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Polyglutamic Acid-Gated Mesoporous Silica Nanoparticles for Enzyme-Controlled Drug Delivery
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Langmuir, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.langmuir.6b01715. ; Mesoporous silica nanoparticles (MSNs) are highly attractive as supports in the design of controlled delivery systems that can act as containers for the encapsulation of therapeutic agents, overcoming common issues such as poor water solubility and poor stability of some drugs and also enhancing their bioavailability. In this context, we describe herein the development of polyglutamic acid (PGA)-capped MSNs that can selectively deliver rhodamine B and doxorubicin. PGA-capped MSNs remain closed in an aqueous environment, yet they are able to deliver the cargo in the presence of pronase because of the hydrolysis of the peptide bonds in PGA. The prepared solids released less than 20% of the cargo in 1 day in water, whereas they were able to reach 90% of the maximum release of the entrapped guest in ca. 5 h in the presence of pronase. Studies of the PGA-capped nanoparticles with SK-BR-3 breast cancer cells were also undertaken. Rhodamine-loaded nanoparticles were not toxic, whereas doxorubicin-loaded nanoparticles were able to efficiently kill more than 90% of the cancer cells at a concentration of 100 μg/mL. ; A.T. wishes to express her gratitude to the Erasmus mundus (Svagata.eu) financial support. A.U. and C. de la T. are grateful to the Spanish Ministry of Education, Culture and Sport for her doctoral fellowship. We thank the Spanish Government (Project MAT2015-64139-C4-1-R, MINECO/FEDER) and Generalitat Valenciana (Project PROMETEOII/2014/047) for their support. The authors also thank UPV electron microscopy services for the technical support. ; Tukappa, A.; Ultimo, A.; De La Torre Paredes, C.; Pardo Vicente, MT.; Sancenón Galarza, F.; Martínez-Máñez, R. (2016). Polyglutamic Acid-Gated Mesoporous Silica ...
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epsilon-Polylysine-Capped Mesoporous Silica Nanoparticles as Carrier of the C9h Peptide to Induce Apoptosis in Cancer Cells
[EN] Apoptotic signaling pathways are altered in numerous pathologies such as cancer. In this scenario, caspase-9/PP2Ac alpha interaction constitutes a key target with pharmacological interest to re-establish apoptosis in tumor cells. Very recently, a short peptide (C9h) known to disrupt caspase-9/PP2Ac alpha interaction with subsequent apoptosis induction was described. Here, we prepared two sets of mesoporous silica nanoparticles loaded with safraninO (S2) or with C9h peptide (S4) and functionalized with epsilon-polylysine as capping unit. Aqueous suspensions of both nanoparticles showed negligible cargo release whereas in the presence of pronase, a marked delivery of safraninO or C9h was observed. Confocal microscopy studies carried out with HeLa cells indicated that both materials were internalized and were able to release their entrapped cargos. Besides, a marked decrease in HeLa cell viability (ca. 50%) was observed when treated with C9h-loaded S4 nanoparticles. Moreover, S4 provides peptide protection from degradation additionally allowing for a dose reduction to observe an apoptotic effect when compared with C9h alone or in combination with a cell-penetrating peptide (i.e., Mut3DPT-C9h). Flow cytometry studies, by means of Annexin V-FITC staining, showed the activation of apoptotic pathways in HeLa as a consequence of S4 internalization, release of C9h peptide and disruption of caspase-9/PP2Ac alpha interaction. ; The authors wish to express their gratitude to the Spanish government (Projects MAT2015-64139-C4-1, SAF2012-31405, SAF2015-67077-R, AGL2015-70235-C2-2-R (MINECO/FEDER)), the Generalitat Valencia (Projects PROMETEOII/2014/047, PROMETEO/2012/061) and the CIBER-BBN for their support. C.T. is grateful to the Spanish Ministry of Science and Innovation for her Ph.D. fellowship. ; De La Torre-Paredes, C.; Domínguez-Berrocal, L.; Murguía, JR.; Marcos Martínez, MD.; Martínez-Máñez, R.; Bravo, J.; Sancenón Galarza, F. (2018). epsilon-Polylysine-Capped Mesoporous Silica Nanoparticles as Carrier of the C9h ...
