Journal article Open Access

Anticancer Activity Driven by Drug Linker Modification in a Polyglutamic Acid‐Based Combination‐Drug Conjugate

Arroyo‐Crespo, Juan J.; Deladriere, Coralie; Nebot, Vicent J.; Charbonnier, David; Masiá, Esther; Paul, Alison; James, Craig; Armiñán, Ana; Vicent, María J.


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  <identifier identifierType="URL">https://zenodo.org/record/1227320</identifier>
  <creators>
    <creator>
      <creatorName>Arroyo‐Crespo, Juan J.</creatorName>
      <givenName>Juan J.</givenName>
      <familyName>Arroyo‐Crespo</familyName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Deladriere, Coralie</creatorName>
      <givenName>Coralie</givenName>
      <familyName>Deladriere</familyName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Nebot,  Vicent J.</creatorName>
      <givenName>Vicent J.</givenName>
      <familyName>Nebot</familyName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Charbonnier, David</creatorName>
      <givenName>David</givenName>
      <familyName>Charbonnier</familyName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Masiá, Esther</creatorName>
      <givenName>Esther</givenName>
      <familyName>Masiá</familyName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Paul, Alison</creatorName>
      <givenName>Alison</givenName>
      <familyName>Paul</familyName>
      <affiliation>School of Chemistry, Cardiff University, Cardiff, UK</affiliation>
    </creator>
    <creator>
      <creatorName>James, Craig</creatorName>
      <givenName>Craig</givenName>
      <familyName>James</familyName>
      <affiliation>School of Chemistry, Cardiff University, Cardiff, UK</affiliation>
    </creator>
    <creator>
      <creatorName>Armiñán, Ana</creatorName>
      <givenName>Ana</givenName>
      <familyName>Armiñán</familyName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain</affiliation>
    </creator>
    <creator>
      <creatorName>Vicent, María J.</creatorName>
      <givenName>María J.</givenName>
      <familyName>Vicent</familyName>
      <affiliation>Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Anticancer Activity Driven by Drug Linker Modification in a Polyglutamic Acid‐Based Combination‐Drug Conjugate</title>
  </titles>
  <publisher>Zenodo</publisher>
  <publicationYear>2018</publicationYear>
  <subjects>
    <subject>breast cancer</subject>
    <subject>combination therapy</subject>
    <subject>polymer therapeutics</subject>
    <subject>polymer–drug conjugates</subject>
    <subject>polypeptides</subject>
  </subjects>
  <dates>
    <date dateType="Issued">2018-04-16</date>
  </dates>
  <language>en</language>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://zenodo.org/record/1227320</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1002/adfm.201800931</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="http://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;Combination nanotherapies for the treatment of breast cancer permits synergistic drug targeting of multiple pathways. However, poor carrier degradability, poor synergism of the combined drugs, low drug release regulation, and a lack of control on final macromolecule solution conformation (which drives the biological fate) limit the application of this strategy. The present study describes the development of a family of drug delivery systems composed of chemotherapeutic (doxorubicin) and endocrine therapy (aromatase inhibitor aminoglutethimide) agents conjugated to a biodegradable poly‐l‐glutamic acid backbone via various linking moieties. Data from in vitro cytotoxicity and drug release assessments and animal model validation select a conjugate family member with optimal biological performance. Exhaustive physicochemical characterization in relevant media (including the study of secondary structure, size measurements, and detailed small‐angle neutron scattering analysis) correlates biological data with the intrinsic supramolecular characteristics of the conjugate. Overall, this study demonstrates how a small flexible Gly linker can modify the spatial conformation of the entire polymer&amp;ndash;drug conjugate, promote the synergistic release of both drugs, and significantly improve biological activity. These findings highlight the need for a deeper understanding of polymer&amp;ndash;drug conjugates at supramolecular level to allow the design of more effective polymer&amp;ndash;drug conjugates.&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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