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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglutethimide / administration & dosage
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Doxorubicin / administration & dosage
  • Drug Carriers / chemistry*
  • Drug Liberation
  • Female
  • Heterografts
  • Humans
  • Hydrogen-Ion Concentration
  • Mice, Inbred BALB C
  • Polyglutamic Acid / chemistry*
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Microenvironment*


  • Antineoplastic Agents
  • Drug Carriers
  • Aminoglutethimide
  • Polyglutamic Acid
  • Doxorubicin