Format

Send to

Choose Destination
Biomaterials. 2018 Dec;186:8-21. doi: 10.1016/j.biomaterials.2018.09.023. Epub 2018 Sep 18.

Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment.

Author information

1
Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain.
2
Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain. Electronic address: aarminan@cipf.es.
3
Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Gainesville, USA.
4
Genomics and Gene Expression Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain.
5
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.
6
Unidad Mixta CIPF-IVP Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia, 46012, Spain.
7
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. Electronic address: mjvicent@cipf.es.

Abstract

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.

KEYWORDS:

Metastatic triple-negative breast cancer; Polymer therapeutics; Polymer-based combination conjugates; Polypeptides; Transcriptomics; Tumor microenvironment

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center