Enhancing anticancer cytotoxicity through bimodal drug delivery from ultrasmall Zr MOF nanoparticles

Dual delivery of dichloroacetate and 5-fluorouracil from Zr MOFs into cancer cells is found to enhance in vitro cytotoxicity. Tuning particle size and, more significantly, surface chemistry, further improves cytotoxicity by promoting caveolae-mediated endocytosis and cytosolic cargo delivery

Image-guided therapy using maghemite-MOF nanovectors

Advances in nanotechnology offer the possibility of tailored delivery of therapeutics with real-time imaging of disease. In this issue of Chem, Steunou and co-workers amalgamate the powerful MRI properties of ultra-small paramagnetic iron oxides with the excellent drug-delivery capabilities of metal-organic frameworks to produce theranostic nanoparticulate devices for cancer treatment and imaging

Advances in solar-pumped laser efficiency and brightness

Advances in both solar-pumped laser efficiency and brightness are herein presented. Several solar laser prototypes with both end-side-pumping and side-pumping configurations were studied and developed to efficiently pump small diameter Nd:YAG laser rods, leading to substantial increase in solar laser collection efficiency and brightness, which have gained international recognitions. All the design parameters were optimized in ZEMAX© non-sequential ray-tracing software. LASCAD© laser cavity analysis software was then used to optimize the laser resonator parameters. Based on the numerically optimization of the solar laser system, the solar laser prototypes were designed and built in Lisbon. Solar energy collection and concentration were achieved through the PROMES-CNRS heliostat-parabolic system, NOVA Fresnel lens system, and the recently new NOVA heliostat-parabolic system. Measurements of the solar input / laser output performance, beam quality M2 factors, and laser beam profiles for both multimode and fundamental mode regime were performed and compared with that of the numerical results. 13.9 W/m2 solar laser collection efficiency was achieved in 2013, through PROMES heliostatparabolic mirror system, by end-side-pumping a 5 mm diameter, 25 mm length Nd:YAG laser rod. This result was further increased to 21.1 W/m2, in 2015, within the same solar facility. In 2016, 25 W/m2 collection efficiency was reported, by end-side-pumping a thinner laser rod through NOVA heliostat-parabolic mirror system. In addition to the enhancement of solar laser collection efficiency, the thermal performance of end-side-pumped solar laser was also substantially improved. In 2017, record solar laser collection efficiency of 31.5 W/m2 was reported by end-sidepumping a 4 mm diameter, 35 mm length Nd:YAG laser rod in PROMES-CNRS heliostatparabolic mirror system. Also, record slope efficiency of 8.9% was achieved. A substantial progress in solar laser beam brightness with Fresnel lens was reported in 2013, through the first TEM00-mode solar laser. 1.9 W solar laser brightness was registered, being 6.6 times more than the previous record. The adoption of an asymmetric laser resonator, for maximum extraction of TEM00-mode solar laser, was also essential for improving significantly the solar laser brightness. By side-pumping a 3 mm diameter, 30 mm length Nd:YAG rod with a double-stage rectangular light guide / 2D-CPC concentrator, 4.0 W solar laser brightness was reported in 2015, doubling the previous record with Fresnel lens. TEM00-mode solar laser collection efficiency of 4.0 W/m2 was obtained by side-pumping a Nd:YAG grooved rod in 2016. Most recently, by endside-pumping a 4 mm diameter, 35 mm length, Nd:YAG rod, the TEM00 mode solar laser collection efficiency was almost doubled, reaching 7.9 W/m2. Record-high solar laser brightness of 6.5 W was also achieved. Advances in solar laser beam stability were also achieved by developing sculptured twisted light guides for efficient uniform redistribution of pump light into a thin and long laser rod. In addition to this, we were also able to demonstrate the first emission of doughnut shaped solar laser beam, which may widen the applications areas of solar-pumped lasers. The research efforts performed during this work for enhancing both solar laser efficiency and beam brightness are explained. Experimental results are discussed and future suggestions are proposed