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Drug delivery nanosystems for the localized treatment of glioblastoma multiforme
[EN] Glioblastoma multiforme is one of the most prevalent and malignant forms of central nervous system tumors. The treatment of glioblastoma remains a great challenge due to its location in the intracranial space and the presence of the blood-brain tumor barrier. There is an urgent need to develop novel therapy approaches for this tumor, to improve the clinical outcomes, and to reduce the rate of recurrence and adverse effects associated with present options. The formulation of therapeutic agents in nanostructures is one of the most promising approaches to treat glioblastoma due to the increased availability at the target site, and the possibility to co-deliver a range of drugs and diagnostic agents. Moreover, the local administration of nanostructures presents significant additional advantages, since it overcomes blood-brain barrier penetration issues to reach higher concentrations of therapeutic agents in the tumor area with minimal side effects. In this paper, we aim to review the attempts to develop nanostructures as local drug delivery systems able to deliver multiple agents for both therapeutic and diagnostic functions for the management of glioblastoma. ; This research was funded by an Ussher start-up funding award (School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin) and the European Union's Horizon 2020 research and innovation program under Grant agreement No. 708036. ; Nam, L.; Coll Merino, MC.; Erthal, L.; De La Torre-Paredes, C.; Serrano, D.; Martínez-Máñez, R.; Santos-Martinez, M. (2018). Drug delivery nanosystems for the localized treatment of glioblastoma multiforme. Materials. 11(5). https://doi.org/10.3390/ma11050779 ; S ; 11 ; 5 ; Goodenberger, M. L., & Jenkins, R. B. (2012). Genetics of adult glioma. Cancer Genetics, 205(12), 613-621. doi:10.1016/j.cancergen.2012.10.009 ; Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., … Kleihues, P. (2007). The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica, ...
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Drug delivery nanosystems for the localized treatment of glioblastoma multiforme
11 5 ; S ; Ma, D. (2014). Enhancing endosomal escape for nanoparticle mediated siRNA delivery. Nanoscale, 6(12), 6415. doi:10.1039/c4nr00018h ; [EN] Glioblastoma multiforme is one of the most prevalent and malignant forms of central nervous system tumors. The treatment of glioblastoma remains a great challenge due to its location in the intracranial space and the presence of the blood-brain tumor barrier. There is an urgent need to develop novel therapy approaches for this tumor, to improve the clinical outcomes, and to reduce the rate of recurrence and adverse effects associated with present options. The formulation of therapeutic agents in nanostructures is one of the most promising approaches to treat glioblastoma due to the increased availability at the target site, and the possibility to co-deliver a range of drugs and diagnostic agents. Moreover, the local administration of nanostructures presents significant additional advantages, since it overcomes blood-brain barrier penetration issues to reach higher concentrations of therapeutic agents in the tumor area with minimal side effects. In this paper, we aim to review the attempts to develop nanostructures as local drug delivery systems able to deliver multiple agents for both therapeutic and diagnostic functions for the management of glioblastoma. This research was funded by an Ussher start-up funding award (School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin) and the European Union's Horizon 2020 research and innovation program under Grant agreement No. 708036. Nam, L.; Coll Merino, MC.; Erthal, L.; De La Torre-Paredes, C.; Serrano, D.; Martínez-Máñez, R.; Santos-Martinez, M. (2018). Drug delivery nanosystems for the localized treatment of glioblastoma multiforme. Materials. 11(5). https://doi.org/10.3390/ma11050779 Goodenberger, M. L., & Jenkins, R. B. (2012). Genetics of adult glioma. Cancer Genetics, 205(12), 613-621. doi:10.1016/j.cancergen.2012.10.009 Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., ...
