Spin-transition frameworks based on bistetrazole and triazine ligands

The present thesis deals with the synthesis and characterisation of new spin-transition materials based on tetrazole and triazine chemistry. The thesis is thus divided in two main parts. The first part examines the iron(II) coordination chemistry with bistetrazoles, which are well-known ligands in the field of spin-crossover research. The central aim is to generate new members of this interesting family of polymeric spin-transition materials based on these ligands, to better assess the structural/coordination features driving the spin-crossover behaviour. An emphasis is therefore given to the analysis of the crystal structures of the various compounds, newly prepared and reported in the literature (both in the high-spin and low-spin states), to be able to evaluate the influence of the various chemical building units on the overall framework. Additionally, the structural changes caused by the spin transition are thoroughly analysed. In the second part, the use of dpyatriz, a triazine-based ligand, as a unit for the construction of spin-transition materials is reported. In the corresponding chapters, the benefit to use triazine chemistry in the field of spin transition is stressed, setting the grounds for future highly promising systems to be developed.UBL - phd migration 201

Development of an Artificial Neural Network for the Detection of Supporting Hindlimb Lameness: A Pilot Study in Working Dogs

[EN] Subjective lameness assessment has been a controversial subject given the lack of agreement between observers; this has prompted the development of kinetic and kinematic devices in order to obtain an objective evaluation of locomotor system in dogs. After proper training, neural networks are potentially capable of making a non-human diagnosis of canine lameness. The purpose of this study was to investigate whether artificial neural networks could be used to determine canine hindlimb lameness by computational means only. The outcome of this study could potentially assess the efficacy of certain treatments against diseases that cause lameness. With this aim, input data were obtained from an inertial sensor positioned on the rump. Data from dogs with unilateral hindlimb lameness and sound dogs were used to obtain differences between both groups at walk. The artificial neural network, after necessary adjustments, was integrated into a web management tool, and the preliminary results discriminating between lame and sound dogs are promising. The analysis of spatial data with artificial neural networks was summarized and developed into a web app that has proven to be a useful tool to discriminate between sound and lame dogs. Additionally, this environment allows veterinary clinicians to adequately follow the treatment of lame canine patientsSIThe APC was funded by Laboratorio Aragó S

Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin

[EN] We report the design, synthesis, characterization and in vitro testing of a novel nanodrug based on a covalent linking model that allows intracellular controlled release of the pharmaceutical payload. A new synthetic strategy is implemented by direct coupling of as-synthesized (pyridin-2-yldisulfanyl)alkyl carbonate derivatives of camptothecin (CPT) with thiol groups of silica hybrid nanoparticles containing a non-porous core and a mesoporous shell. Upon reaction with thiols in physiological conditions, disulfide bridge cleavage occurs, releasing the naked drug after an intramolecular cyclization mechanism. Additional incorporation of a fluorophore into particles core facilitates imaging at the subcellular level for the monitoring of uptake and delivery. Confocal microscopy experiments in HeLa cervix cancer cells confirms that nanoparticles enter the cells by endocytosis but are able to escape from endo-lysosomes and enter the cytosolic compartment to release their cargo. The incorporation to cells of L-buthionine-sulfoximine, a glutathione inhibitor allows concluding that the intracellular releasing mechanism is mainly driven by the reducing activity of this tripeptide. This camptothecin nanoplatform shows the same cytotoxic activity than the free drug and is clearly superior to those release systems depending on enzymatic hydrolysis (as determined by calculation of the IC50 ratios).This work was financially supported by "Comision Interministerial de Ciencia y Tecnologia" of Spain (projects CSD2009-00050 and MAT2012-39290-C02-02), and grants from CIBER-BBN (NanoMets Intramural Grant) "Fondo de Investigaciones Sanitarias - Instituto de Salud Carlos III" (PI080771) y "Universidad Catolica de Valencia San Vicente Martir" (PI2011-011-010). CM thanks the Spanish "Ministerio de Economia y Competitividad" for a FPU Ph.D. studentship (AP2008-02851). SSA thanks the "Universidad Catolica de Valencia San Vicente Martir" for a Ph.D. studentship.Muniesa Lajara, C.; Vicente Vilas, V.; Quesada Vilar, M.; Saez-Atienzar, S.; Blesa-Blesa, JR.; Abasolo, I.; Fernández, Y.... (2013). Glutathione-sensitive nanoplatform for monitored intracellular delivery and controlled release of Camptothecin. RSC Advances. 3(35):15121-15131. https://doi.org/10.1039/c3ra41404cS151211513133

