Biomaterials to suppress cancer stem cells and disrupt their tumoral niche

Lack of improvement in the treatment options of several types of cancer can largely be attributed to the presence of a subpopulation of cancer cells with stem cell signatures and to the tumoral niche that supports and protects these cells. This review analyses the main strategies that specifically modulate or suppress cancer stem cells (CSCs) and the tumoral niche (TN), focusing on the role of biomaterials (i.e. implants, nanomedicines, etc.) in these therapies. In the case of CSCs, we discuss differentiation therapies and the disruption of critical signaling networks. For the TN, we analyze diverse strategies to modulate tumor hypervascularization and hypoxia, tumor extracellular matrix, and the inflammatory and tumor immunosuppressive environment. Due to their capacity to control drug disposition and integrate diverse functionalities, biomaterial- based therapies can provide important benefits in these strategies. We illustrate this by providing case studies where biomaterial-based therapies either show CSC suppression and TN disruption or improved delivery of major modulators of these features. Finally, we discuss the future of these technologies in the framework of these emerging therapeutic conceptsFundación BBVA, Proyectos de Investigación en Biomedicina (2014-PO0110) Ministerio de Economía y Competitividad (SAF2014-58189-R, FEDER Funds)S

New scaffolds encapsulating TGF-β3/BMP-7 combinations driving strong chondrogenic differentiation

The regeneration of articular cartilage remains an unresolved question despite the current access to a variety of tissue scaffolds activated with growth factors relevant to this application. Further advances might result from combining more than one of these factors; here, we propose a scaffold composition optimized for the dual delivery of BMP-7 and TGF-β3, two proteins with described chondrogenic activity. First, we tested in a mesenchymal stem cell micromass culture with TGF-β3 whether the exposure to microspheres loaded with BMP-7 would improve cartilage formation. Histology and qRT-PCR data confirmed that the sustained release of BMP-7 cooperates with TGF-β3 towards the generation of chondrogenic differentiation. Then, we optimized a scaffold prototype for tissue culture and dual encapsulation of BMP-7 and TGF-β3. The scaffolds were prepared from poly(lactic-co-glycolic acid), and BMP-7/TGF-β3 were loaded as nanocomplexes with heparin and Tetronic 1107. The scaffolds showed the sustained release of both proteins over four weeks, with minimal burst effect. We finally cultured human mesenchymal stems cells on these scaffolds, in the absence of exogenous chondrogenic factor supplementation. The cells cultured on the scaffolds loaded with BMP-7 and TGF-β3 showed clear signs of cartilage formation macroscopically and histologically. RT-PCR studies confirmed a clear upregulation of cartilage markers SOX9 and Aggrecan. In summary, scaffolds encapsulating BMP-7 and TGF-β3 can efficiently deliver a cooperative growth factor combination that drives efficient cartilage formation in human mesenchymal stem cell cultures. These results open attractive perspectives towards in vivo translation of this technology in cartilage regeneration experimentsFundación Ramón Areces (CIVP16A1832), Xunta de Galicia (Proxectos de Investigación Desenvolvidos por Investigadores Emerxentes, EM2013/042), Fundación BBVA, Proyectos de Investigación en Biomedicina (2014- PO0110) y Ministerio de Economía y Competitividad (SAF2014-58189-R)S

Polyphosphazenes for the delivery of biopharmaceuticals

This is the peer reviewed version of the following article: Hsu, W‐H., Csaba, N., Alexander, C., Garcia‐Fuentes, M. (2020), Polyphosphazenes for the delivery of biopharmaceuticals. J Appl Polym Sci, 137, 48688. doi: https://doi.org/10.1002/app.48688, which has been published in final form at https://doi.org/10.1002/app.48688. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsPolyphosphazenes (PPZs) are a relatively new family of polymers based on a nitrogen- phosphorous backbone where organic side-groups can be grafted. The synthetic route to PPZs is highly versatile such that it is possible to add many different functionalities that change completely the physicochemical and biological properties of the polymers. For instance, PPZs can be designed with a variety of organic side groups that render these materials biodegradable and highly biocompatible. Based on these positive features, PPZs have been explored for many biomedical applications including the design of numerous advanced drug delivery systems. In this area, PPZs have been particularly investigated as materials for the formulation of biopharmaceuticals of high added value. These include protein- and polynucleotide-based medicines, applications where PPZ carriers have obtained very positive results in pre-clinical models. A further area of major interest for PPZs has been vaccination, where these materials have obtained excellent results in vivo as polymer adjuvants and have advanced to clinical evaluation.This work has been funded by Ministerio de Economía y Competitividad (MINECO-RETOS, Grant MAT2017-84361-R, Feder Funds) and Xunta de Galicia (Grupos de Referencia Competitiva, Feder Funds) to MGF and Engineering and Physical Sciences Research Council Grants EP/N006615/1, EP/ N03371X/1 to CA. WHH was a recipient of a contract from EU Erasmus Mundus NanoFar joint doctorate programS

