Inhibiting metastatic breast cancer cell migration via the synergy of targeted, pH-triggered siRNA delivery and chemokine axis blockade

Mol Pharm. 2014 Mar 3;11(3):755-65. doi: 10.1021/mp4004699. Epub 2014 Feb 12.

Abstract

Because breast cancer patient survival inversely correlates with metastasis, we engineered vehicles to inhibit both the C-X-C chemokine receptor type 4 (CXCR4) and lipocalin-2 (Lcn2) mediated migratory pathways. pH-responsive liposomes were designed to protect and trigger the release of Lcn2 siRNA. Liposomes were modified with anti-CXCR4 antibodies to target metastatic breast cancer (MBC) cells and block migration along the CXCR4-CXCL12 axis. This synergistic approach--coupling the CXCR4 axis blockade with Lcn2 silencing--significantly reduced migration in triple-negative human breast cancer cells (88% for MDA-MB-436 and 92% for MDA-MB-231). The results suggested that drug delivery vehicles engineered to attack multiple migratory pathways may effectively slow progression of MBC.

Publication types

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

MeSH terms

  • Acute-Phase Proteins / antagonists & inhibitors*
  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / metabolism
  • Antibodies, Monoclonal / pharmacology*
  • Apoptosis
  • Blotting, Western
  • Cell Movement*
  • Cell Proliferation
  • Combined Modality Therapy
  • Drug Delivery Systems
  • Drug Synergism
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hydrogen-Ion Concentration
  • Lipocalin-2
  • Lipocalins / antagonists & inhibitors*
  • Lipocalins / genetics
  • Lipocalins / metabolism
  • Liposomes
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics*
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / immunology
  • Receptors, CXCR4 / metabolism
  • Signal Transduction
  • Triple Negative Breast Neoplasms / secondary
  • Triple Negative Breast Neoplasms / therapy*
  • Tumor Cells, Cultured

Substances

  • Acute-Phase Proteins
  • Antibodies, Monoclonal
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Liposomes
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Receptors, CXCR4