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SUMMARYAxolotl limb regeneration is accompanied by the transient induction of cellular senescence within the blastema, the structure which nucleates regeneration. The precise role of this blastemal senescent cell (bSC) population, however, remains unknown. Here, through a combination of gain- and loss-of-function assays, we elucidate the functions and molecular features of cellular senescence in vivo. We demonstrate that cellular senescence plays a positive role during axolotl regeneration, by creating a pro-proliferative niche that supports progenitor cell expansion and blastema outgrowth. Mechanistically, these effects are mediated by the provision of Wnt ligands by bSCs. Further, we uncover a link between Wnt signalling and senescence induction, and propose that bSC-derived Wnt signals facilitate the proliferation of neighbouring cells in part by preventing their induction into senescence. This work defines the roles of cellular senescence in regeneration of complex structures.

[EN] The induction of senescence produces a stable cell cycle arrest in cancer cells, thereby inhibiting tumor growth; however, the incomplete immune cell-mediated clearance of senescent cells may favor tumor relapse, limiting the long-term anti-tumorigenic effect of such drugs. A combination of senescence induction and the elimination of senescent cells may, therefore, represent an efficient means to inhibit tumor relapse. In this study, we explored the antitumor efficacy of a combinatory senogenic and targeted senolytic therapy in an immunocompetent orthotopic mouse model of the aggressive triple negative breast cancer subtype. Following palbociclib-induced senogenesis and senolysis by treatment with nano-encapsulated senolytic agent navitoclax, we observed inhibited tumor growth, reduced metastases, and a reduction in the systemic toxicity of navitoclax. We believe that this combination treatment approach may have relevance to other senescence-inducing chemotherapeutic drugs and additional tumor types. Significance: While the application of senescence inducers represents a successful treatment strategy in breast cancer patients, some patients still relapse, perhaps due to the subsequent accumulation of senescent cells in the body that can promote tumor recurrence. We now demonstrate that a combination treatment of a senescence inducer and a senolytic nanoparticle selectively eliminates senescent cells, delays tumor growth, and reduces metastases in a mouse model of aggressive breast cancer. Collectively, our results support targeted senolysis as a new therapeutic opportunity to improve outcomes in breast cancer patients., The M.O. laboratory members thank the financial support from the Spanish Government (project SAF2017-84689-R (MINECO/AEI/FEDER, EU)) and the Generalitat Valenciana (project PROMETEO/2019/065). The R.M. laboratory members thank the financial support from the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22 (MCUI/FEDER, EU) and the Generalitat Valenciana (project PROMETEO 2018/024). Both I.G. and B.L-T. are grateful to the Generalitat Valenciana and the Spanish Ministry of Economy, respectively, for their Ph.D. grants. I.G. would like to thank I. Borreda and J. Forteza and the Instituto Valenciano de Patologia for their special collaboration and F. Sancenon for his appreciated help

[EN] Essential oil components (EOCs) such as eugenol play a significant role in plant antimicrobial defense. Due to the volatility and general reactivity of these molecules, plants have evolved smart systems for their storage and release, which are key prerequisites for their efficient use. In this study, biomimetic systems for the controlled release of eugenol, inspired by natural plant defense mechanisms, were prepared and their antifungal activity is described. Delivery and antifungal studies of mesoporous silica nanoparticles (MSN) loaded with eugenol and capped with different saccharide gates-starch, maltodextrin, maltose and glucose-against fungus Aspergillus niger-were performed. The maltodextrin- and maltose-capped systems show very low eugenol release in the absence of the fungus Aspergillus niger but high cargo delivery in its presence. The anchored saccharides are degraded by exogenous enzymes, resulting in eugenol release and efficient inhibition of fungal growth., This research was funded by the project NutRisk (Project No: CZ.02.1.01/0.0/0.0/16_019/0000845), the Spanish Government (projects RTI2018-100910-B-C41, RTI2018-101599-B-C22-AR and RTI2018-101599-B-C21-AR (MINECO/FEDER)) and the GeneralitatValenciana (project PROME-TEO 2018/024); by the National Agency for Agricultural Research of the Ministry of Agriculture of the Czech Republic under project Biostore QK21010064; and by the Research Infrastructure METROFOOD-CZ supported by the Ministry of Education, Youth, and Sports of the Czech Republic under project number LM201810. A.B. thanks the Spanish Government for financial support.

[EN] The development of new food preservatives is essential to prevent foodborne outbreaks or food spoilage due to microbial growth, enzymatic activity or oxidation. Furthermore, new compounds that substitute the commonly used synthetic food preservatives are needed to stifle the rising problem of microbial resistance. In this scenario, we report herein, as far as we know, for the first time the use of the zein protein as a gating moiety and its application for the controlled release of essential oil components (EOCs). The design of microdevices consist of mesoporous silica particles loaded with essential oils components (thymol, carvacrol and cinnamaldehyde) and functionalized with the zein (prolamin) protein found in corn as a molecular gate. The zein protein grafted on the synthesized microdevices is degraded by the proteolytic action of bacterial enzymatic secretions with the consequent release of the loaded essential oil components efficiently inhibiting bacterial growth. The results allow us to conclude that the new microdevice presented here loaded with the essential oil component cinnamaldehyde improved the antimicrobial properties of the free compound by decreasing volatility and increasing local concentration., This research was funded by the Government of Spain (projects RTI2018-100910-B-C41, RTI2018-101599-B-C22-AR and RTI2018-101599-B-C21-AR (MCUI/FEDER, EU)) and the Generalitat Valenciana (project PROMETEO 2018/024, grant numbers ACIF/2016/023 and APOSTD/2019/118).