Gobernanza de la sustentabilidad local: índices de mediatización hídrica para la Ciudad de México

Los estudios de la mediatización de la gestión, autogestión y cogestión hídrica advierten diferencias entre los actores políticos y sociales con respecto al establecimiento de tarifas por los servicios hídricos. En este sentido, el objetivo del presente estudio fue establecer un índice para la ponderación de la difusión de los medios en cuanto a las problemáticas hídricas. Se llevó a cabo un estudio no experimental, retrospectivo y exploratorio con una selección no probabilística de 100 notas de prensa, considerando la circulación local y nacional, las palabras clave de “disponibilidad”, “abastecimiento” y “tarifas”, así como el periodo de publicación de enero de 1990 a diciembre de 2016. Los resultados muestran una prevalencia de la difusión de la gestión estatal (IMGH = 57 de 100 notas) con respecto a la autogestión social (IMAGH = 31 de 100 notas) y la cogestión socioestatal (IMCGH = 12 de 100 notas). Se advierte el estudio de los determinantes de la cogestión como línea de investigación explicativa de las diferencias entre autoridades y usuarios con respecto a la gobernanza o cogestión de los recursos y los servicios hídricos

Protein delivery based on uncoated and chitosan-coated mesoporous silicon microparticles

Mesoporous silicon is a biocompatible, biodegradable material that is receiving increased attention for pharmaceutical applications due to its extensive specific surface. This feature enables to load a variety of drugs in mesoporous silicon devices by simple adsorption-based procedures. In this work, we have addressed the fabrication and characterization of two new mesoporous silicon devices prepared by electrochemistry and intended for protein delivery, namely: (i) mesoporous silicon microparticles and (ii) chitosan-coated mesoporous silicon microparticles. Both carriers were investigated for their capacity to load a therapeutic protein (insulin) and a model antigen (bovine serum albumin) by adsorption. Our results show that mesoporous silicon microparticles prepared by electrochemical methods present moderate affinity for insulin and high affinity for albumin. However, mesoporous silicon presents an extensive capacity to load both proteins, leading to systems were protein could represent the major mass fraction of the formulation. The possibility to form a chitosan coating on the microparticles surface was confirmed both qualitatively by atomic force microscopy and quantitatively by a colorimetric method. Mesoporous silicon microparticles with mean pore size of 35 nm released the loaded insulin quickly, but not instantaneously. This profile could be slowed to a certain extent by the chitosan coating modification. With their high protein loading, their capacity to provide a controlled release of insulin over a period of 60-90 min, and the potential mucoadhesive effect of the chitosan coating, these composite devices comprise several features that render them interesting candidates as transmucosal protein delivery systems

Implantable controlled release devices for BMP-7 delivery and suppression of glioblastoma initiating cells

Designing therapeutic devices capable of manipulating glioblastoma initiating cells (GICs) is critical to stop tumor recurrence and its associated mortality. Previous studies have indicated that bone morphogenetic protein-7 (BMP-7) acts as an endogenous suppressor of GICs, and thus, it could become a treatment for this cancer. In this work, we engineer an implantable microsphere system optimized for the controlled release of BMP-7 as a bioinspired therapeutic device against GICs. This microsphere delivery system is based on the formation of a heparin- BMP-7 nanocomplex, first coated with Tetronic® and further entrapped in a biodegradable polyester matrix. The obtained microspheres can efficiently encapsulate BMP-7, and release it in a controlled manner with minimum burst effect for over two months while maintaining protein bioactivity. Released BMP-7 showed a remarkable capacity to stop tumor formation in a GICs cell culture model, an effect that could be mediated by forced reprogramming of tumorigenic cells towards a non-tumorigenic astroglial lineage.This work was financed by Ministerio de Ciencia e Innovación, Programa de Investigación en Salud (PS09/1786) and Xunta de Galicia (EM2013/042). ERN acknowledges a grant from Agencia Española de Cooperación Internacional. MF had a contract from Asociación Española contra el Cáncer. NC and MGF acknowledge their Isidro Parga Pondal contracts from Xunta de Galicia. Dr. Helena Mira and Dr. Pilar González advised us on the neurosphere culture model and the cell testing assays. Katrin Viertel and Ida Fejos provided technical help at the preformulation stages. Prof. Anxo Vidal and Erea Borrajo provided technical help for FACS analysis. We thank Prof. Maria J. Alonso for the supporting group infrastructure

