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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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<oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd">
  <dc:creator>Juan J. Arroyo-Crespo</dc:creator>
  <dc:creator>Ana Armiñán</dc:creator>
  <dc:creator>David Charbonnier</dc:creator>
  <dc:creator>Leandro Balzano-Nogueira</dc:creator>
  <dc:creator>Francisco Huertas-López</dc:creator>
  <dc:creator>Cristina Martí</dc:creator>
  <dc:creator>Sonia Tarazona</dc:creator>
  <dc:creator>Jerónimo Forteza</dc:creator>
  <dc:creator>Ana Conesa</dc:creator>
  <dc:creator>María J. Vicent</dc:creator>
  <dc:date>2018-09-18</dc:date>
  <dc: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 –omics-based analysis to accelerate anticancer DDS.</dc:description>
  <dc:identifier>https://zenodo.org/record/1434029</dc:identifier>
  <dc:identifier>10.1016/j.biomaterials.2018.09.023</dc:identifier>
  <dc:identifier>oai:zenodo.org:1434029</dc:identifier>
  <dc:language>eng</dc:language>
  <dc:relation>info:eu-repo/grantAgreement/EC/H2020/648831/</dc:relation>
  <dc:rights>info:eu-repo/semantics/openAccess</dc:rights>
  <dc:rights>https://creativecommons.org/licenses/by/4.0/legalcode</dc:rights>
  <dc:source>Biomaterials</dc:source>
  <dc:subject>Polymer therapeutics</dc:subject>
  <dc:subject>Polypeptides</dc:subject>
  <dc:subject>Polymer-based combination conjugates</dc:subject>
  <dc:subject>tumor microenvironment</dc:subject>
  <dc:subject>metastatic triple-negative breast cancer</dc:subject>
  <dc:subject>Transcriptomics</dc:subject>
  <dc:title>Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment</dc:title>
  <dc:type>info:eu-repo/semantics/article</dc:type>
  <dc:type>publication-article</dc:type>
</oai_dc:dc>
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