Spin-transition frameworks based on bistetrazole and triazine ligands

The present thesis deals with the synthesis and characterisation of new spin-transition materials based on tetrazole and triazine chemistry. The thesis is thus divided in two main parts. The first part examines the iron(II) coordination chemistry with bistetrazoles, which are well-known ligands in the field of spin-crossover research. The central aim is to generate new members of this interesting family of polymeric spin-transition materials based on these ligands, to better assess the structural/coordination features driving the spin-crossover behaviour. An emphasis is therefore given to the analysis of the crystal structures of the various compounds, newly prepared and reported in the literature (both in the high-spin and low-spin states), to be able to evaluate the influence of the various chemical building units on the overall framework. Additionally, the structural changes caused by the spin transition are thoroughly analysed. In the second part, the use of dpyatriz, a triazine-based ligand, as a unit for the construction of spin-transition materials is reported. In the corresponding chapters, the benefit to use triazine chemistry in the field of spin transition is stressed, setting the grounds for future highly promising systems to be developed

Hybrid PLGA-Organosilica Nanoparticles with Redox-Sensitive Molecular Gates

[EN] A novel type of hybrid material based on a PLGA nanoparticle core and a redox-responsive amorphous organosilica shell have been successfully synthesized. The outer layer is obtained by self-assembly of silicate ions with a silsesquioxane containing a disulfide bridge. These organic linkers work as molecular gates that can be selectively cleaved by reducing agents. This system is particularly suitable for storage and release of hydrophobic molecules, as the treatment with dithiothreitol leaves open doors that allow for the discharge of encapsulated molecules in the organic matrix. Using pyrene as a probe molecule, it has been shown that after partial disruption of the organic−inorganic coating, the release mechanism from PLGA particles fits pretty well into Higuchi s model, corresponding to a diffusion-mediated process. These nanohybrids impose a better control and slower release of encapsulated molecules than bare PLGA nanoparticles, are reasonably stable in a physiological medium, and show great potential as stimuli-responsive vehicles for drug delivery.The authors are thankful for financial support by "CICYT" of Spain (projects CSD2009-00050 and MAT2012-39290-C02-02). C.M. thanks the Spanish "Ministerio de Economia y Competitividad" for an FPU Ph.D. studentship (AP2008-02851). We kindly appreciate the technical support of the Electronic Microscopy Service of UPV.Quesada Vilar, M.; Muniesa Lajara, C.; Botella Asuncion, P. (2013). Hybrid PLGA-Organosilica Nanoparticles with Redox-Sensitive Molecular Gates. Chemistry of Materials. 25(13):2597-2602. doi:10.1021/cm400700gS25972602251

Synthesis of ordered mesoporous silica templated with biocompatible surfactants and applications in controlled release of drugs