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Nanoparticle-cell-nanoparticle communication by stigmergy to enhance poly(I:C) induced apoptosis in cancer cells
[EN] Nanoparticle-cell-nanoparticle communication by stigmergy was demonstrated using two capped nanodevices. The first community of nanoparticles (i.e.S(RA)(IFN)) is loaded with 9-cis-retinoic acid and capped with interferon-gamma, whereas the second community of nanoparticles (i.e.S(sulf)(PIC)) is loaded with sulforhodamine B and capped with poly(I:C). The uptake ofS(RA)(IFN)by SK-BR-3 breast cancer cells enhanced the expression of TLR3 receptor facilitating the subsequent uptake ofS(sulf)(PIC)and cell killing. ; We thank the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22 (MCUI/FEDER, EU)), Generalitat Valenciana (project PROMETEO2018/024) and CIBER-BBN (project NANOCOMMUNITY) for support. A. U. and C. G are grateful to the Ministry of Education, Culture and Sport for her doctoral FPU grant. ; Ultimo, A.; De La Torre-Paredes, C.; Giménez, C.; Aznar, E.; Coll, C.; Marcos Martínez, MD.; Murguía, JR. (2020). Nanoparticle-cell-nanoparticle communication by stigmergy to enhance poly(I:C) induced apoptosis in cancer cells. Chemical Communications. 56(53):7273-7276. https://doi.org/10.1039/d0cc02795b ; S ; 7273 ; 7276 ; 56 ; 53 ; Schaming, D., & Remita, H. (2015). Nanotechnology: from the ancient time to nowadays. Foundations of Chemistry, 17(3), 187-205. doi:10.1007/s10698-015-9235-y ; Hauert, S., & Bhatia, S. N. (2014). Mechanisms of cooperation in cancer nanomedicine: towards systems nanotechnology. Trends in Biotechnology, 32(9), 448-455. doi:10.1016/j.tibtech.2014.06.010 ; Theraulaz, G., & Bonabeau, E. (1999). A Brief History of Stigmergy. Artificial Life, 5(2), 97-116. doi:10.1162/106454699568700 ; Llopis-Lorente, A., Díez, P., Sánchez, A., Marcos, M. D., Sancenón, F., Martínez-Ruiz, P., … Martínez-Máñez, R. (2017). Interactive models of communication at the nanoscale using nanoparticles that talk to one another. Nature Communications, 8(1). doi:10.1038/ncomms15511 ; Luis, B., Llopis‐Lorente, A., Rincón, P., Gadea, J., Sancenón, F., Aznar, E., … Martínez‐Máñez, R. (2019). ...
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Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles
"This is the peer reviewed version of the following article: Llopis-Lorente, Antoni, Paula Díez, Cristina de la Torre, Alfredo Sánchez, Félix Sancenón, Elena Aznar, María D. Marcos, Paloma Martínez-Ruíz, Ramón Martínez-Máñez, and Reynaldo Villalonga. 2017. Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles. Chemistry - A European Journal 23 (18). Wiley: 4276 81. doi:10.1002/chem.201700603, which has been published in final form at https://doi.org/10.1002/chem.201700603. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." ; [EN] This work reports a new gated nanodevice for acetylcholine-triggered cargo delivery. We prepared and characterized Janus Au-mesoporous silica nanoparticles functionalized with acetylcholinesterase on the Au face and with supramolecular b-cyclodextrin: benzimidazole inclusion complexes as caps on the mesoporous silica face. The nanodevice is able to selectively deliver the cargo in the presence of acetylcholine via enzyme-mediated acetylcholine hydrolysis, locally lowering the pH and opening the supramolecular gate. Given the key role played by ACh and its relation with Parkinson's disease and other nervous system diseases, we believe that these findings could help design new therapeutic strategies. ; A.L.L. is grateful to "La Caixa" Banking Foundation for his PhD fellowship. The authors are gratitude to the Spanish Government (MINECO Projects MAT2012-38429-C04-01, MAT2015-64139-C4-1, CTQ2014-58989-P and CTQ2015-71936-REDT) and the Generalitat Valencia (Project PROMETEOII/2014/047) for support. The Comunidad de Madrid (S2013/MIT-3029, Programme NANOAVANSENS) is also gratefully acknowledged. ; Llopis-Lorente, A.; Díez, P.; De La Torre-Paredes, C.; Sanchez, A.; Sancenón Galarza, F.; Aznar, E.; Marcos Martínez, MD. (2017). Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles. Chemistry - ...