Mesoporous silica microparticles functionalized with lactose for the specific release of essential oil components (EOCs) in the small intestine are presented. In vitro and in vivo intestinal models were applied to validate the microparticles (M41-EOC-L), in which the presence of lactase acts as the triggering stimulus for the controlled release of EOCs. Among the different microdevices prepared (containing thymol, eugenol and cinnamaldehyde), the one loaded with cinnamaldehyde showed the most significant Caco-2 cell viability reduction. On the other hand, interaction of the particles with enterocyte-like monolayers showed a reduction of EOCs permeability when protected into the designed microdevices. Then, a microdevice loaded with cinnamaldehyde was applied in the in vivo model of Wistar rat. The results showed a reduction in cinnamaldehyde plasma levels and an increase in its concentration in the lumen of the gastrointestinal tract (GIT). The absence of payload release in the stomach, the progressive release throughout the intestine and the prolonged stay of the payload in the GIT-lumen increased the bioavailability of the encapsulated compound at the site of the desired action. These innovative results, based on the specific intestinal controlled delivery, suggest that the M41-payload-L could be a potential hybrid microdevice for the protection and administration of bioactive molecules in the small intestine and colon., Ministerio de Ciencia, Innovación y Universidades (Spanish Government) )the Agencia Estatal de Investigación (AEI) and European Union (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22-AR (MCIU/AEI/ FEDER, EU)), Ministerio de Universidades (Spanish Government) (BG20/00020, A.B. Beatriz Galindo contract), Agencia Estatal de Investigación and European Union through FEDER (Fondo Europeo de Desarrollo Regional, AEI/FEDER EU, project SAF2016-78756), Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana (project PROMETEO 2018/024 and E.P-R. predoctoral grant ACIF/2016/023)

[EN] Mesoporous silica nanoparticles loaded with rhodamine B and capped with a bisphenol A aptamer were used for the selective and sensitive detection of this lethal chemical. The pores of the nanoparticles are selectively opened in the presence of bisphenol A (through its selective coordination with the aptamer) with subsequent rhodamine B delivery. With this capped material a limit of detection as low as 3.5 mu m of bisphenol A was measured., We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. A.R. thanks UPV for her predoctoral fellowship. A.B. thanks the Spanish Government for the finantial support "Juan de la Cierva-Incorporacion" (IJCI-2014-21534). The authors also thank the Electron Microscopy Service at the UPV for support.

[EN] Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal beta-galactosidase (SA-beta-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-beta-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclax-induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities., Royal Society, Grant/Award Number: RG160806; Medical Research Council, Grant/Award Number: MR/R000530/1; Cancer Research UK, Grant/Award Number: C62187/A26989 and C62187/A29760; CRUK Cambridge Centre Early Detection Programme, Grant/Award Number: RG86786

[EN] In recent decades, the versatility of mesoporous silica particles and their relevance to develop controlled release systems have been demonstrated. Within them, gated materials able to modulate payload delivery represent great advantages. However, the role played by the porous matrix in this kind of systems is scarce. In this work, different mesoporous silica materials (MCM-41, MCM-48, SBA-15 and UVM-7) are functionalized with oleic acid as a molecular gate. All systems are fully characterized and their ability to confine the entrapped cargo and release it in the presence of bile salts is validated with release assays and in vitro digestion experiments. The cargo release profile of each synthesized support is studied, paying attention to the inorganic scaffold. Obtained release profiles fit to Korsmeyer-Peppas model, which explains the differences among the studied supports. Based on the results, UVM-7 material was the most appropriate system for duodenal delivery and was tested in an in vivo model of the Wistar rat. Payload confinement and its complete release after gastric emptying is achieved, establishing the possible use of mesoporous silica particles as protection and direct release agents into the duodenum and, hence, demonstrating that these systems could serve as an alternative to the administration methods employed until now., This research was funded by the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22-AR (MCUI/FEDER, EU)) and the Generalitat Valenciana (project PROMETEO/2018/024 and ACIF/2016/023 grant).