[EN] A novel series of mesoporous silica materials has been developed by using non-ionic, biocompatible alkyl maltoside surfactants as organic structure directing agents and working under biomimetic conditions (e. g., room temperature and almost neutral pH) to avoid modifications of potential drugs occluded within. The obtained mesophases were tuned by changing the template and its concentration. These sugar surfactant-silica platforms were used as drug delivery carriers for ibuprofen, by encapsulating drug molecules within the hydrophobic core of the template micelles. The obtained surfactant-assisted delivery systems constitute a new approach towards controlled release of small therapeutic molecules.The authors wish to thank CICYT (MAT2006-14274-C02-01) and CSIC (200880I092) for their financial support. We kindly appreciate the technical support of the Electronic Microscopy Service of UPV.Botella Asuncion, P.; Corma Canós, A.; Quesada Vilar, M. (2012). Synthesis of ordered mesoporous silica templated with biocompatible surfactants and applications in controlled release of drugs. Journal of Materials Chemistry. 22(13):6394-6401. doi:10.1039/c2jm16291aS639464012213Shi, J., Votruba, A. R., Farokhzad, O. C., & Langer, R. (2010). Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications. Nano Letters, 10(9), 3223-3230. doi:10.1021/nl102184cVallet-Regí, M., Balas, F., & Arcos, D. (2007). Mesoporous Materials for Drug Delivery. Angewandte Chemie International Edition, 46(40), 7548-7558. doi:10.1002/anie.200604488Manzano, M., & Vallet-Regí, M. (2010). New developments in ordered mesoporous materials for drug delivery. Journal of Materials Chemistry, 20(27), 5593. doi:10.1039/b922651fRosenholm, J. M., & Lindén, M. (2008). Towards establishing structure–activity relationships for mesoporous silica in drug delivery applications. 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Functionalization of mesoporous materials with long alkyl chains as a strategy for controlling drug delivery pattern. J. Mater. Chem., 16(5), 462-466. doi:10.1039/b510101hLu, J., Choi, E., Tamanoi, F., & Zink, J. I. (2008). Light-Activated Nanoimpeller-Controlled Drug Release in Cancer Cells. Small, 4(4), 421-426. doi:10.1002/smll.200700903Aznar, E., Martínez-Máñez, R., & Sancenón, F. (2009). Controlled release using mesoporous materials containing gate-like scaffoldings. Expert Opinion on Drug Delivery, 6(6), 643-655. doi:10.1517/17425240902895980Zhao, Y., Vivero-Escoto, J. L., Slowing, I. I., Trewyn, B. G., & Lin, V. S.-Y. (2010). Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery. Expert Opinion on Drug Delivery, 7(9), 1013-1029. doi:10.1517/17425247.2010.498816Corma, A., Moliner, M., Díaz-Cabañas, M. J., Serna, P., Femenia, B., Primo, J., & García, H. (2008). Biomimetic synthesis of microporous and mesoporous materials at room temperature and neutral pH, with application in electronics, controlled release of chemicals, and catalysis. New Journal of Chemistry, 32(8), 1338. doi:10.1039/b808697bCorma, A., Díaz-Cabañas, M. J., Moliner, M., & Rodríguez, G. (2006). Synthesis of micro- and mesoporous molecular sieves at room temperature and neutral pH catalyzed by functional analogues of silicatein. Chem. Commun., (29), 3137-3139. doi:10.1039/b605909kClifford, N. W., Iyer, K. S., & Raston, C. L. (2008). Encapsulation and controlled release of nutraceuticals using mesoporous silica capsules. J. Mater. Chem., 18(2), 162-165. doi:10.1039/b715100dHe, Q., Shi, J., Chen, F., Zhu, M., & Zhang, L. (2010). An anticancer drug delivery system based on surfactant-templated mesoporous silica nanoparticles. Biomaterials, 31(12), 3335-3346. doi:10.1016/j.biomaterials.2010.01.015Vlachy, N., Touraud, D., Heilmann, J., & Kunz, W. (2009). Determining the cytotoxicity of catanionic surfactant mixtures on HeLa cells. Colloids and Surfaces B: Biointerfaces, 70(2), 278-280. doi:10.1016/j.colsurfb.2008.12.038Tyner, K. M., Schiffman, S. R., & Giannelis, E. P. (2004). Nanobiohybrids as delivery vehicles for camptothecin. Journal of Controlled Release, 95(3), 501-514. doi:10.1016/j.jconrel.2003.12.027Li, F., Jin, L., Han, J., Wei, M., & Li, C. (2009). Synthesis and Controlled Release Properties of Prednisone Intercalated Mg−Al Layered Double Hydroxide Composite. Industrial & Engineering Chemistry Research, 48(12), 5590-5597. doi:10.1021/ie900043rTsai, C.