Pegylated lipid nanocapsules with improved drug encapsulation and controlled release properties

Drugs with poor lipid and water solubility are some of the most challenging to formulate in nanocarriers, typically resulting in low encapsulation efficiencies and uncontrolled release profiles. PEGylated nano- capsules (PEG-NC) are known for their amenability to diverse modifications that allow the formation of domains with different physicochemical properties, an interesting feature to address a drug encapsulation problem. We explored this problem by encapsulating in PEG-NC the promising anticancer drug candidate F10320GD1, used herein as a model for compounds with such characteristics. The nanocarriers were pre- pared from Miglyol®, lecithin and PEG-sterate through a solvent displacement technique. The resulting system was a homogeneous suspension of particles with size around 200 nm. F10320GD1 encapsulation was found to be very poor (<15%) if PEG-NC were prepared using water as continuous phase; but we were able to improve this value to 85% by fixing the pH of the continuous phase to 9. Interestingly, this modification also improved the controlled release properties and the chemical stability of the formulation during storage. These differences in pharmaceutical properties together with physicochemical data sug- gest that the pH of the continuous phase used for PEG-NC preparation can modify drug allocation, from the external shell towards the inner lipid core of the nanocapsules. Finally, we tested the bioactivity of the drug-loaded PEG-NC in several tumor cell lines, and also in endothelial cells. The results indicated that drug encapsulation led to an improvement on drug cytotoxicity in tumor cells, but not in non-tumor en- dothelial cells. Altogether, the data confirms that PEG-NC show adequate delivery properties for F10320GD1, and underlines its possible utility as an anticancer therapy.The authors would like to acknowledge financial support from CENIT-NANOFAR XS53 project, FAES Farma S.A. (Spain), Xunta de Galicia (Competitive Reference Ref. GRC2014/043, FEDER Funds) and the European Commission FP7 EraNet — EuroNanoMed Program-Instituto Carlos III (Lymphotarg pro- yect, Ref. PS09/02670). MGF was a recipient of an Isidro Parga Pondal contract

Motivación de logro en deportistas de combate de élite : evaluación objetiva computeritzada

El objetivo del estudio fue identificar las diferencias en la motivación relacionadas con la tarea, la motivación hacia las metas personales, el nivel de aspiración y la motivación relacionada con la competencia en deportes de combate, según género, tipo de deporte y nivel competitivo. Para superar las limitaciones de las evaluaciones de la motivación mediante autoinformes, se evaluó la motivación de logro mediante una prueba objetiva computerizada, el Objective Achievement Motivation Test (OLMT, Schuhfried®). La muestra estuvo compuesta por 69 deportistas de combate de judo y lucha. Se realizó un análisis MANOVA para analizar las diferencias en género (masculino y femenino), tipo de deporte (lucha y judo) y nivel competitivo (deportistas de alto rendimiento y deportistas de menor nivel), así como pruebas t para muestras independientes. Se encontraron únicamente diferencias significativas en la variable nivel de aspiración respecto al género, con un tamaño del efecto moderado alto a favor de las mujeres (d ® .6). Estos resultados apuntan en dos direcciones: en primer lugar, a plantear las diferencias respecto a otros estudios sobre motivación de logro en los que aparecen diferencias significativas mediante el uso de autoinformes. En segundo lugar, enfatizar la importancia de profundizar en el estudio del nivel de aspiración como aspecto central de la motivación de logro, que podría explicar la implicación deportiva en los deportes de combate, así como su relación con variables como satisfacción, tolerancia a la frustración o abandono deportivo. Se defiende el uso de la evaluación psicológica computerizada, justificando pruebas como el OLMT para ser más precisos en los resultados de los estudios realizados en el marco de la motivación deportiva.The objective of the study was to identify the differences in task motivation, personal goal motivation, aspiration level, and competence motivation in combat sports, depending on gender, type of sport and competitive level. To overcome the limitations of self-report motivation assessments, achievement motivation was assessed by means of a computerised objective test, the Objective Achievement Motivation Test (OLMT, Schuhfried®). The sample comprised 69 judo and wrestling combat athletes. A MANOVA test was carried out to analyse the differences in gender (male and female), type of sport (wrestling and judo), and competitive level (high-performance athletes and lower level athletes), as well as t-tests for independent samples. Significant differences were only found in the aspiration level variable in terms of gender, with a moderate-to-high effect size in favour of women (d ® .6). These results point in two directions: first, to consider differences in comparison to other studies on achievement motivation, in which significant differences appear when self-report is used. Second, emphasise the importance of going deeper into the study of the aspiration level as a core aspect of achievement motivation, which could explain sports engagement in combat sports, as well as its relationship with variables such as satisfaction, tolerance to frustration or sport abandonment. The use of the computerised psychological assessment is defended by justifying tests such as the OLMT to achieve more accurate results in studies conducted within the framework of sport motivation. O objetivo do estudo foi identificar as diferenças de motivação relacionadas à tarefa e às metas pessoais, nível de aspiração e a motivação à competição em esportes de combate, em função das variáveis: sexo; modalidade esportiva; e nível competitivo. Para superar as limitações das avaliações do constructo motivação por meio de autorrelatos, a motivação para a conquista foi mensurada com o uso do teste objetivo computadorizado Objective Achievement Motivation Test (OLMT, Schuhfried®). A amostra foi composta por 69 atletas de judô e luta livre. Para testagem das variáveis sexo (feminino e masculino), modalidade esportiva (luta livre e judô) e nível competitivo (elite e atletas de nível inferior), utilizou-se a análise de variância multivariada (MANOVA) e o teste t para amostras independentes. Diferenças significativas foram encontradas apenas para a variável nível de aspiração, quando relacionada ao sexo, com um tamanho de efeito moderadamente alto em favor das mulheres (d ® .6). Esses resultados apontam para duas direções: primeiro, aumenta as diferenças com relação a outros estudos sobre motivação para a conquista, nos quais diferenças significativas são encontradas com o uso de autorrelatos. Em segundo lugar, enfatiza a importância de aprofundar o estudo do nível de aspiração como um aspecto central da motivação para a conquista, o que poderia explicar o envolvimento esportivo em modalidades de combate, bem como sua relação com variáveis como satisfação, tolerância à frustração ou abandono esportivo. Defende-se o uso da avaliação psicológica computadorizada, por meio de testes como o OLMT, visando a maior precisão nos resultados de estudos relacionados da motivação esportiva

