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

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...

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Autores: Arroyo-Crespo JJ, Armiñán A, Charbonnier D, Balzano-Nogueira L, Huertas-López F, Martí C, Tarazona S, Forteza J, Conesa A, Vicent MJ
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Centro de Investigación Principe Felipe (CIPF)
Repositorio:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
OAI Identifier:oai:cipf.fundanetsuite.com:p2237
Acceso en línea:https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2237
Access Level:acceso abierto
Palabra clave:Polymer therapeutics
Polypeptides
Tumor microenvironment
Polymer-based combination conjugates
Metastatic triple-negative breast cancer
Transcriptomics
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spelling Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatmentArroyo-Crespo JJArmiñán ACharbonnier DBalzano-Nogueira LHuertas-López FMartí CTarazona SForteza JConesa AVicent MJPolymer therapeuticsPolypeptidesTumor microenvironmentPolymer-based combination conjugatesMetastatic triple-negative breast cancerTranscriptomicsThe 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.ELSEVIER SCI LTD2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2237BIOMATERIALSISSN: 01429612ISSNe: 18785905reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)instname:Centro de Investigación Principe Felipe (CIPF)Inglésinfo:eu-repo/semantics/openAccessoai:cipf.fundanetsuite.com:p22372026-06-17T11:19:47Z
dc.title.none.fl_str_mv Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
title Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
spellingShingle Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
Arroyo-Crespo JJ
Polymer therapeutics
Polypeptides
Tumor microenvironment
Polymer-based combination conjugates
Metastatic triple-negative breast cancer
Transcriptomics
title_short Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
title_full Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
title_fullStr Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
title_full_unstemmed Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
title_sort Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
dc.creator.none.fl_str_mv Arroyo-Crespo JJ
Armiñán A
Charbonnier D
Balzano-Nogueira L
Huertas-López F
Martí C
Tarazona S
Forteza J
Conesa A
Vicent MJ
author Arroyo-Crespo JJ
author_facet Arroyo-Crespo JJ
Armiñán A
Charbonnier D
Balzano-Nogueira L
Huertas-López F
Martí C
Tarazona S
Forteza J
Conesa A
Vicent MJ
author_role author
author2 Armiñán A
Charbonnier D
Balzano-Nogueira L
Huertas-López F
Martí C
Tarazona S
Forteza J
Conesa A
Vicent MJ
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Polymer therapeutics
Polypeptides
Tumor microenvironment
Polymer-based combination conjugates
Metastatic triple-negative breast cancer
Transcriptomics
topic Polymer therapeutics
Polypeptides
Tumor microenvironment
Polymer-based combination conjugates
Metastatic triple-negative breast cancer
Transcriptomics
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2237
url https://cipf.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2237
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ELSEVIER SCI LTD
publisher.none.fl_str_mv ELSEVIER SCI LTD
dc.source.none.fl_str_mv BIOMATERIALS
ISSN: 01429612
ISSNe: 18785905
reponame:r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
instname:Centro de Investigación Principe Felipe (CIPF)
instname_str Centro de Investigación Principe Felipe (CIPF)
reponame_str r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
collection r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF)
repository.name.fl_str_mv
repository.mail.fl_str_mv
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