-H., Vivero-Escoto, J. L., Slowing, I. I., Fang, I.-J., Trewyn, B. G., & Lin, V. S.-Y. (2011). Surfactant-assisted controlled release of hydrophobic drugs using anionic surfactant templated mesoporous silica nanoparticles. Biomaterials, 32(26), 6234-6244. doi:10.1016/j.biomaterials.2011.04.077Rahman, M. S., & Rankin, S. E. (2010). Predictive synthesis of ordered mesoporous silica with maltoside and cationic surfactants based on aqueous lyotropic phase behavior. Journal of Colloid and Interface Science, 342(1), 33-42. doi:10.1016/j.jcis.2009.10.021Bagshaw, S. A., Prouzet, E., & Pinnavaia, T. J. (1995). Templating of Mesoporous Molecular Sieves by Nonionic Polyethylene Oxide Surfactants. Science, 269(5228), 1242-1244. doi:10.1126/science.269.5228.1242Kim, S.-S., Pauly, T. R., & Pinnavaia, T. J. (2000). Non-ionic surfactant assembly of wormhole silica molecular sieves from water soluble silicates. Chemical Communications, (10), 835-836. doi:10.1039/b001012jŠtangar, U. L., & Hüsing, N. (2003). Alkyl-glycoside surfactants in the synthesis of mesoporous silica films. Silicon Chemistry, 2(3/4), 157-165. doi:10.1023/b:silc.0000046724.80191.21Pang, J., Eric Hampsey, J., Hu, Q., Wu, Z., John, V. T., & Lu, Y. (2004). Mesoporous silica with Ia3d cubic structure and good thermal stability. Chem. Commun., (6), 682-683. doi:10.1039/b316501aBeck, J. S., Vartuli, J. C., Roth, W. J., Leonowicz, M. E., Kresge, C. T., Schmitt, K. D., … Schlenker, J. L. (1992). A new family of mesoporous molecular sieves prepared with liquid crystal templates. Journal of the American Chemical Society, 114(27), 10834-10843. doi:10.1021/ja00053a020Brunauer, S., Emmett, P. H., & Teller, E. (1938). Adsorption of Gases in Multimolecular Layers. Journal of the American Chemical Society, 60(2), 309-319. doi:10.1021/ja01269a023Barrett, E. P., Joyner, L. G., & Halenda, P. P. (1951). The Determination of Pore Volume and Area Distributions in Porous Substances. I. Computations from Nitrogen Isotherms. Journal of the American Chemical Society, 73(1), 373-380. doi:10.1021/ja01145a126Rosen, M. J., & Sulthana, S. B. (2001). The Interaction of Alkylglycosides with Other Surfactants. Journal of Colloid and Interface Science, 239(2), 528-534. doi:10.1006/jcis.2001.7537Enders, S., & Kahl, H. (2007). Aggregation behaviour of n-alkyl-β-d-glucopyranoside+water+alcohol mixtures. Fluid Phase Equilibria, 261(1-2), 221-229. doi:10.1016/j.fluid.2007.07.038Auvray, X., Petipas, C., Anthore, R., Rico-Lattes, I., & Lattes, A. (1995). X-ray Diffraction Study of the Ordered Lyotropic Phases Formed by Sugar-Based Surfactants. Langmuir, 11(2), 433-439. doi:10.1021/la00002a012Petitto, C., Galarneau, A., Driole, M.-F., Chiche, B., Alonso, B., Di Renzo, F., & Fajula, F. (2005). Synthesis of Discrete Micrometer-Sized Spherical Particles of MCM-48. Chemistry of Materials, 17(8), 2120-2130. doi:10.1021/cm050068jPouxviel, J. C., Boilot, J. P., Beloeil, J. C., & Lallemand, J. Y. (1987). NMR study of the sol/gel polymerization. Journal of Non-Crystalline Solids, 89(3), 345-360. doi:10.1016/s0022-3093(87)80277-6Simonutti, R., Comotti, A., Bracco, S., & Sozzani, P. (2001). Surfactant Organization in MCM-41 Mesoporous Materials As Studied by13C and29Si Solid-State NMR. Chemistry of Materials, 13(3), 771-777. doi:10.1021/cm001088iBotella, P., Corma, A., & Navarro, M. T. (2007). Single Gold Nanoparticles Encapsulated in Monodispersed Regular Spheres of Mesostructured Silica Produced by Pseudomorphic Transformation. Chemistry of Materials, 19(8), 1979-1983. doi:10.1021/cm0629457Kung, K. H. S., & Hayes, K. F. (1993). Fourier transform infrared spectroscopic study of the adsorption of cetyltrimethylammonium bromide and cetylpyridinium chloride on silica. Langmuir, 9(1), 263-267. doi:10.1021/la00025a050Kačuráková, M., & Mathlouthi, M. (1996). FTIR and laser-Raman spectra of oligosaccharides in water: characterization of the glycosidic bond. Carbohydrate Research, 284(2), 145-157. doi:10.1016/0008-6215(95)00412-2Holmberg, K. (2001). Natural surfactants. Current Opinion in Colloid & Interface Science, 6(2), 148-159. doi:10.1016/s1359-0294(01)00074-7Wei, H., Zhang, X.-Z., Zhou, Y., Cheng, S.-X., & Zhuo, R.-X. (2006). 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Bimetallic nanosized solids with acid and redox properties for catalytic activation of C-C and C-H bonds