[EN] Bacterial infections are the main cause of chronic infections and even mortality. In fact, due to extensive use of antibiotics and, then, emergence of antibiotic resistance, treatment of such infections by conventional antibiotics has become a major concern worldwide. One of the promising strategies to treat infection diseases is the use of nanomaterials. Among them, mesoporous silica materials (MSMs) have attracted burgeoning attention due to high surface area, tunable pore/particle size, and easy surface functionalization. This review discusses how one can exploit capacities of MSMs to design and fabricate multifunctional/controllable drug delivery systems (DDSs) to combat bacterial infections. At first, the emergency of bacterial and biofilm resistance toward conventional antimicrobials is described and then how nanoparticles exert their toxic effects upon pathogenic cells is discussed. Next, the main aspects of MSMs (e.g., physicochemical properties, multifunctionality, and biosafety) which one should consider in the design of MSM-based DDSs against bacterial infections are introduced. Finally, a comprehensive analysis of all the papers published dealing with the use of MSMs for delivery of antibacterial chemicals (antimicrobial agents functionalized/adsorbed on mesoporous silica (MS), MS-loaded with antimicrobial agents, gated MS-loaded with antimicrobial agents, MS with metal-based nanoparticles, and MS-loaded with metal ions) is provided., The authors thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047 and PROMETEO/2018/024) for support. A.B. thanks the Spanish Government for her Juan de la Cierva incorporacion contract IJCI-2014-21534.

Bioaerosols play an important role in Cultural Heritage (CH) spaces air quality and biodeterioration risk and there is a growing interest to reduce them in actual conservation strategies. Essential oils (EOs) have been well-known in several fields for their antimicrobial properties and they have found use in a number of applications. In this work Melaleuca alternifolia (Tea tree) and Thymus vulgaris (Thyme) EOs are cold diffused in unventilated lab spaces for reducing air bacterial and fungi contamination. Moreover, Tea tree EO was also tested in an unventilated real CH space. The effectiveness of EOs in reducing air bacterial and fungi contamination in unventilated indoor spaces during 24 h was evaluated. Air quality was also analyzed by means of temperature, humidity and particulate matter variation. EOs’ diffusion system CH artworks risks was studied by means of thermography, diffusion range and EOs compounds deposition on the artistic materials by GC–MS. Tea tree EOs vaporization showed the best results with 77,3% and 95,0% fungi and bacteria air contamination reduction, with no thermohydrometric alteration and absence of EOs components deposition on the artistic vault.

[EN] Mesoporous silica nanoparticles loaded with fluorescein and capped by a pseudorotaxane, formed between a naphthalene derivative and cyclobis(paraquat-p-phenylene) (CBPQT(4+)), were used for the selective and sensitive fluorogenic detection of 3,4-methylenedioxy-methamphetamine (MDMA)., The authors acknowledge the financial support from the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (project GVA/2014/13). B. L-T. is grateful to the Ministerio de Economia y Competitividad for her PhD grant. A. B. thanks the Spanish Government for the financial support "Juan de la CiervaIncorporacion'' (IJCI-2014-21534). J. O. J. thanks The Danish Natural Science Research Council (FNU, project no. 11-106744) and the Villum Foundation for financial support.

The main goal of this study was to develop poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) films with long-term antimicrobial capacity of interest in food packaging applications. To this end, eugenol was first highly efficiently encapsulated at 50 wt.-% in the pores of mesoporous silica nanoparticles by vapor adsorption. The eugenol-containing nanoparticles were then loaded in the 2.5–20 wt.-% range into PHBV by electrospinning and the resultant electrospun composite fibers were annealed at 155 °C to produce continuous films. The characterization showed that the PHBV films filled with mesoporous silica nanoparticles containing eugenol present sufficient thermal resistance and enhanced mechanical strength and barrier performance to water vapor and limonene. The antimicrobial activity of the films was also evaluated against foodborne bacteria for 15 days in open vs. closed conditions in order to simulate real packaging conditions. The electrospun PHBV films with loadings above 10 wt.-% of mesoporous silica nanoparticles containing eugenol successfully inhibited the bacterial growth, whereas the active films stored in hermetically closed systems increased their antimicrobial activity after 15 days due to the volatile portion accumulated in the system’s headspace and the sustained release capacity of the films. The resultant biopolymer films are, therefore, potential candidates to be applied in active food packaging applications to provide shelf life extension and food safety., This research was supported by the Ministry of Science, Innovation, and Universities (MICIU) program numbers AGL2015-63855-C2-1-R and MAT2015-64139-C4-1-R, by the Generalitat Valenciana (GVA) PROMETEO/2018/024 program, and by the EU H2020 projects YPACK (reference number 773872) and ResUrbis (reference number 730349)., We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

Staphylococcus aureus is a major human pathogen that is responsible for both hospital- and community-acquired infections. Stilbenes are polyphenol compounds of plant origin known to possess a variety of pharmacological properties, such as antibacterial, antiviral, and antifungal effects. This study reports the in vitro growth-inhibitory potential of eight naturally occurring stilbenes against six standard strains and two clinical isolates of S. aureus, using a broth microdilution method, and expressing the results as minimum inhibitory concentrations (MICs). Pterostilbene (MICs = 32–128 μg/ml), piceatannol (MICs = 64–256 μg/ml), and pinostilbene (MICs = 128 μg/ml) are among the active compounds that possess the strongest activity against all microorganisms tested, followed by 3′-hydroxypterostilbene, isorhapontigenin, oxyresveratrol, and rhapontigenin with MICs 128–256 μg/ml. Resveratrol (MIC = 256 μg/ml) exhibited only weak inhibitory effect. Furthermore, structure–activity relationships were studied. Hydroxyl groups at ortho-position (B-3′ and -4′) played crucial roles for the inhibitory effect of hydroxystilbene piceatannol. Compounds with methoxy groups at ring A (3′-hydroxypterostilbene, pinostilbene, and pterostilbene) produced stronger effect against S. aureus than their analogues (isorhapontigenin and rhapontigenin) with methoxy groups at ring B. These findings provide arguments for further investigation of stilbenes as prospective leading structures for development of novel antistaphylococcal agents for topical treatment of skin infections.

