Metabolomics facilitates the discrimination of the specific anti-cancer effects of free- and polymer-conjugated doxorubicin in breast cancer models

Biomaterials. 2018 Apr;162:144-153. doi: 10.1016/j.biomaterials.2018.02.015. Epub 2018 Feb 8.

Abstract

Metabolomics is becoming a relevant tool for understanding the molecular mechanisms involved in the response to new drug delivery systems. The applicability of this experimental approach to cell cultures and animal models makes metabolomics a useful tool for establishing direct connections between in vitro and in vivo data, thus providing a reliable platform for the characterization of chemotherapeutic agents. Herein, we used metabolomic profiles based on nuclear magnetic resonance (NMR) spectroscopy to evaluate the biochemical pathways involved in the response to a chemotherapeutic anthracycline drug (Doxorubicin, Dox) and an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-conjugated form (HPMA-Dox) in an in vitro cell culture model and an in vivo orthotopic breast cancer model. We also used protein expression and flow cytometry studies to obtain a better coverage of the biochemical alterations associated with the administration of these compounds. The overall analysis revealed that polymer conjugation leads to increased apoptosis, reduced glycolysis, and reduced levels of phospholipids when compared to the free chemotherapeutic drug. Our results represent a first step in the application of integrated in vitro and in vivo metabolomic studies to the evaluation of drug delivery systems.

Keywords: Breast cancer; Metabolomics; NMR; Nanomedicine; Polymer therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / therapeutic use*
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Doxorubicin / chemistry*
  • Doxorubicin / therapeutic use*
  • Drug Delivery Systems / methods
  • Female
  • Humans
  • MCF-7 Cells
  • Magnetic Resonance Spectroscopy
  • Metabolomics / methods*
  • Mice
  • Nanomedicine
  • Polymers / chemistry*
  • Reactive Oxygen Species / metabolism

Substances

  • Antineoplastic Agents
  • Polymers
  • Reactive Oxygen Species
  • Doxorubicin