Suchergebnisse

[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 ...

This is the peer reviewed version of the following article: B. Lozano-Torres, J. F. Blandez, I. Galiana, A. García-Fernández, M. Alfonso, M. D. Marcos, M. Orzáez, F. Sancenón, R. Martínez-Máñez, Angew. Chem. Int. Ed. 2020, 59, 15152., which has been published in final form at https://doi.org/10.1002/anie.202004142. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. ; [EN] In vivo detection of cellular senescence is accomplished by using mesoporous silica nanoparticles loaded with the NIR-FDA approved Nile blue (NB) dye and capped with a galactohexasaccharide (S3). NB emission at 672 nm is highly quenched inside S3, yet a remarkable emission enhancement is observed upon cap hydrolysis in the presence of beta-galactosidase and dye release. The efficacy of the probe to detect cellular senescence is tested in vitro in melanoma SK-Mel-103 and breast cancer 4T1 cells and in vivo in palbociclib-treated BALB/cByJ mice bearing breast cancer tumor. ; R.M. thanks financial support from the Spanish Government (RTI2018-100910-B-C41 and RTI2018-101599-B-C22 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (PROMETEO 2018/024). M.O. thanks the financial support from SAF2017-84689-R project and MINECO/AEI/FEDER, UE and the Generalitat Valenciana (PROMETEO/2019/065). B.L.-T. is grateful to the Spanish Ministry of Economy for her PhD grant. I.G. thanks her contract from IDM. J.F.-B. and M.A. thank the UPV for their postdoctoral fellowship. ; Lozano-Torres, B.; Blandez, JF.; Galiana, I.; García-Fernández, A.; Alfonso-Navarro, M.; Marcos Martínez, MD.; Orzáez, M. (2020). Real-Time In Vivo Detection of Cellular Senescence through the Controlled Release of the NIR Fluorescent Dye Nile Blue. Angewandte Chemie International Edition. 59(35):15152-15156. https://doi.org/10.1002/anie.202004142 ; S ; 15152 ; 15156 ; 59 ; 35 ; He, S., & Sharpless, N. E. (2017). Senescence in Health and Disease. Cell, 169(6), 1000-1011. doi:10.1016/j.cell.2017.05.015 ; Lozano-Torres, ...

[EN] A bio-inspired nanodevice for the selective and sensitive fluorogenic detection of 3,4- methylenedioxypyrovalerone (MDPV), usually known as Cannibal drug, is reported. The sensing nanodevice is based on mesoporous silica nanoparticles (MSNs), loaded with a fluorescent reporter (rhodamine B) and functionalized on their external surface with a dopamine derivative (3), which specifically interacts with the recombinant human dopamine transporter (DAT), capping the pores. In the presence of MDPV, DAT detaches from the MSNs consequently causing rhodamine B release and allowing drug detection. The nanosensor shows a detection limit of 5.2 µM and it is able to detect the MDPV drug both in saliva and blood plasma samples. ; The authors thank the Spanish Government (projects RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE) and CTQ2017-87954-P) and the Generalitat Valencia (PROMETEO/2018/024) for support. E.G. is grateful to the Spanish MEC for her FPU grant. M.A. thanks her postdoctoral fellowship (PAID -10-17). The authors also thank the Electron Microscopy Service at the UPV for support. ; Garrido-García, EM.; Alfonso-Navarro, M.; Díaz De Greñu-Puertas, B.; Marcos Martínez, MD.; Costero, AM.; Gil Grau, S.; Sancenón Galarza, F. (2020). A sensitive nanosensor for the in situ detection of the cannibal drug. ACS Sensors. 5(9):2966-2972. https://doi.org/10.1021/acssensors.0c01553 ; S ; 2966 ; 2972 ; 5 ; 9 ; World drug report United Nations Office on Drugs and Crime (UNODC). Inform; 2019. ; European drug report Trends and Developments. European Monitoring Centre for Drugs and Drug Addition (EMCDDA). Inform; 2019. ; Zawilska, J. B., & Wojcieszak, J. (2013). Designer cathinones—An emerging class of novel recreational drugs. Forensic Science International, 231(1-3), 42-53. doi:10.1016/j.forsciint.2013.04.015 ; Coppola, M., & Mondola, R. (2012). 3,4-Methylenedioxypyrovalerone (MDPV): Chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online. Toxicology Letters, 208(1), 12-15. ...