In this chapter, we report on the diverse applications of silica-based nanomaterials relevant for the food industry. The encapsulation of food ingredients and nutraceuticals and their use as antimicrobial agents and sensors has been explored. In the case of food ingredients, controlled-release materials responsive to pH changes and enzymes (i.e., proteases or esterases) are the main approximation. For antimicrobial agents, the materials are able to modulate the activity of the biocide, increasing the duration of the active substances. Also, an increase of the biocide activity up to ninefold and a broadening of the activity spectra have been observed for a capped material. Finally, due to their present relevance in the sensors area, we review examples of nanogated silica materials and optoelectronic noses.

[EN] Organic-inorganic hybrid nanomaterials offer extremely valuable tools for monitoring many types of analytes in solution. Within this framework, aptamer-based nanomaterials for heavy metal detection are still very scarce. Herein, a novel sensing nanoprobe for the selective and sensitive detection of As(III) based on the combination of aptamers with mesoporous silica nanoparticles has been developed. The efficiency of the sensor is demonstrated in environmental conditions, showing a great potential in As(III) monitoring assays., The authors thank the financial support from the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (project GVA/2014/13). M.O. is grateful to the Universitat Politecnica for her PhD grant. A.B. thanks the Spanish Government for the finantial support "Juan de la Cierva-Incorporacion" (IJCI-2014-21534). C.C. thanks the Generalitat Valenciana for her postdoctoral contract VALi+D.

BACKGROUND Essential oil components (EOCs) are known for their antifungal properties; however, their high volatility limits their application as antimicrobial agents. Strategies used for controlling the volatility of EOCs include encapsulation or loading into porous materials. This study evaluated the in vitro antifungal activity of selected EOCs (carvacrol, cinnamaldehyde, eugenol and thymol) against the fungus Aspergillus niger when loaded into MCM-41 and β-cyclodextrin (β-CD). RESULTS Carvacrol and thymol in Mobil Composition of Matter No. 41 (MCM-41) displayed remarkable enhanced antifungal properties in comparison to the pure or β-CD-encapsulated EOCs. In fact, carvacrol and thymol were able to maintain antifungal activity and inhibit fungal growth for 30 days, suggesting better applicability of these EOCs as natural preservatives. CONCLUSIONS The sustained antifungal effect of EOCs encapsulated into silica mesoporous supports was described. © 2014 Society of Chemical Industry

[EN] This review summarises examples of capped mesoporous silica materials for controlled delivery that use enzymes as external triggers or functional components of the gating ensemble., Financial support from the Spanish Government and FEDER funds (Project MAT2015-64139-C4-1) and the Generalitat Valencia (Project PROMETEOII/2014/047) is gratefully acknowledged. A. Llopis-Lorente is grateful to "La Caixa'' Banking Foundation for his PhD fellowship. B. Lozano-Torres is grateful to the Spanish Ministry of Economy and Competitiveness (MEC) for her FPU grant. Also A. Bernardos thanks the Spanish MEC for her Juan de la Cierva Contract.

[EN] Aptamers have been used as recognition elements for several molecules due to their great affinity and selectivity. Additionally, mesoporous nanomaterials have demonstrated great potential in sensing applications. Based on these concepts, we report herein the use of two aptamer¿capped mesoporous silica materials for the selective detection of ochratoxin¿A (OTA). A specific aptamer for OTA was used to block the pores of rhodamine¿B¿loaded mesoporous silica nanoparticles. Two solids were prepared in which the aptamer capped the porous scaffolds by using a covalent or electrostatic approach. Whereas the prepared materials remained capped in water, dye delivery was selectively observed in the presence of OTA. The protocol showed excellent analytical performance in terms of sensitivity (limit of detection: 0.5¿0.05¿nm), reproducibility, and selectivity. Moreover, the aptasensors were tested for OTA detection in commercial foodstuff matrices, which demonstrated their potential applicability in real samples, We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. A.R. thanks UPV for her predoctoral fellowship. S.S. thanks the Instituto de Salud Carlos III and the European Social Fund for the financial support "Sara Borrell" (CD16/000237). A.B. thanks the Spanish Government for financial support by the "Juan de la Cierva-Incorporacion" (IJCI-2014-21534). The authors also thank the Electron Microscopy Service at UPV for support.