A new approach is presented to form self-supported bimetallic nanosized solids with acid and redox catalytic properties. They are water-, air- and H-2-stable, and are able to activate demanding C-C and C-H reactions. A detailed mechanistic study on the formation of the Ag-Fe bimetallic system shows that a rapid redox-coupled sequence between Ag+, O-2 (air) and Fe2+ occurs, giving monodisperse Ag nanoparticles supported by O-bridged diatomic Fe3+ triflimides. The system can be expanded to Ag nanoparticles embedded within a matrix of Cu2+, Bi3+ and Yb3+ triflimide.Financial support by the "Severo Ochoa" program, RETOS program (CTQ2014-55178 R) and Ramon y Cajal Program (A.L.-P.) by MINECO (Spain), and also by "Convocatoria 2014 de Ayudas Fundacion BBVA a Investigadores y Creadores Culturales" are acknowledged. The Electron Microscopy Service of the UPV is also acknowledged.Cabrero Antonino, JR.; Tejeda-Serrano, M.; Quesada Vilar, M.; Vidal Moya, JA.; Leyva Perez, A.; Corma Canós, A. (2017). Bimetallic nanosized solids with acid and redox properties for catalytic activation of C-C and C-H bonds. Chemical Science. 8(1):689-696. https://doi.org/10.1039/c6sc03335kS68969681Antoniotti, S., Dalla, V., & Duñach, E. (2010). Metal Triflimidates: Better than Metal Triflates as Catalysts in Organic Synthesis-The Effect of a Highly Delocalized Counteranion. Angewandte Chemie International Edition, 49(43), 7860-7888. doi:10.1002/anie.200906407White, M. C. (2012). Adding Aliphatic C-H Bond Oxidations to Synthesis. Science, 335(6070), 807-809. doi:10.1126/science.1207661Felpin, F.-X., & Fouquet, E. (2008). Heterogeneous Multifunctional Catalysts for Tandem Processes: An Approach toward Sustainability. ChemSusChem, 1(8-9), 718-724. doi:10.1002/cssc.200800110Díaz, U., Brunel, D., & Corma, A. (2013). Catalysis using multifunctional organosiliceous hybrid materials. Chemical Society Reviews, 42(9), 4083. doi:10.1039/c2cs35385gRey, I., Johansson, P., Lindgren, J., Lassègues, J. C., Grondin, J., & Servant, L. (1998). Spectroscopic and Theoretical Study of (CF3SO2)2N-(TFSI-) and (CF3SO2)2NH (HTFSI). The Journal of Physical Chemistry A, 102(19), 3249-3258. doi:10.1021/jp980375vKurtz, D. M. (1990). Oxo- and hydroxo-bridged diiron complexes: a chemical perspective on a biological unit. Chemical Reviews, 90(4), 585-606. doi:10.1021/cr00102a002Cabrero-Antonino, J. R., Leyva-Pérez, A., & Corma, A. (2012). Regioselective Hydration of Alkynes by Iron(III) Lewis/Brønsted Catalysis. Chemistry - A European Journal, 18(35), 11107-11114. doi:10.1002/chem.201200580Desireddy, A., Conn, B. E., Guo, J., Yoon, B., Barnett, R. N., Monahan, B. M., … Bigioni, T. P. (2013). Ultrastable silver nanoparticles. Nature, 501(7467), 399-402. doi:10.1038/nature12523Skupinska, J. (1991). Oligomerization of .alpha.