This is the peer reviewed version of the following article: E. Garrido, M. Alfonso, B. Díaz de Greñu, B. Lozano-Torres, M. Parra, P. Gaviña, M. D. Marcos, R. Martínez-Máñez, F. Sancenón, Chem. Eur. J. 2020, 26, 2813, which has been published in final form at https://doi.org/10.1002/chem.201905688. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. ; [EN] This work reports the synthesis, characterization, and sensing behavior of a hybrid nanodevice for the detection of the potent abuse drug 25I-NBOMe. The system is based on mesoporous silica nanoparticles, loaded with a fluorescent dye, functionalized with a serotonin derivative and capped with the 5-HT2A receptor antibody. In the presence of 25I-NBOMe the capping antibody is displaced, leading to pore opening and rhodamine B release. This delivery was ascribed to 5-HT2A receptor antibody detachment from the surface due to its stronger coordination with 25I-NBOMe present in the solution. The prepared nanodevice allowed the sensitive (limit of detection of 0.6 mm) and selective recognition of the 25I-NBOMe drug (cocaine, heroin, mescaline, lysergic acid diethylamide, MDMA, and morphine were unable to induce pore opening and rhodamine B release). This nanodevice acts as a highly sensitive and selective fluorometric probe for the 25I-NBOMe illicit drug in artificial saliva and in sweets. ; The authors thank the Spanish Government (projects RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE) and CTQ2017-87954-P) and the Generalitat Valencia (PROMETEO/2018/024) for support. E.G. is grateful to the Spanish MEC for her FPU grant. The authors also thank the Electron Microscopy Service at the UPV for support. ; Garrido-García, EM.; Alfonso-Navarro, M.; Díaz De Greñu-Puertas, B.; Lozano-Torres, B.; Parra Álvarez, M.; Gaviña, P.; Marcos Martínez, MD. (2020). Nanosensor for Sensitive Detection of the New Psychedelic Drug 25I-NBOMe. Chemistry - A European Journal. 26(13):2813-2816. ...

This is the peer reviewed version of the following article: E. Añón, A. M. Costero, P. Amorós, J. El Haskouri, R. Martínez-Mánez, M. Parra, S. Gil, P. Gaviña, M. C. Terencio, M. Alfonso, ChemistrySelect 2020, 5, 3618., which has been published in final form at https://doi.org/10.1002/slct.202000417. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. ; [EN] Osteoporosis is an illness which appears when the osteoblast/osteoclast activities are unbalanced taking place bone resorption (caused by osteoclasts) in higher extension than bone formation (induced by osteoblasts). Alendronate is one of the most used drugs for osteoporosis treatment despite its scarce bioavailability. Here we present the synthesis and characterization of mesoporous gated nanoparticles (two sets) for the controlled release of alendronate. The first set of nanoparticles (S1) were loaded with sulforhodamine B and capped with a peptide that could be selectively hydrolyzed by cathepsin K enzyme (overexpressed in osteoclasts). The second set (S2) was functionalized with aminopropyl moieties, loaded with nitrobenzofurazan labelled alendronate and capped with the same peptide. Both nanoparticles were internalized by RAW 264.7 macrophages (which could differentiate in osteoclasts) and were able to release its entrapped cargo in the presence of cathepsin K added in the macrophage lysates. Using S2 nanoparticles 4.2% of the total alendronate amount in contact with the cells is liberated inside them and could produce its therapeutic effect. ; We thank the Spanish Government (RTI2018-100910-B-C41, RTI2018-100910-B-C42 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (PROMETEU/2018/024) for support. SCSIE (Universitat de Valencia) is gratefully acknowledged for all the equipment employed. NMR was registered at the U26 facility of ICTS "NANBIOSIS" at the Universitat of Valencia. ; Añón, E.; Costero, AM.; Amorós Del Toro, P.; El Haskouri, J.; Martínez-Máñez, R.; Parra Álvarez, M.; Gil ...