[EN] A naphthalimide-based two-photon probe (AHGa) for the detection of cell senescence is designed. The probe contains a naphthalimide core, an L-histidine methyl ester linker, and an acetylated galactose bonded to one of the aromatic nitrogen atoms of the L-histidine through a hydrolyzable N-glycosidic bond. Probe AHGa is transformed into AH in senescent cells resulting in an enhanced fluorescent emission intensity. In vivo detection of senescence is validated in mice bearing tumor xenografts treated with senescence-inducing chemotherapy., The authors thank the financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R) and the Generalitat Valenciana (Project PROMETEOII/2014/047). B.L-T. is grateful to the Spanish Ministry of Economy for her PhD grant. I.G. thanks the Generalitat Valenciana for her PhD grant. A.B. thanks the Spanish Government for the financial support "Juan de la Cierva-Incorporacion". M.R. is grateful to "La Caixa" foundation for his PhD scholarship. Work in the M.S. group was funded by the CNIO and by grants from Spanish Ministry of Economy, the European Regional Development Fund (SAF project) the European Research Council (ERC Advanced Grant), and the Botin Foundation and Banco Santander (Santander Universities Global Division). D.M.-E. was funded by a "Ramon y Cajal" Programme Senior Grant and the "RETOS" National Programme for Research (MINECO), Cancer Research UK, and the CRUK Cambridge Centre Early Detection Programme.

[EN] The antimicrobial activity of essential oils components (EOCs) is well-known. However, their high volatility and powerful aroma limit their application in the formulation of a wide range of food products. In this context, the antimicrobial activity of carvacrol, eugenol, thymol and vanillin grafted onto the surface of three silica supports with different morphologies, textural properties and chemical reactivities (fumed silica, amorphous silica and MCM-41) was evaluated herein. Materials characterization revealed a good immobilization yield and all the devices showed a micro-scale particle size. Sensory evaluation revealed that sensory perception of EOCs decreases after covalent immobilization. Moreover, immobilization greatly enhanced the antimicrobial activity of the essential oil components against Listeria innocua and Escherichia coli compared to free components. The incorporation of EOCs immobilized on silica particles into pasteurized milk inoculated with L. innocua demonstrated their effectiveness not only for in vitro conditions, but also in a real food system., Authors gratefully acknowledge the financial support from the Ministerio de Economia, Industria y Competitividad and FEDER funds (Projects AGL2015-70235-C2-1-R, AGL2015-70235-C2-2-R and MAT2015-64139-C4-1-R (MINECO/FEDER)) and the Generalitat Valenciana (Project PROMETEOII/2014/047). M.R.R. is grateful to the Ministerio de Education, Cultura y Deporte for her grant (AP2010-4369). The authors also thank the Electron Microscopy Service at the UPV for support.

This paper describes the design of new controlled delivery systems consisting of a mesoporous support functionalized on the pore outlets with a certain hapten able to interact with an antibody that acts as a nanoscopic cap. The opening protocol and delivery of the entrapped guest is related by a displacement reaction involving the presence in the solution of the antigen to which the antibody is selective. As a proof-of-the-concept, the solid MCM-41 was selected as support and was loaded with the dye [Ru(bipy)(3)]Cl(2). Then a suitable derivative of the hapten 4-(4-aminobenzenesulfonylamino)benzoic acid was anchored on the outer surface of the mesoporous support (solid S1). Finally the pores were capped with a polyclonal antibody for sulfathiazole (solid S1-AB). Delivery of the dye in the presence of a family of sulfonamides was studied in phosphate-buffered saline (PBS; pH 7.5). A selective uncapping of the pores and dye delivery was observed for sulfathiazole. This delivery behavior was compared with that shown by other solids that were prepared as models to assess the effect of the hapten and its interaction with antibody in the dye delivery control in the presence of the antigen.

Essential oils (EOs) are strong plant-derived antimicrobials. For their efficient use in the agri-food industry, the problems with technology of their application have to be solved. In vitro antifungal activity of cinnamon, oregano, lemongrass and clove essential oils (EOs) was tested by innovative method using EO in combination with warm air flow (WAF). EOs in concentrations from 0.25 to 512 mL/L of air were tested against eleven phytopathogenic fungi. Application of EOs in concentration of 4 and 16 mL/L by WAF method was used for treatment of apples inoculated with Penicillium expansum. Detailed sensory analysis of treated apples was performed. The WAF was more effective compare to standard disc volatilization method (DVM), the average minimum inhibitory concentrations in vitro were 5.6 mL/L during 5 min WAF treatment, compared to 136 mL/L during the DVM 24 h treatment. EOs applied by WAF delayed the incidence and development of P. expansum on apples with minimal adverse effect on their sensory profile. The WAF treatment could be considered for the development of antifungal treatments in the agrifood industry., This study was supported by the European Social Fund in the Czech Republic - project CZ.1.07/2.3.00/30.0040 (Postdok CZU), and by Ministry of Education, Youth and Sports of the Czech Republic, project No. LD13013, and CULS Internal Grant Agency (CIGA 20162004). The author wish to thank Beth Green for the proofread.