Co-delivery of RNAi and Chemokine by Polyarginine Nanocapsules Enables the Modulation of Myeloid-Derived Suppressor Cells

Myeloid-Derived Suppressor Cells (MDSCs), immunosuppressive cells that promote tumor growth, represent an attractive target in cancer immunotherapy. However, the clinical success of this strategy is limited by the lack of efficient drug delivery vehicles targeting this cell compartment. The objective of this work was to develop a delivery carrier, multilayer polymer nanocapsules, with the capacity to co-encapsulate two types of immunomodulatory drugs, a chemokine and an RNAi sequence, aimed at reverting MDSC-mediated immunosuppression. The chemokine CCL2, intended to attract monocyte-macrophage MDSCs, was encapsulated within the L2 inverse micellar aqueous domains of the lipid core of these nanocapsules. On the other hand, two different RNAi sequences that modulate the CCAAT/enhancer-binding protein beta (C/EBPβ) pathway, shC/EBPβ and miR 142-3p, were successfully associated to their polymer shell. These RNAi sequences were covered by subsequent layers of polyarginine and hyaluronic acid, thereby creating multi-layered assemblies that protected them and facilitated their targeted delivery. The in vitro studies performed in primary MDSCs cultures showed the capacity of miR 142-3p-loaded nanocapsules to reduce the highly immunosuppressive monocyte- macrophage subset. Additionally, the encapsulation of CCL2 within the nanocapsules induced a potent monocyte-macrophage chemoattraction that could be used to direct the therapy to these cell subsets. Finally, in vitro and in vivo studies showed the capacity of shC/EBPβ-loaded nanocapsules to downregulate C/EBPβ levels in MDSCs and to reduce monocyte differentiation into tumor-associated macrophages in an MCA-203 fibrosarcoma mice model. In conclusion, the multilayer polymer nanocapsules described here are efficient vehicles for the co-delivery of proteins and RNA, and are potential candidates as nanomedicines for the modulation of MDSCs.This work was supported by LYMPHOTARG (ERA-NET EuroNanoMed ProgramISCIII, ref PS09/02670) and NICHE projects (ERA-NET EuroNanoMed II framework by ISCIII through CIBER- BBN), which received funding from the European Union's Seventh Framework Programme. The SAXS measurements were completed on the SAXS/WAXS beamLine at the Australian Synchrotron. A. M. L. was supported by a FPU fellowship from the Spanish Ministry of EducationS