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Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment

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Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment

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dc.contributor.author Arroyo-Crespo, Juan J. es_ES
dc.contributor.author Armiñán, Ana es_ES
dc.contributor.author Charbonnier, David es_ES
dc.contributor.author Balzano-Nogueira, Leandro es_ES
dc.contributor.author Huertas-López, Francisco es_ES
dc.contributor.author Martí, Cristina es_ES
dc.contributor.author Tarazona Campos, Sonia es_ES
dc.contributor.author Forteza, Jerónimo es_ES
dc.contributor.author Conesa, A. es_ES
dc.contributor.author Vicent Docon, Maria Jesus es_ES
dc.date.accessioned 2020-06-12T03:33:43Z
dc.date.available 2020-06-12T03:33:43Z
dc.date.issued 2018-12 es_ES
dc.identifier.issn 0142-9612 es_ES
dc.identifier.uri http://hdl.handle.net/10251/146174
dc.description.abstract [EN] The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (-90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of -omits-based analysis to accelerate anticancer DDS. es_ES
dc.description.sponsorship The authors would like to thank Dr. Stuart P. Atkinson for his collaboration in manuscript preparation and English revision, and Irene Borreda for essential immunohistological support. This work has been supported by the European Research Council (grant ERC-CoG-2014-648831 "MyNano") and the Spanish Ministry of Science and Innovation (CTQ2010-18195, SAF2013-44848-R, BES-2008-006801, IPT-2012-0712-010000, Programa I3, and BIO2015-71658-R). LBN is funded through a University of South Florida-Helmsley Foundation award. FHL is funded through NIH grant. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with FEDER funds (PO FEDER of Comunitat Valenciana 2014-2020). es_ES
dc.language Inglés es_ES
dc.publisher Elsevier es_ES
dc.relation MICINN/CTQ2010-18195 es_ES
dc.relation MICINN/SAF2013-44848-R es_ES
dc.relation MICINN/BES-2008-006801 es_ES
dc.relation MICINN/IPT-2012-0712-010000 es_ES
dc.relation MINISTERIO DE ECONOMIA Y EMPRESA/BIO2015-71658-R es_ES
dc.relation.ispartof Biomaterials es_ES
dc.rights Reconocimiento - No comercial - Sin obra derivada (by-nc-nd) es_ES
dc.subject Polymer therapeutics es_ES
dc.subject Polypeptides es_ES
dc.subject Tumor microenvironment es_ES
dc.subject Polymer-based combination conjugates es_ES
dc.subject Metastatic triple-negative breast cancer es_ES
dc.subject Transcriptomics es_ES
dc.subject.classification ESTADISTICA E INVESTIGACION OPERATIVA es_ES
dc.title Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1016/j.biomaterials.2018.09.023 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/648831/EU es_ES
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Departamento de Estadística e Investigación Operativa Aplicadas y Calidad - Departament d'Estadística i Investigació Operativa Aplicades i Qualitat es_ES
dc.description.bibliographicCitation Arroyo-Crespo, JJ.; Armiñán, A.; Charbonnier, D.; Balzano-Nogueira, L.; Huertas-López, F.; Martí, C.; Tarazona Campos, S.... (2018). Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment. Biomaterials. 186:8-21. https://doi.org/10.1016/j.biomaterials.2018.09.023 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion https://doi.org/ 10.1016/j.biomaterials.2018.09.023 es_ES
dc.description.upvformatpinicio 8 es_ES
dc.description.upvformatpfin 21 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 186 es_ES
dc.identifier.pmid 30278346 es_ES
dc.relation.pasarela S\368658 es_ES
dc.contributor.funder Generalitat Valenciana es_ES
dc.contributor.funder University of South Florida es_ES
dc.contributor.funder Ministerio de Economía y Empresa es_ES
dc.contributor.funder European Regional Development Fund es_ES
dc.contributor.funder Ministerio de Ciencia e Innovación es_ES
dc.contributor.funder National Institutes of Health, EEUU es_ES


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