A new hybrid material based on sulforhodamine-B dye-loaded silica mesoporous nanoparticles capped with a self-immolative gate has been synthesized and characterized. The gated material's controlled release behavior is monitored under different pH conditions. Under acidic and neutral conditions, a low level of dye release is detected. However, at slightly basic pH, significant dye release occurs owing to deprotonation of the phenol moiety in the capping molecule, which results in its disassembly., We thank MINECO/FEDER (MAT2015-64139-C4-1-R and MAT2015-64139-C4-4-R) and Generalitat Valenciana (PROMETEOII/2014/047) for support. SCSIE (Universidad de Valencia) is gratefully acknowledged for all the equipment employed.

[EN] A study on the controlled release of folic acid (FA) from pH-responsive gated mesoporous silica particles (MSP) is reported. The MCM-41 support was synthesized using tetraethyl orthosilicate (TEOS) as hydrolytic inorganic precursor and the surfactant hexadecyltrimethylammonium bromide (CTAB) as porogen species. Calcination of the mesostructured phase resulted in the starting solid. This solid was loaded with FA to obtain the initial support S0. Moreover, this FA-loaded material was further functionalized with 3-[2-(2-aminoethylamino)ethylamino]propyltrimethoxysilane (N3) in order to obtain the gated polyamine-functionalised material S1. Solids S0 and S1 were characterized using standard solid state procedures. It was found that the functionalization process and the inclusion of FA on the pores did not modify the mesoporous structure of the starting material. FA delivery studies in water with solids S0 and S1 were carried out in water at pH 2 and 7.5. S0 was not able to completely inhibit FA delivery at acidic pH yet a rapid FA release at neutral pH was observed in few minutes. In contrast, S1 was tightly capped at pH 2 and displayed a sustained delivery of FA when the pH was switched to 7.5. In the second part of the study, FA loading and functionalization of S1-like supports was optimized. In particular, solids loaded with FA in phosphate buffered saline (PBS) and capped with N3 in acetate buffer at pH 2 exhibited a delivery capacity up to 95 μg FA/mg solid. Finally, FA release from the selected optimized supports was studied following an in vitro digestion procedure. The results showed that amine-capped MSP were not only able to hinder the release of the vitamin in gastric fluids (pH 2), but were also capable of deliver progressively the FA in presence of a simulated intestinal juice (pH 7.5) offering a suitable mechanism to control the bioaccessibility of the vitamin, Authors gratefully acknowledge the financial support from the Ministerio de Economia y Competitividad (Projects AGL201239597-C02 and MAT2012-38429-004-01) and the Generalitat Valenciana (project PROMETEO/2009/016). E.P. is grateful to the Ministerio de Ciencia e Innovacion for his Grant (AP2008-00620). C.C. thanks the Generalitat Valenciana for her post-doctoral contract VALi+D.

Essential oil components (EOCs) are known for their antifungal properties; however, their high volatility limits their application as antimicrobial agents. Strategies used for controlling the volatility of EOCs include encapsulation or loading into porous materials. This study evaluated the in vitro antifungal activity of selected EOCs (carvacrol, cinnamaldehyde, eugenol and thymol) against the fungus Aspergillus niger when loaded into MCM-41 and β-cyclodextrin (β-CD).Carvacrol and thymol in Mobil Composition of Matter No. 41 (MCM-41) displayed remarkable enhanced antifungal properties in comparison to the pure or β-CD-encapsulated EOCs. In fact, carvacrol and thymol were able to maintain antifungal activity and inhibit fungal growth for 30 days, suggesting better applicability of these EOCs as natural preservatives.The sustained antifungal effect of EOCs encapsulated into silica mesoporous supports was described.

Núria Mas,1–3 Irene Galiana,3 Silvia Hurtado,† Laura Mondragón,1–3 Andrea Bernardos,1–3 Félix Sancenón,1–3 María D Marcos,1–3 Pedro Amorós,4 Nuria Abril-Utrillas,5 Ramón Martínez-Máñez,1–3 José Ramón Murguía1,3 1Centro de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Centro Mixto Universidad Politécnica de Valencia, Universidad de Valencia, Valencia, Spain; 2Departamento de Química, Universidad Politécnica de Valencia, Valencia, Spain; 3CIBER de Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain; 4Institut de Ciència del Materials (ICMUV), Universitat de València, Valencia, Spain; 5Servicio Ginecología y Obstetricia, Hospital de la Plana, Vila-real, Spain†Silvia Hurtado passed away in September 2013 Abstract: pH-sensitive gated mesoporous silica nanoparticles have been synthesized. Increased extracellular pH and internalization into living yeast cells triggered molecular gate aperture and cargo release. Proper performance of the system was demonstrated with nanodevices loaded with fluorescein or with the antifungal agent tebuconazole. Interestingly, nanodevices loaded with tebuconazole significantly enhanced tebuconazole cytotoxicity. As alterations of acidic external pH are a key parameter in the onset of fungal vaginitis, this nanodevice could improve the treatment for vaginal mycoses.Keywords: capped mesoporous nanoparticles, intracellular release, pH-responsive nanoparticles, Saccharomyces cerevisiae, tebuconazole loading