-olefins to higher oligomers. Chemical Reviews, 91(4), 613-648. doi:10.1021/cr00004a007Choi, J. H., Kwon, J. K., RajanBabu, T. V., & Lim, H. J. (2013). Highly Efficient Catalytic Dimerization of StyrenesviaCationic Palladium(II) Complexes. Advanced Synthesis & Catalysis, 355(18), 3633-3638. doi:10.1002/adsc.201300864Bedford, R. B., Betham, M., Blake, M. E., Garcés, A., Millar, S. L., & Prashar, S. (2005). Asymmetric styrene dimerisation using mixed palladium–indium catalysts. Tetrahedron, 61(41), 9799-9807. doi:10.1016/j.tet.2005.06.083Wang, C.-C., Lin, P.-S., & Cheng, C.-H. (2004). Cobalt-catalyzed dimerization of alkenes. Tetrahedron Letters, 45(32), 6203-6206. doi:10.1016/j.tetlet.2004.04.085Cabrero-Antonino, J. R., Leyva-Pérez, A., & Corma, A. (2010). Iron-Catalysed Regio- and Stereoselective Head-to-Tail Dimerisation of Styrenes. Advanced Synthesis & Catalysis, 352(10), 1571-1576. doi:10.1002/adsc.201000096Shimura, S., Miura, H., Tsukada, S., Wada, K., Hosokawa, S., & Inoue, M. (2012). Highly Selective Linear Dimerization of Styrenes by Ceria-Supported Ruthenium Catalysts. ChemCatChem, 4(12), 2062-2067. doi:10.1002/cctc.201200342Hintermann, L., & Labonne, A. (2007). Catalytic Hydration of Alkynes and Its Application in Synthesis. Synthesis, 2007(8), 1121-1150. doi:10.1055/s-2007-966002Ebule, R. E., Malhotra, D., Hammond, G. B., & Xu, B. (2016). Ligand Effects in the Gold Catalyzed Hydration of Alkynes. Advanced Synthesis & Catalysis, 358(9), 1478-1481. doi:10.1002/adsc.201501079Liang, S., Jasinski, J., Hammond, G. B., & Xu, B. (2014). Supported Gold Nanoparticle-Catalyzed Hydration of Alkynes under Basic Conditions. Organic Letters, 17(1), 162-165. doi:10.1021/ol5033859Leyva, A., & Corma, A. (2009). Isolable Gold(I) Complexes Having One Low-Coordinating Ligand as Catalysts for the Selective Hydration of Substituted Alkynes at Room Temperature without Acidic Promoters. The Journal of Organic Chemistry, 74(5), 2067-2074. doi:10.1021/jo802558eNairoukh, Z., Avnir, D., & Blum, J. (2013). Acid-Catalyzed Hydration of Alkynes in Aqueous Microemulsions. ChemSusChem, 6(3), 430-432. doi:10.1002/cssc.201200838Mameda, N., Peraka, S., Marri, M. R., Kodumuri, S., Chevella, D., Gutta, N., & Nama, N. (2015). Solvent-free hydration of alkynes over Hβ zeolite. Applied Catalysis A: General, 505, 213-216. doi:10.1016/j.apcata.2015.07.038Alonso, F., Beletskaya, I. P., & Yus, M. (2004). Transition-Metal-Catalyzed Addition of Heteroatom−Hydrogen Bonds to Alkynes. Chemical Reviews, 104(6), 3079-3160. doi:10.1021/cr0201068Lennon, P., Rosan, A. M., & Rosenblum, M. (1977). Metal assisted carbon-carbon bond formation. Addition of carbon nucleophiles to dicarbonyl .eta.5-cyclopentadienyl(olefin)iron cations. Journal of the American Chemical Society, 99(26), 8426-8439. doi:10.1021/ja00468a009Qian, H., & Widenhoefer, R. A. (2003). Mechanism of the Palladium-Catalyzed Intramolecular Hydroalkylation of 7-Octene-2,4-dione. Journal of the American Chemical Society, 125(8), 2056-2057. doi:10.1021/ja0293002Kischel, J., Michalik, D., Zapf, A., & Beller, M. 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Surface-modified silica nanoparticles for tumor-targeted delivery of camptothecin and its biological evaluation

