Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
Por:
Arroyo-Crespo JJ, Armiñán A, Charbonnier D, Balzano-Nogueira L, Huertas-López F, Martí C, Tarazona S, Forteza J, Conesa A and Vicent MJ
Publicada:
1 dic 2018
Resumen:
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 -omits-based analysis to accelerate anticancer DDS.
Filiaciones:
:
Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain
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Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain
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Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain
Balzano-Nogueira L:
Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA
Huertas-López F:
Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA
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Genomics and Gene Expression Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain
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Genomics and Gene Expression Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain
Department of Applied Statistics, Operations Research and Quality, Universitat Politècnica de València, Spain
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Unidad Mixta CIPF-IVP Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain
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Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA
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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
Hybrid Gold, Green Accepted, Green Published
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