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", 
    "description": "<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>", 
    "language": "eng", 
    "title": "Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment", 
    "license": {
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    "journal": {
      "title": "Biomaterials"
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        "title": "Towards the design of Personalised Polymer-based Combination Nanomedicines for Advanced Stage Breast Cancer Patients", 
        "acronym": "MyNano", 
        "program": "H2020", 
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    "keywords": [
      "Polymer therapeutics", 
      "Polypeptides", 
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    "publication_date": "2018-09-18", 
    "creators": [
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        "affiliation": "Polymer Therapeutics Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain", 
        "name": "Juan J. Arroyo-Crespo"
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      {
        "affiliation": "Polymer Therapeutics Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain", 
        "name": "Ana Armi\u00f1\u00e1n"
      }, 
      {
        "affiliation": "Polymer Therapeutics Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain", 
        "name": "David Charbonnier"
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      {
        "affiliation": "Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA", 
        "name": "Leandro Balzano-Nogueira"
      }, 
      {
        "affiliation": "Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA", 
        "name": "Francisco Huertas-L\u00f3pez"
      }, 
      {
        "affiliation": "Genomics and Gene Expression Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain", 
        "name": "Cristina Mart\u00ed"
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      {
        "affiliation": "Genomics and Gene Expression Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain / Department of Applied Statistics, Operations Research and Quality, Universitat Polit\u00e8cnica de Val\u00e8ncia, Spain", 
        "name": "Sonia Tarazona"
      }, 
      {
        "affiliation": "Unidad Mixta CIPF-IVP Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain", 
        "name": "Jer\u00f3nimo Forteza"
      }, 
      {
        "affiliation": "Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA", 
        "name": "Ana Conesa"
      }, 
      {
        "affiliation": "Polymer Therapeutics Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain / Screening Platform, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Av. Eduardo Primo Y\u00fafera 3, Valencia, 46012, Spain", 
        "name": "Mar\u00eda J. Vicent"
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