People with disabilities and Cultural Tourism: an unfinished reality

[Abstract] At the beginning of this century speak of the existence of the Right to Leisure should not be something surprising since this law is a social achievement recognized in many important statements by international bodies. In these early twenty-first century, Leisure being increasingly recognized as an element of the quality of life of societies and individuals. It can even be said that there has been an institutional recognition of this phenomenon, and public authorities are involved in economic and political issues, management of facilities, services, advertising, etc., of different leisure environments (culture, sports, tourism and recreation). It is part of the defense and claim the Right to Leisure since this is a right recognized in the Third Generation of Human Rights and as such are innate attributes to humans, ie , born to him and which are inseparable from its status person. Based on these ideas, it would be necessary to justify the right to the tourism and cultural tourism by people with disabilities, but the reality is that this is not always the case, since this right is not always guaranteed to all citizens.[Resumen] Las personas con discapacidad y el Turismo Cultural: una realidad inconclusa. Al inicio de este siglo XXI hablar de la existencia del Derecho al Ocio no debiera ser algo sorprendente puesto que, este derecho, es una conquista social reconocida en numerosas e importantes declaraciones de organismos internacionales. En estos inicios del siglo XXI, el Ocio está siendo reconocido cada vez más como un elemento de la calidad de vida de las sociedades y de los individuos. Incluso puede decirse que se ha producido un reconocimiento institucional de este fenómeno, y los poderes públicos están implicados en cuestiones económicas y políticas, gestión de equipamientos, servicios, publicidad, etc., de los diferentes entornos de ocio (cultura, deporte, turismo y recreación). Se parte de la defensa y reivindicación del Derecho al Ocio ya que éste es un derecho reconocido dentro de la Tercera Generación de Derechos Humanos y como tales son atributos innatos al ser humano, es decir, que nacen con él y que son inseparables de su condición de persona. Partiendo de estas ideas, no sería necesario justificar el derecho al disfrute del turismo y del turismo cultural por parte de las personas con discapacidad, pero la realidad demuestra que esto no siempre es así, puesto que este derecho no siempre está garantizado para todos los ciudadanos

Application of zirconium MOFs in drug delivery and biomedicine

Nanoparticulate metal-organic frameworks (MOFs) have the requisite high storage capacities, tailorable structures, ease of functionalisation, and excellent biocompatibilities for application as nanoscale drug delivery devices (DDSs). Zirconium MOFs in particular combine optimal stability towards hydrolysis and postsynthetic modification with low toxicity, and so are particularly suited for biological applications. This review covers the use of Zr MOFs as DDSs with focus on the different physical properties that makes them attractive for use. The various methods for modifying the surfaces of Zr MOFs are described with pertinent examples of the resulting enhancements in aqueous stability, colloidal dispersion, and stimuli-responsive drug release. The in vitro and in vivo application of Zr MOFs for photodynamic therapy and drug delivery are discussed with respect to the structural features of the MOFs and their surface functionality, and perspectives on their future applications and analogous hafnium MOFs are given

Menores extranjeros no acompañados. La situación en España

The arrival to Spain of foreigners under age, that travel alone or with adults that do not have legal responsibility on them, has become a new and significant migratory strategy. Law attempts to answer to this reality in an intent of equilibrium between the interests that protects Immigration Law and the interest of the child, axis of the Child Care Law. There is no doubt that interest of child should prevail –also this of the foreigner- because, according to the Convention of United Nations, it is over any other interest. In the following pages both the state of the question and the recent position of the Courts are pointed out.La llegada a España de extranjeros menores de edad, que viajan solos o con adultos que no tienen responsabilidad sobre ellos, se ha convertido en una nueva y significativa estrategia migratoria. El derecho trata de responder a esta realidad en un intento de equilibrio entre los intereses que protege el derecho de extranjería y el interés del menor, eje del derecho de protección de menores. No hay duda de que debe prevalecer el interés del menor –también del menor extranjero- pues, conforme a la Convención de Naciones Unidas, es superior a cualquier otro interés. En las páginas que siguen se presenta el estado de la cuestión y las recientes posiciones jurisprudenciales

Interpersonality in ELF (Non)Academic Blogs: Self-mentions and Engagement Markers through Different Disciplines.