[EN] Gold nanostars coated with a mesoporous silica shell and functionalized with poly(ethylene glycol) containing photolabile 2-nitrobenzyl moieties are able to release doxorubicin after NIR light irradiation at low power irradiance via a multiphoton absorption photo-dissociation process. ; The authors gratefully acknowledge financial support from the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22 (MCUI/AEI/FEDER,UE)), the Generalitat Valenciana (Project PROMETEO2018/024) and the European Union (Programme European Union Action 2-Erasmus Mundus Partnerships, Grant Agreement Number-2014-0870/001-001). A.H.-M. thanks the Erasmus Mundus Programme for his PhD scholarship for the EuroInkaNet project. ; Hernández-Montoto, A.; Gorbe, M.; Llopis-Lorente, A.; Terrés-Haro, JM.; Montes-Robles, R.; Cao Milán, R.; Díaz De Greñu-Puertas, B. (2019). A NIR light-triggered drug delivery system using core-shell gold nanostars-mesoporous silica nanoparticles based on multiphoton absorption photo-dissociation of 2-nitrobenzyl PEG. Chemical Communications. 55(61):9039-9042. https://doi.org/10.1039/c9cc04260a ; S ; 9039 ; 9042 ; 55 ; 61 ; Koutsopoulos, S. (2012). Molecular fabrications of smart nanobiomaterials and applications in personalized medicine. Advanced Drug Delivery Reviews, 64(13), 1459-1476. doi:10.1016/j.addr.2012.08.002 ; Bao, G., Mitragotri, S., & Tong, S. (2013). Multifunctional Nanoparticles for Drug Delivery and Molecular Imaging. Annual Review of Biomedical Engineering, 15(1), 253-282. doi:10.1146/annurev-bioeng-071812-152409 ; Descalzo, A. B., Martínez-Máñez, R., Sancenón, F., Hoffmann, K., & Rurack, K. (2006). The Supramolecular Chemistry of Organic–Inorganic Hybrid Materials. Angewandte Chemie International Edition, 45(36), 5924-5948. doi:10.1002/anie.200600734 ; Ariga, K., Ishihara, S., Labuta, J., & P. Hill, J. (2011). Supramolecular Approaches to Nanotechnology: Switching Properties and Dynamic Functions. Current Organic Chemistry, 15(21), 3719-3733. ...

"This is the peer reviewed version of the following article: Hernández Montoto, Andy, Antoni Llopis-Lorente, Mónica Gorbe, José M. Terrés, Roberto Cao Milán, Borja Díaz de Greñu, María Alfonso, et al. 2019. Janus Gold Nanostars Mesoporous Silica Nanoparticles for NIR-Light-Triggered Drug Delivery. Chemistry A European Journal 25 (36). Wiley: 8471 78. doi:10.1002/chem.201900750, which has been published in final form at https://doi.org/10.1002/chem.201900750. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." ; [EN] Janus gold nanostar-mesoporous silica nanoparticle (AuNSt-MSNP) nanodevices able to release an entrapped payload upon irradiation with near infrared (NIR) light were prepared and characterized. The AuNSt surface was functionalized with a thiolated photolabile molecule (5), whereas the mesoporous silica face was loaded with a model drug (doxorubicin) and capped with proton-responsive benzimidazole-beta-cyclodextrin supramolecular gatekeepers (N 1). Upon irradiation with NIR-light, the photolabile compound 5 photodissociated, resulting in the formation of succinic acid, which induced the opening of the gatekeeper and cargo delivery. In the overall mechanism, the gold surface acts as a photochemical transducer capable of transforming the NIR-light input into a chemical messenger (succinic acid) that opens the supramolecular nanovalve. The prepared hybrid nanoparticles were non-cytotoxic to HeLa cells, until they were irradiated with a NIR laser, which led to intracellular doxorubicin release and hyperthermia. This induced a remarkable reduction in HeLa cells viability. ; The authors gratefully acknowledge financial support from the Spanish Government [Projects MAT2015-64139-C4-1-R, AGL2015-70235-C2-2-R and SAF2017-84689-R (MINECO/AEI/FEDER, UE)], the Generalitat Valenciana (Project PROMETEO2018/024) and European Union (Erasmus Mundus Programme, Action 2, grant agreement number 2014-0870/001001). A.H. thanks the Erasmus Mundus Programme ...