Learning to let go with age: Intracellular controlled release of molecules within senescent cells was achieved using mesoporous silica nanoparticles (MSNs) capped with a galacto-oligosaccharide (GOS) to contain the cargo molecules (magenta spheres; see scheme). The GOS is a substrate of the senescent biomarker, senescence-associated β-galactosidase (SA-β-gal), and releases the cargo upon entry into SA-β-gal expressing cells., We thank the Spanish Government (projects MAT2009-14564-C04 and FIS PI11-0949) the Generalitat Valencia (project PROMETEO/2009/016), and the Universidad Politécnica de Valencia (UPV PAID-05-09) for support. We thank Fundación Ramón Areces for support. C.M.-G. is supported by CIBERER. L.M. thanks the Generalitat Valenciana for her VALI+D postdoctoral contract.

11 páginas, 7 figuras, 3 tablas y 2 esquemas, The preparation of a new capped silica mesoporous material, Rh-Azo-S, for on-command delivery applications in the presence of target enzymes is described. The material consists of nanometric mesoporous MCM-41-like supports loaded with Rhodamine B and capped with an azopyridine derivative. The material was designed to show “zero delivery” and to display a cargo release in the presence of reductases and esterases, which are usually present in the colon, mainly due to intestinal microflora. The opening and cargo release of Rh-Azo-S in vitro studies were assessed and seen to occur in the presence of these enzymes, whereas no delivery was noted in the presence of pepsine. Moreover, Rh-Azo-S nanoparticles were used to study controlled Rhodamine B dye delivery in intracellular media. HeLa cells were employed for testing the “non”-toxicity of nanoparticles. Moreover, delivery of the dye in these cells, through internalization and enzyme-mediated gate opening, was confirmed by confocal microscopy. Furthermore, the nanoparticles capped with the Azo group and loaded with a cytotoxic camptothecin (CPT) were also prepared (solid CPT-Azo-S) and used as delivery nanodevices in HeLa cells. When this solid was employed, the cell viability decreased significantly due to internalization of the nanoparticles and delivery of the cytotoxic agent., We thank the Spanish Government (projects MAT2009-14564-C04, MAT2012-38429-C04-01, CTQ2007-64735-AR07 and SAF2010-15512) the Generalitat Valenciana (projects PROMETEO/2009/016 and /2010/ 005) for their support. N.M. thanks the Ministerio de Ciencia e Innovaci n for her FPU grant. A.A. and L.M. thank the Generalitat Valenciana for their Santiago Grisolia fellowships and VALI+D postdoctoral contracts.

The synthesis and characterisation of new capped silica mesoporous nanoparticles for on-command delivery applications is reported. Functional capped hybrid systems consist of MCM-41 nanoparticles functionalised on the external surface with polyesters bearing azobenzene derivatives and rhodamine¿B inside the mesopores. Two solid materials, Rh-PAzo8-S and Rh-PAzo6-S, containing two closely related polymers, PAzo8 and PAzo6, in the pore outlets have been prepared. Materials Rh-PAzo8-S and Rh-PAzo6-S showed an almost zero release in water due to steric hindrance imposed by the presence of anchored bulky polyesters, whereas a large delivery of the cargo was observed in the presence of an esterase enzyme due to the progressive hydrolysis of polyester chains. Moreover, nanoparticles Rh-PAzo8-S and Rh-PAzo6-S were used to study the controlled release of the dye in intracellular media. Nanoparticles were not toxic for HeLa cells and endocytosis-mediated cell internalisation was confirmed by confocal microscopy. Furthermore, the possible use of capped materials as a drug-delivery system was demonstrated by the preparation of a new mesoporous silica nanoparticle functionalised with PAzo6 and loaded with the cytotoxic drug camptothecin (CPT-PAzo6-S). Following cell internalisation and lysosome resident enzyme-dependent gate opening, CPT-PAzo6-S induced CPT-dependent cell death in HeLa cells., We thank the Spanish Government (projects MAT2009-14564-C04, CTQ2007-64735-AR07 and SAF2010-15512) and the Generalitat Valencia (projects PROMETEO/2009/016 and PROMETEO/2010/005) for support. A. B. is grateful to the Universidad Politecnica de Valencia for an FPI grant. L. M. thanks the Generalitat Valenciana for the Santiago Grisolia Fellowship she received and the VALI+D postdoctoral contract. We thank the CIPF confocal microscopy service for its technical support.

A hybrid nanoscopic capped mesoporous material, that is selectively opened in the presence of nerve agent simulants, has been prepared and used as a probe for the chromo-fluorogenic detection of these chemicals. © 2011 The Royal Society of Chemistry., Financial support from the Spanish Government (project MAT2009-14564-C04-01 and -02) and Generalitat Valenciana (project PROMETEO/2009/016) is gratefully acknowledged. I. C. thanks the UPV for her Fellowship. SCSIE (Universidad de Valencia) is gratefully acknowledged for all the equipment employed.