Abstract This study offers an analysis of interpersonality indicators, concretely self-mentions and engagement markers, in both academic and non-academic blogs belonging to four different disciplines, then consequently subjected to different conventions. In order to carry out this research, I have selected a corpus consisting of five blogs in ELF (English as a Lingua Franca) written by Spanish speakers, three of them non-academic – a cooking blog and two fashion blogs – and two of them academic – belonging to the fields of biology and psychology. The analysis of the results has been completed using Hyland’s metadiscourse paradigm (2005), exploring the frequency of appearance of self-mentions and engagement markers in each corpus. Resumen Este estudio pretende analizar los indicadores de interpersonalidad, más concretamente las auto-menciones del autor y las marcas de inclusión del lector, en varios blogs tanto académicos como no académicos pertenecientes a cuatro disciplinas diferentes, y por tanto sujetos a distintas convenciones. Para llevar a cabo el estudio, se ha seleccionado un corpus de cinco blogs en ELF (inglés como lengua franca) escritos por hablantes del español, tres de los cuales no son académicos – un blog sobre cocina y dos blogs sobre moda – y dos de los cuales sí son académicos – pertenecientes a los campos de la biología y la psicología. El análisis de los resultados se ha producido usando el paradigma de metadiscurso de Hyland (2005), observando la frecuencia de aparición de las auto-menciones y de las inclusiones del lector en cada uno de los corpus.<br /

Citizen deliberation in the context of Uruguay’s first National Water Plan

As part of the formulation of the first National Water Plan (NWP) in Uruguay, a mini-public process called ‘Citizen Deliberation on Water (Deci Agua)’ was developed in 2016. While the draft of the plan was being discussed in the formal arenas of water governance (Basin Commissions and Regional Water Resources Councils), a University research team (led by the authors), in coordination with the national water authority, adapted the mechanism of consensus conferences in order to incorporate the citizens’ visions and to contribute to public understanding of the NWP challenges. This article analyses the main aspects of the developed participation strategy and discusses them regarding a set of quality criteria used to evaluate deliberative processes. Although the final version of the NWP (passed by decree in 2017) incorporated some of the contributions of the Citizen Panel, an in-depth analysis of the scope of the deliberative process of Deci Agua allows us to delve into some key aspects related to the quality of participation processes and the challenges. A mixed approach that combines stakeholder participation and lay citizens is novel and desirable in water governance since it increases the scope of participation, deepens the legitimacy of decision-making and improves the public debate

Una necesidad imperiosa en la educación general: El desarrollo de la actividad cognoscitiva productiva

Con el advenimiento del siglo XXI, se hace necesaria una educación para el futuro, en que se prepare a las nuevas generaciones para el cambio, para la variación de paradigmas científicos y tecnológicos, y no para la estabilidad, para lo rutinario, como ocurre actualmente en muchos centros docentes. ¿Qué significado tiene esta nueva exigencia? De esto se desprende la necesidad imperiosa de una activación productiva de la enseñanza, la cual ha sido una preocupación desde la Antigüedad. En Cuba, hay referencia de eminentes pedagogos; por ejemplo, José J. Martí Pérez (1853-1895), nuestro Maestro de todos los Maestros, insistió en esto, siempre con su proyección de futuro, desde el siglo XIX: “Cada hombre trae en sí el deber de añadir, de domar, de revelar. Son culpables las vidas empleadas en la repetición cómoda de las verdades descubiertas”. “…el profesor no ha de ser un molde donde los alumnos echan la inteligencia y el carácter, para salir con sus lobanillos y jorobas…” ¿Por qué tanta insistencia en desarrollar la producción cognoscitiva? ¿Qué hacer en nuestras clases para contribuir a su logro? En el presente trabajo se propone fundamentar la necesidad del desarrollo de la actividad cognoscitiva productiva en la educación generalWith the coming of the XXI century, it becomes necessary an education for the future in that gets ready to the new generations for the change, for the variation of scientific and technological paradigms, and it doesn't stop the stability, for the routine thing, like it happens at the moment in many educational centers. How meaning has this new demand? Of this he comes off the imperious necessity of a productive activation of the teaching, which has been a concern from the Antiquity. In Cuba, there is eminent educators' reference; for example, José J. Martí Pérez (1853-1895), our Teacher of all the Teachers, insisted in this, always with his future projection, from the XIX century: "Each man brings in yes the duty of adding, of taming, of revealing. Are the lives guilty used in the comfortable repetition of the discovered truths". "…el professor a mould must be where the students toss the intelligence and the character, to go out with their cysts and humps…" why so much insistence in developing the cognitive production? What to make in our classes to contribute to their achievement? Presently work intends to base the necessity of the development of the productive cognitive activity in the general educatio