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Caspase 3 Targeted Cargo Delivery in Apoptotic Cells Using Capped Mesoporous Silica Nanoparticles
[EN] Excessive apoptotic cell death is at the origin of several pathologies, such as degenerative disorders, stroke or ischemia-reperfusion damage. In this context, strategies to improve inhibition of apoptosis and other types of cell death are of interest and may represent a pharmacological opportunity for the treatment of cell-death-related disorders. In this scenario new peptide-containing delivery systems (solids S1-P1and S1-P2) are described based on meso-porous silica nanoparticles (MSNs) loaded with a dye and capped with the KKGDEVDKKARDEVDK (P1) peptide that contains two repeats of the DEVD target sequence that are selectively hydrolyzed by caspase3 (C3). This enzyme plays a central role in the execution-phase of apoptosis. HeLa cells electroporated with S1 P1are able to deliver the cargo in the presence of staurosporin (STS), which induces apoptosis with the consequent activation of the cytoplasmic C3 enzyme. Moreover, the nanoparticles S1-P2,containing both a cell-penetrating TAT peptide and P1 also entered in HeLa cells and delivered the cargo preferentially in cells treated with the apoptosis inducer cisplatin. ; We thank the Spanish Government (Project MAT2012-38429-C04 and SAF2010-15512) and the Generalitat Valenciana (PROMETEOII/2014/061) for support. C.T. is grateful to the Spanish Ministry of Science and Innovation for her PhD fellowship. L.M. thanks the Generalitat Valenciana (VALI+D program), Nice city council ("Aides Individuelles aux Jeunes Chercheurs - 2011") and Fondation de la Recherche Medicale for her postdoctoral contracts. C.C. thanks the Generalitat Valenciana for their postdoctoral contract VALI+D. We thank the confocal microscopy service, Alberto Hernandez from CIPF confocal microscopy service for their technical support. ; De La Torre Paredes, C.; Mondragón Martínez, L.; Coll Merino, MC.; García-Fernández, A.; Sancenón Galarza, F.; Martínez-Máñez, R.; Amorós, P. (2015). Caspase 3 Targeted Cargo Delivery in Apoptotic Cells Using Capped Mesoporous Silica Nanoparticles. Chemistry - A ...
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Ex Vivo Tracking of Endogenous CO with a Ruthenium(II) Complex
[EN] A two-photon fluorescent probe based on a ruthenium(II) vinyl complex is capable of selectively detecting carbon monoxide in cells and ex vivo using mice with a subcutaneous air pouch as a model for inflammation. This probe combines highly selective and sensitive ex vivo detection of endogenous CO in a realistic model with facile, inexpensive synthesis, and displays many advantages over the widely used palladium-based systems. ; The authors thank the Spanish government (Project MAT2015-64139-C4-1), the Generalitat Valencia (Project PROME-TEOII/2014/047), CIBER-BBN, IC Global Engagements fund, Santander Mobility Award. C.T. is grateful to the Spanish Ministry of Science and Innovation, A.T. thanks the Leverhulme Trust (RPG-2012-634) and J.A.R. thanks the EPSRC, for PhD studentships. ; De La Torre-Paredes, C.; Toscani, A.; Marín-Hernández, C.; Robson, JA.; Terencio, MC.; White, AJ.; Alcaraz, MJ. (2017). Ex Vivo Tracking of Endogenous CO with a Ruthenium(II) Complex. Journal of the American Chemical Society. 139(51):18484-18487. https://doi.org/10.1021/jacs.7b11158 ; S ; 18484 ; 18487 ; 139 ; 51
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Azide and sulfonylazide functionalized fluorophores for the selective and sensitive detection of hydrogen sulfide
