications due to their multivalence and the versatile conjugation of the amino groups. However, the high reactivity of these terminal groups can be decreased by steric hindrance, limiting their possible bioapplications. Herein, we report the divergent synthesis of slightly sterically hindered amino terminal polyamide dendrimers. A simple and unique AB2 scaffold has been chosen to build the dendritic structures, where only amide bonds have been used as the connecting unit. The 1–7 relative positions of the amino groups in the AB2 monomers avoid the steric congestion of the macromolecules, allowing the construction of robust dendrimers up to the fifth generation. The construction of the dendrimers is based on two well-established reactions, using simple and cheap reactants, with yields above 90% on a gram scale and easy purification procedures. This synthetic methodology constitutes an easy and efficient way for the preparation of stable and aqueous soluble dendrimers on a gram scale, representing a substantial improvement over the synthesis of this kind of aliphatic polyamide amino terminal dendrimer. The prepared structures were completely characterized and evaluated by size exclusion chromatography, diffusion ordered spectroscopy and atomic force microscopy to determine their size. Molecular dynamics simulations were also carried out and the values obtained were consistent with the experimentally determined values.This work was supported by the Ministerio de Ciencia y Educación (PID2019-104293GB-I00), Ministerio de Ciencia e Innovación (Proyectos de I+D+I “Programación Conjunta Internacional”), EuroNanoMed 2019 (PCI2019-111825-2), Instituto de Salud Carlos III (ISCIII; RETIC ARADYAL RD16/0006/0012) and Junta de Andalucía and Universidad de Málaga (UMA18-FEDERJA-007). We gratefully acknowledge the computer resources provided by the SCBI (Supercomputing and Bioinformatics Center) of the University of Malaga. NMR experiments have been performed in the ICTS “NANBIOSIS”, in the U28 Unit at the Andalusian Centre for Nanomedicine and Biotechnology (BIONAND)

Diseño y síntesis de nuevos dendrones para aplicaciones biomédicas

Los dendrímeros han sido empleados en una gran variedad de aplicaciones, entre las que destacan las del campo de la biomedicina. Estas macromoléculas multivalentes ofrecen la posibilidad de incorporar múltiples funcionalidades en partes precisas de su estructura y muestran grandes expectativas para su aplicación en nanomedicina.1 Sin embargo, es crucial desarrollar dendrímeros multifuncionales con estructuras bien definidas y con el mismo nivel de precisión que las moléculas biológicas. Un requisito clave para producir un nuevo material dendrimérico es el desarrollo de nuevos esquemas sintéticos que puedan ofrecer el grado requerido de precisión estructural.2 Recientemente se ha presentado una nueva clase de dendrímero basado en unidades de 2,2-Bis(Aminoalquil) PropanAmiDas denominado BAPAD. El enfoque sintético empleado consiste en el empleo del ácido 3,3’-diazidopiválico como unidad de crecimiento, empleando el ácido carboxílico en la generación de nuevos enlaces amidas.3 El control de la síntesis de los correspondientes dendrones nos ha permitido el diseño de una serie de estructuras dendriméricas con funcionalidades específicas para determinadas aplicaciones. Estos dendrones han sido empleados en estudios de maduración de células dendríticas.4 En esta comunicación se presenta el diseño de nuevos dendrones para aplicaciones biológicas.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Diseño de dendrímeros amino-terminales basados en enlaces tipo amidas. Estructuras con menor repulsión estérica y síntesis a gran escala

La estructura ramificada y la elevada multivalencia que presentan los dendrímeros los convierten en excelentes compuestos con potenciales aplicaciones en el campo de la biomedicina. En concreto, los dendrímeros con grupos amino terminales han resultado ser una herramienta muy útil en este campo gracias a la gran versatilidad que presentan. Nuestro grupo de investigación tiene una gran experiencia en el diseño y síntesis de dendrímeros amino-terminales [1]. La inserción de estas unidades dendriméricas en complejos luminiscentes nos ha permitido obtener macromoléculas con excelentes propiedades como biomarcadores [2]. Además, la modificación superficial de implantes orales de titanio con este tipo de estructuras ha contribuido a mejorar la biocompatibilidad de los mismos [3]. En esta comunicación presentamos una nueva familia de dendrímeros de poliamida amino-terminales. Su diseño implica una mayor separación entre los grupos terminales, generando así estructuras con menor congestión estérica. La metodología sintética se basa en procedimientos bien establecidos, utilizando reactivos sencillos y económicos, con rendimientos superiores al 90%, en escala de gramos y evitando procedimientos de purificación tediosos [4