The effect of surface functionalisation on cancer cells internalisation and selective cytotoxicity of zirconium metal organic frameworks

A considerable amount of effort has been directed to develop porous materials as drug delivery systems (DDSs) – one of the most promising emerging applications in healthcare, as most anticancer therapeutics have toxic dose dependence due to a lack of tumour selectivity – as their hierarchical porosity can be used to store and release challenging drugs. Among them, Metal-Organic Frameworks (MOFs) – emerging hybrid, highly porous crystalline structures – offer several advantages compared to other available DDS, as they combine desirable features from both organic (biocompatibility, e.g. porous polymers) and inorganic (high loadings, e.g. mesoporous silica) porous materials. MOFs are highly amenable to functionalisation, meaning fine control over their physical properties can be achieved, and thus they have experienced tremendous development during the past decade in many applications. Despite surface engineering being advantageous for diverse fields – in biomedicine, it can both improve stability and dispersion, and provide the possibility of targeted carriers, decreasing the immune system recognition – surface functionalization of MOFs is underdeveloped. The multiple synthetic steps – synthesis, drug loading and surface modification – and the lack of orthogonality between them hinder their industrial manufacturing as DDSs. This thesis focuses on the development of surface functionalisation protocols of Zirconium MOFs, particularly UiO-66, a Zr-terephthalate MOF, the study of their cell internalisation fate and routes and the correlation with their therapeutic activity. During Chapter 1, an introduction to the use of DDSs in anticancer therapy, followed by examples of the most relevant MOFs from a coordination chemistry point of view, is given, in which zirconium MOFs and their synthesis are highlighted. Particular focus is given to the coordination modulation process, in which monodentate modulators are introduced to the MOFs synthesis to compete with the multidentate linkers during nucleation, enhancing properties such as porosity through the induction of defects. Then, the most relevant examples of surface functionalization of Zr MOFs for drug delivery are discussed with respect to the effects on properties such as colloidal dispersion in aqueous solvents, physiological stability, and drug release kinetics. In Chapter 2 different functionalised modulators (i.e p-functionalised benzoic acids, folic acid or biotin) are introduced to UiO-66 synthesis to obtain surface-functionalised UiO-66 with the appropriate size for drug delivery by one-pot synthesis. Full characterisation of the materials shows them to be remarkably porous due to the defects formed when modulators attach to available zirconium positions in the pores and on the surfaces of the MOFs. Furthermore, the use of a carboxylate-containing anticancer metabolic target (dichloroacetic acid, DCA) as a modulator of UiO-66 synthesis is explored, and co-modulated samples, in which both DCA and functionalised modulators are introduced to UiO-66 synthesis, are synthesised and fully characterised, resulting in drug-containing (ca. 20% w/w) surface-functionalised MOFs by one pot syntheses. Importantly, DCA modulation induces a high number of defects, and consequently highly charged nanoparticles which are colloidally stable in aqueous solvents. Particle size control in the DCA modulated synthesis of the UiO family of isoreticular MOFs – including UiO-66 and its bromo, amino and nitro derivatives, and extended structures Zr-Naphthalenedicarboxylate (NDC) and Zr-Biphenyldicarboxylate (BPDC) – is achieved, obtaining ca. 100 nm particles of UiO-66 derivatives and microcrystals of Zr-NDC and Zr-BPDC when ZrCl4 is the metal precursor, and mesoporous < 20 nm UiO-66 derivatives and ca. 200 nm Zr-NDC and Zr-BPDC when ZrOCl2 is used as the metal precursor. The high porosity of the DCA modulated samples, due to DCA attachment to the inner and outer surface at defect sites, allows the loading of a second drug, the well-known anticancer drug 