Nanotechnology is a multidisciplinary field of current interest. The huge possibilities in most industries are making nanoscience grow at a rapid pace, but what is the real impact of nanotechnology in a traditional industry such as food? The study of patents published in the last 20 years provides the answer, and the results are quite surprising; the food industry is the fifth largest sector in terms of patents related to nanotechnology.

The synthesis of new capped silica mesoporous nanoparticles for on-command delivery applications is described. The gate-like functional hybrid systems consisted of nanoscopic MCM-41-based materials functionalized on the pore outlets with different “saccharide” derivatives and a dye contained in the mesopores. A series of hydrolyzed starch products as saccharides were selected. The mesoporous silica nanoparticles S1, S2, and S3 containing the grafted starch derivatives Glucidex 47, Gludicex 39, and Glucidex 29 were synthesized. Additionally, for comparative purposes solid S4 containing lactose was prepared. Delivery studies in pure water in the presence of pancreatin or -D-galactosidase were carried out for S1S3 and S4, respectively. S1, S2, and especially S3 showed very low release in the absence of enzyme, but displayed cargo delivery in the presence of the corresponding enzyme. Moreover, nanoparticles of S1 were used to study the controlled release of the dye in intracellular media. Cell viability assays using HeLa and LLC-PK1 cells indicated that S1 nanoparticles were devoid of unspecific cell toxicity. The endocytosis process for S1 nanoparticle internalization in HeLa cells was confirmed, and the anchored starch was degraded by the lysosomal enzymes. Furthermore, a new mesoporous silica nanoparticle functionalized with Glucidex 47 and loaded with a cytotoxic, S1-DOX, was developed. The cell viability with S1-DOX decreased due to the internalization of the nanoparticle, enzyme-dependent opening of the saccharide molecular gate and the consequent release of the cytotoxic agent. As far as the authors know, this is the first example of enzyme-induced in-cell delivery using capped silica mesoporous nanoparticles., The authors wish to express their gratitude to the Spanish Government (Projects MAT2009 14564 C04 01 MAT2009 14564 C04 04 and BIO2007 60066) and the Generalitat Valencia (Projects PROMETEO/2009/016 and PROMETEO/2010/005) for support A B is grateful to the Universidad Politecnica de Valencia for an FPI grant E A thanks the MICINN for a FPU contract We thank Roquette for the Glucidex samples We would like to thank the CIPF confocal microscopy service for technical support

A study on the controlled release of vitamin B2 in pure water from mesoporous silica-based materials containing a pH- and anion-controlled nano-supramolecular gate-like ensembles built up by anchoring suitable polyamines on the external surface is reported (solid S1). This solid contains the vitamin (the delivered molecule) onto the pores, whereas the amine-based gate-like ensemble is anchored on the pore outlets. To obtain solid S1 the mesoporous MCM-41 support was first synthesized using tetraethyl orthosilicate (TEOS) as hydrolytic inorganic precursor and the surfactant hexadecyltrimethylammonium bromide (CTAB) as porogen species. Calcination of the mesostructured phase resulted in the starting solid. Then, first the vitamin and the latter an excess of 3-[2-(2-aminoethylamino)ethylamino]propyl-trimethoxysilane were added to the suspension containing the MCM-41 scaffolding and stirred. Solid S1 was characterized using standard solid state procedures. It was found that the functionalization process and the inclusion of the vitamin on the pores do not modify the mesoporous structure of the starting material. Delivery studies in water were carried out at pH 2 and 7. At pH 2 all the anions studied (sulfate, phosphate, GMP and ATP) strongly hinder vitamin release (Canion = 1 × 10− 2 mol dm− 3), whereas at pH 7 the delivery was observed for sulfate and GMP whereas the gate remained closed in the presence of ATP and phosphate. Selective delivery at neutral pH and no-liberation in acidic conditions can also be controlled with ATP and GMP using a suitable concentration of anion. The remarkable anion-controllable response of the gate-like ensemble at a certain pH can be explained in terms of anion complex formation with the tethered polyamines. Finally, selectivity patterns have been discussed in terms of kinetic rates of vitamin B2 release. The pH-controlled gate-like scaffoldings on S1 might be a suitable prototype for the development of orally applicable delivery systems designed to have the particular ability to protect the cargo from the acidic conditions of the stomach (acid pH, gate closed) but will release the load at the intestine (basic pH, gate open).

Folic acid deficiency causes serious disorders in humans and supplementation has numerous health benefits. However, there is initial evidence that suggest a negative impact of an increased exposure to folic with respect to certain developmental and degenerative disorders. In this line, controlled release of folic acid by using mesoporous silica materials, MCM-41, has been studied as an alternative to direct supplementation. For this purpose, various mesoporous solids MCM-41 loaded with folic acid (S1) and functionalized with 3-[2-(2- aminoethylamino)ethylamino]propyl-trimethoxysilane (S2) acting as “gate” have been tested. The results show that at pH 2 a strongly hindered vitamin release is observed, whereas at pH 7.5 a controlled delivery is found. Based on the obtained results of this study, folic acid controlled release could be feasible during a period of 5 h using a sensitive to pH gate, and this might reduce traditional fortification negative effects, while nutritional benefits are maintained.