Adaptation and initial psychometric study of the anxiety and fear of COVID-19 scale in the United Kingdom population

Objective: The aim of the study was the initial psychometric study to validate the anxiety and fear of COVID-19 (AMICO) assessment scale in the general population of the United Kingdom population. Materials and methods: A descriptive, cross-sectional, psychometric validation and descriptive study was conducted, performing univariate and bivariate analyses, as well as exploratory and confirmatory factor analysis. Results: The sample was 658 people living in the United Kingdom over 16 years. Of the total, 80.5% were female, with a mean age of 48.25 years (SD = 14.861). A mean score for the AMICO scale of 4.85 (SD = 2.398) was obtained, with a range of scores from 1 to 10. The study of percentiles and quartiles allowed for the identification of three proposed levels of anxiety. Conclusion: The AMICO_UK scale is reliable to measure the presence of anxiety and fear related to the COVID-19 disease in the United Kingdom population. The majority of the United Kingdom population presented low levels of anxiety and fear at the time the scale was administeredFunding for open access charge: University of Huelva / CBUA

Management Pearls on the Treatment of Actinic Keratoses and Field Cancerization

Field cancerization (FC) is a chronic disease involving multiple clinical and subclinical actinic keratoses (AK) on large photo-exposed surfaces with multifocal areas of dysplasia and precancerous changes. Patients and treatment must be properly monitored and managed to avoid aggravation and progression of the disease. Management of actinic keratoses includes lesion-directed treatments, such as cryotherapy and field-directed therapies. Field-directed therapies may have the potential to address subclinical damage, reduce AK recurrence rates and potentially reduce the risk of squamous cell carcinoma development. Multiple studies have demonstrated the efficacy of field-directed treatments, including 5-fluorouracil, photodynamic therapy, imiquimod, chemical exfoliation with trichloroacetic acid and diclofenac gel, for multiple AK and FC. The choice of therapy should be based on multiple factors, such as efficacy, tolerability, patient risk profile, costs and cosmetic results. Management of AK includes not only treatment but also prevention. Medical devices, such as sunscreens containing liposome-encapsulated DNA repair enzymes, can repair DNA damage associated with chronic UV radiation and reduce the number of new AK lesions. Here we provide therapeutic pearls and expert opinions on the treatment of AK and FC (as monotherapy or in combination) with the overall aim to achieve better, faster, and well-tolerated clinical responses

Anxiety and fear of COVID-19 in the UK general population: A cross-sectional study

There is still a generalized feeling of uncertainty in the population due to the coronavirus disease 2019 (COVID-19) pandemic, as restrictions on daily routines and social contact, accompanied by a large number of infections, negatively affect different areas of people’s lives and, therefore, their mental health. The aim of the present study was to assess the presence of anxiety and fear of COVID-19 in the general UK population, using the Anxiety and Fear to COVID-19 Assessment Scale (Ansiedad y Miedo al COVID-19) (AMICO) scale. A descriptive, cross-sectional study based on a questionnaire was conducted in a sample of the UK general population in 2021. Socio-demographic and employment variables were included. The AMICO scale was included to measure fear and anxiety about COVID-19. The relationship between variables was studied with a categorical regression analysis. In general, participants regarded themselves as well-informed about the pandemic, although 62.6% had only received 1 dose of the vaccine. Regarding the AMICO scale the total score was 4.85 (out of 10; standard deviation 2.398). Women showed higher scores for the AMICO than men. The bivariate analysis revealed statistically significant differences in relation to self-confidence, amount of information received, and vaccination variables as related to the mean AMICO scores. An average level of anxiety and fear of COVID-19 is shown in the general UK population, which is lower than most of the studies that assessed the impact of the pandemic on the general population