5-fluorouracil (5-FU), into the pores of the isoreticular MOFs to create dual DDSs. Different postsynthetic modes of surface coating, based in both coordination and covalent chemistry, are studied during Chapter 3. The functionalities of the p-functionalised benzoic acid modulators, introduced to UiO-66 structure during Chapter 2, are used to covalently attach short-chain alkanes and long-chain polymers to UiO-66 surface through copper-catalysed azide-alkyne cycloaddition. Exhaustive characterisation confirms that the attachment occurs through covalent chemistry and not through surface adhesion or electrostatic forces. Folic acid and biotin, which are introduced to UiO-66 surface as synthetic modulators during Chapter 2, are also introduced to UiO-66 surface postsynthetically. Colloidal dispersion and stability towards phosphates are investigated and compared to bare MOFs, in order to gain insights into the effect of both surface chemistry and mode of attachment on physical properties. A comprehensive overview of in vitro studies of cellular internalisation of zirconium MOFs is given in Chapter 4, focussing on the relevance of the endocytosis internalisation routes, which are strictly correlated with therapeutic efficacy. The postsynthetic surface functionalisation protocols investigated in Chapter 3 are applied to analogous calcein-loaded UiO-66 samples. Calcein is a fluorescent molecule not able to efficiently cross the cell membrane by itself, and hence serves as an in ideal probe of MOFs cellular internalisation. Its release from bare and poly(ethylene glycol) coated UiO-66 into phosphate buffered saline at pH 7.4 and 5.5, in order to simulate extracellular and intracellular conditions, is found to be pH responsive (more pronounced at 5.5) for all MOFs, but an ideal decrease in calcein release at pH 7.4 occurs only for PEGylated MOFs. Internalisation of calcein-loaded MOFs by HeLa cervical cancer cells is studied by fluorescence assisted cell sorting, highlighting the effects of surface chemistry on endocytosis efficiencies and internalisation mechanisms. A discussion of in vitro studies into anticancer drug delivery from Zr MOFs is provided in Chapter 5, alongside a summary of the therapeutic effects of DCA and approaches to enhance its anticancer efficacy. Experimental assessment of the in vitro anticancer performance towards MCF-7 breast cancer cells of the DCA-containing MOFs of the UiO family of different sizes (ca. 100 nm and <20 nm), synthesised by coordination modulation during Chapter 2, is given. The effect of dual-drug containing MOFs (DCA and 5-FU) is also examined, to investigate the possible synergic effect of the drug combination. Then, the cytoxicity of bare and surface functionalised, DCA-loaded and empty UiO-66 MOFs is studied at first upon incubation with HeLa cells, for which the cellular routes of internalisation were elucidated in Chapter 4. The most promising MOFs are then tested for selective anticancer activity against a series of cancerous and healthy cells lines, and their macrophage uptake and ROS production is also analysed, to determine the effect of surface functionalization. The selective anticancer cytotoxicity of folate-coated MOFs is attributed to a combination of cancer cell targeting and optimal cell internalisation routes. To summarise, the one-pot synthesis of drug-loaded, surface functionalised UiO-66 has been successfully performed, resulting in porous, crystalline MOFs with the appropriate size for drug delivery. The use of a carboxylate-containing anticancer metabolic target as a modulator has been explored for the UiO family of isoreticular MOFs, resulting in well-dispersed nanoMOFs with enhanced anticancer activity, into which a second drug can be loaded, enabling the creation of dual DDSs. A series of postsynthetic surface modifications are performed, enabling the study of the MOF’s properties (colloidal dispersion, physiological stability and biocompatibility) with respect to their surface chemistry and coating mode, but more importantly providing valuable insights into correlations between surface chemistry, routes of cellular internalisation and therapeutic effect