[EN] Three fluorescent probes (1–3) for the selective and sensitive detection of hydrogen sulfide have been synthesized and characterized. Probe 1 is a coumarin derivative functionalized with an azide moiety whereas 2 contain the azide reactive group into a naphthalene fluorophore backbone. Probe 3 is composed also by a naphthalene fluorophore but, in this case, functionalized with a sulfonylazide reactive moiety. Probes 1 and 3 are non-fluorescent whereas 2 is weakly emissive in HEPES (10 mM, pH 7.4)–DMSO 99:1 (v/v). The emission behavior of the three probes was tested against selected anions, bio-thiols and oxidant molecules. Of all the chemical species tested, only HS− is able to induce an enhancement in the emission intensity (50, 11 and 20-fold for 1, 2 and 3, respectively). The observed emission in the presence of hydrogen sulfide is ascribed, in the case of probes 1 and 2, to an azide–amine reduction induced by HS− anion, whereas for probe 3 the sensing mechanism is related with a sulfonylazide–sulfonamide conversion. The three probes are very sensitive to HS− anion with limits of detection of 0.17, 0.20 and 0.40 mM for 1, 2 and 3 respectively. Cell viability studies demonstrated that 1–3 probes are essentially non-toxic at concentrations 10–50 μM and are well suited for in vivo studies. Finally, probe 1 was used for the detection on intracellular HS− anion in HeLa cells by means of confocal microscopy. ; Financial support from the Spanish Government (Project MAT2012-38429-004-01) and the Generalitat Valenciana (Project PROMETEO/2009/016) is gratefully acknowledged. S.E. is grateful to the Generalitat Valenciana for his Santiago Grisolia fellow. C.T. also thanks the Ministerio de Ciencia e Innovacion for her FPU grant. L.E.S.F. thanks the Carolina Foundation and UPNFM-Honduras for his doctoral grant. ; El Sayed Shehata Nasr, S.; De La Torre Paredes, C.; Santos Figueroa, LE.; Marín Hernández, C.; Martínez Mañez, R.; Sancenón Galarza, F.; Costero Nieto, AM. (2015). Azide and sulfonylazide functionalized ...
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Amidase-responsive controlled release of antitumoral drug into intracellular media using gluconamide-capped mesoporous silica nanoparticles
MCM-41 silica nanoparticles were used as inorganic scaffolding to prepare a nanoscopic-capped hybrid material S1, which was able to release an entrapped cargo in the presence of certain enzymes, whereas in the absence of enzymes, a zero release system was obtained. S1 was prepared by loading nanoparticles with Safranine O dye and was then capped with a gluconamide derivative. In the absence of enzymes, the release of the dye from the aqueous suspensions of S1 was inhibited as a result of the steric hindrance imposed by the bulky gluconamide derivative, the polymerized gluconamide layer and the formation of a dense hydrogen-bonded network around the pore outlets. Upon the addition of amidase and pronase enzymes, delivery of Safranine O dye was observed due to the enzymatic hydrolysis of the amide bond in the anchored gluconamide derivative. S1 nanoparticles were not toxic for cells, as demonstrated by cell viability assays using HeLa and MCF-7 cell lines, and were associated with lysosomes, as shown by confocal microscopy. Finally, the S1¿CPT material loaded with the cytotoxic drug camptothecin and capped with the gluconamide derivative was prepared. The HeLa cells treated with S1¿CPT underwent cell death as a result of material internalization, and of the subsequent cellular enzyme-mediated hydrolysis and aperture of the molecular gate, which induced the release of the camptothecin cargo. ; We thank the Spanish Government (Project MAT2009-14564-C04 and SAF2010-15512) and the Generalitat Valenciana (Project PROMETEO/2009/016and/2010/005) for support. I. C. thanks the Universitat Politecnica de Valencia for her fellowship. L. M. thanks the Generalitat Valenciana for her post-doctoral VALi+d contract. E. A. and C. T. also thank the CIBER-BBN for contracts. We thank Eva Maria Lafuente Villarreal and Alberto Hernandez Cano from the Confocal Microscopy service of CIPF and the Electronic Microscopy service of UPV for their technical support. ; Candel Busquets, I.; Aznar Gimeno, E.; Mondragón Martínez, L.; De La Torre ...
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