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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    <subfield code="a">Jerónimo Forteza</subfield>
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    <subfield code="u">Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA</subfield>
    <subfield code="a">Ana Conesa</subfield>
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    <subfield code="u">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</subfield>
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    <subfield code="u">Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain</subfield>
    <subfield code="a">Juan J. Arroyo-Crespo</subfield>
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    <subfield code="a">Towards the design of Personalised Polymer-based Combination Nanomedicines for Advanced Stage Breast Cancer Patients</subfield>
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    <subfield code="a">&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;</subfield>
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