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.

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.

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*

Substances

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