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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{
  "DOI": "10.1016/j.biomaterials.2018.09.023", 
  "container_title": "Biomaterials", 
  "language": "eng", 
  "title": "Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment", 
  "issued": {
    "date-parts": [
      [
        2018, 
        9, 
        18
      ]
    ]
  }, 
  "abstract": "<p>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 (&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 &ndash;omics-based analysis to accelerate anticancer DDS.</p>", 
  "author": [
    {
      "family": "Juan J. Arroyo-Crespo"
    }, 
    {
      "family": "Ana Armi\u00f1\u00e1n"
    }, 
    {
      "family": "David Charbonnier"
    }, 
    {
      "family": "Leandro Balzano-Nogueira"
    }, 
    {
      "family": "Francisco Huertas-L\u00f3pez"
    }, 
    {
      "family": "Cristina Mart\u00ed"
    }, 
    {
      "family": "Sonia Tarazona"
    }, 
    {
      "family": "Jer\u00f3nimo Forteza"
    }, 
    {
      "family": "Ana Conesa"
    }, 
    {
      "family": "Mar\u00eda J. Vicent"
    }
  ], 
  "type": "article-journal", 
  "id": "1434029"
}
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