[EN] Here we report the design, synthesis and biological evaluation of surface-modified silica nanoparticles (SNP) for the delivery of camptothecin (CPT). Drug has been covalently linked to the nanoparticle through an ester bond with the 20-hydroxy moiety, in order to stabilize its lactone ring and to avoid unspecific release of the drug. The obtained material is highly stable in plasma, with low release of the cargo at physiological pH. Cell internalization and in vitro efficacy assays demonstrated that nanoparticles carrying CPT (SNP-CPT) entered cells via endocytosis and the intracellular release of the cargo induced cell death with half maximal inhibitory concentration (IC(50)) values and cell cycle distribution profiles similar to those observed for the naked drug. Further, in vivo biodistribution, therapeutic efficacy and biocompatibility of the SNP-CPT were evaluated in human colorectal cancer xenografts using in vivo fluorescence or bioluminescence optical imaging. In vivo tumor-accumulation and whole-body tissue distribution were carried out based on the acquisition of fluorescence emission of a fluorophore (Cy5.5) conjugated to the SNP-CPT, as well as by HPLC quantification of tissue CPT levels. The results showed that, although SNP-CPT tended to accumulate in organs of the reticuloendothelial system, nanoparticles boost CPT concentration in tumor vs administration of the free drug. Accordingly, SNP-CPT treatment delayed the growth of subcutaneous tumors while significantly reducing the systemic toxicity associated with CPT administration. These results indicate that the SNP-CPT could be used as a robust drug delivery system for antitumoral treatments based on CPT. (C) 2011 Elsevier B. V. All rights reserved.This work was financially supported by "Comision Interministerial de Ciencia y Tecnologia" of Spain (project MAT2006-14274-C02-01 to A. C.), Spanish National Research Council (project 200880I092 to P. B.) and grants from CIBER-BBN (NanoMets Intramural Grant) and "Fondo de Investigaciones Sanitarias - Instituto de Salud Carlos III" (PI080771) to S. S. CM thanks the Spanish "Ministerio de Ciencia e Innovacion" for a FPU Ph D studentship (AP2008-02851).Botella Asuncion, P.; Abasolo, I.; Fernández, Y.; Muniesa Lajara, C.; Miranda, S.; Quesada Vilar, M.; Ruiz Carrascal, J.... (2011). Surface-modified silica nanoparticles for tumor-targeted delivery of camptothecin and its biological evaluation. Journal of Controlled Release. 156(2):246-257. https://doi.org/10.1016/j.jconrel.2011.06.039S246257156

