Journal article Open Access

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

Juan J. Arroyo-Crespo; Ana Armiñán; David Charbonnier; Leandro Balzano-Nogueira; Francisco Huertas-López; Cristina Martí; Sonia Tarazona; Jerónimo Forteza; Ana Conesa; María J. Vicent


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  <identifier identifierType="URL">https://zenodo.org/record/1434029</identifier>
  <creators>
    <creator>
      <creatorName>Juan J. Arroyo-Crespo</creatorName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Ana Armiñán</creatorName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>David Charbonnier</creatorName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Leandro Balzano-Nogueira</creatorName>
      <affiliation>Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA</affiliation>
    </creator>
    <creator>
      <creatorName>Francisco Huertas-López</creatorName>
      <affiliation>Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA</affiliation>
    </creator>
    <creator>
      <creatorName>Cristina Martí</creatorName>
      <affiliation>Genomics and Gene Expression Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Sonia Tarazona</creatorName>
      <affiliation>Genomics and Gene Expression Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain / Department of Applied Statistics, Operations Research and Quality, Universitat Politècnica de València, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Jerónimo Forteza</creatorName>
      <affiliation>Unidad Mixta CIPF-IVP Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Ana Conesa</creatorName>
      <affiliation>Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA</affiliation>
    </creator>
    <creator>
      <creatorName>María J. Vicent</creatorName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain / Screening Platform, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment</title>
  </titles>
  <publisher>Zenodo</publisher>
  <publicationYear>2018</publicationYear>
  <subjects>
    <subject>Polymer therapeutics</subject>
    <subject>Polypeptides</subject>
    <subject>Polymer-based combination conjugates</subject>
    <subject>tumor microenvironment</subject>
    <subject>metastatic triple-negative breast cancer</subject>
    <subject>Transcriptomics</subject>
  </subjects>
  <dates>
    <date dateType="Issued">2018-09-18</date>
  </dates>
  <language>en</language>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://zenodo.org/record/1434029</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1016/j.biomaterials.2018.09.023</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="https://creativecommons.org/licenses/by/4.0/legalcode">Creative Commons Attribution 4.0 International</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">&lt;p&gt;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 (&amp;sim;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 &amp;ndash;omics-based analysis to accelerate anticancer DDS.&lt;/p&gt;</description>
  </descriptions>
  <fundingReferences>
    <fundingReference>
      <funderName>European Commission</funderName>
      <funderIdentifier funderIdentifierType="Crossref Funder ID">10.13039/501100000780</funderIdentifier>
      <awardNumber awardURI="info:eu-repo/grantAgreement/EC/H2020/648831/">648831</awardNumber>
      <awardTitle>Towards the design of Personalised Polymer-based Combination Nanomedicines for Advanced Stage Breast Cancer Patients</awardTitle>
    </fundingReference>
  </fundingReferences>
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