Multifunctional hybrid materials for combined photo and chemotherapyof cancer

[EN] Combined chemo and photothermal therapy in in vitro testing has been achieved by means of multifunctional nanoparticles formed by plasmonic gold nanoclusters with a protecting shell of porous silica that contains an antitumor drug. We propose a therapeutic nanoplatform that associates the optical activity of small gold nanoparticles aggregates with the cytotoxic activity of 20(S)-camptothecin simultaneously released for the efficient destruction of cancer cells. For this purpose, a method was used for the controlled assembly of gold nanoparticles into stable clusters with a tailored absorption crosssection in the vis/NIR spectrum, which involves aggregation in alkaline medium of 15 nm diameter gold colloids protected with a thin silica layer. Clusters were further encapsulated in an ordered homogeneous mesoporous silica coating that provides biocompatibility and stability in physiological fluids. After internalization in 42-MG-BA human glioma cells, these protected gold nanoclusters were able to produce effective photothermolysis under femtosecond pulse laser irradiation of 790 nm. Cell death occurred by combination of a thermal mechanism and mechanical disruption of the membrane cell due to induced generation of micrometer-scale bubbles by vaporizing the water inside the channels of the mesoporous silica coating. Moreover, the incorporation of 20(S)-camptothecin within the pores of the external shell, which was released during the process, provoked significant cell death increase. This therapeutic model could be of interest for application in the treatment and suppression of non-solid tumors.This work was financially supported by Comision Interministerial de Ciencia y Tecnologia of Spain through the projects FIS2006-09319, SAF2008-03694, MAT2006-14274-C02-01 and MULTICAT (Consolider-Ingenio 2010). CM thanks the Spanish "Ministerio de Economia y Competitividad" for a FDU Ph D studentship (AP2008-02851).Botella Asuncion, P.; Ortega, I.; Quesada Vilar, M.; Madrigal Madrigal, RF.; Muniesa Lajara, C.; Fimia Gil, A.; Fernandez Jover, E.... (2012). Multifunctional hybrid materials for combined photo and chemotherapyof cancer. Dalton Transactions. 41(31):9243-9554. https://doi.org/10.1039/c2dt30381gS92439554413

Intracellular Delivery of Anti-SMC2 Antibodies against Cancer Stem Cells

Structural maintenance of chromosomes protein 2 (SMC2) is a central component of the condensin complex involved in DNA supercoiling, an essential process for embryonic stem cell survival. SMC2 over-expression has been related with tumorigenesis and cancer malignancy and its inhibition is regarded as a potential therapeutic strategy even though no drugs are currently available. Here, we propose to inhibit SMC2 by intracellular delivery of specific antibodies against the SMC2 protein. This strategy aims to reduce cancer malignancy by targeting cancer stem cells (CSC), the tumoral subpopulation responsible of tumor recurrence and metastasis. In order to prevent degradation and improve cellular internalization, anti-SMC2 antibodies (Ab-SMC2) were delivered by polymeric micelles (PM) based on Pluronic ® F127 amphiphilic polymers. Importantly, scaffolding the Ab-SMC2 onto nanoparticles allowed its cellular internalization and highly increased its efficacy in terms of cytotoxicity and inhibition of tumorsphere formation in MDA-MB-231 and HCT116 breast and colon cancer cell lines, respectively. Moreover, in the case of the HCT116 cell line G1, cell-cycle arrest was also observed. In contrast, no effects from free Ab-SMC2 were detected in any case. Further, combination therapy of anti-SMC2 micelles with paclitaxel (PTX) and 5-Fluorouracil (5-FU) was also explored. For this, PTX and 5-FU were respectively loaded into an anti-SMC2 decorated PM. The efficacy of both encapsulated drugs was higher than their free forms in both the HCT116 and MDA-MB-231 cell lines. Remarkably, micelles loaded with Ab-SMC2 and PTX showed the highest efficacy in terms of inhibition of tumorsphere formation in HCT116 cells. Accordingly, our data clearly suggest an effective intracellular release of antibodies targeting SMC2 in these cell models and, further, strong cytotoxicity against CSC, alone and in combined treatments with Standard-of-Care drug