Combined mTOR inhibitor rapamycin and doxorubicin-loaded cyclic octapeptide modified liposomes for targeting integrin α3 in triple-negative breast cancer

Biomaterials. 2014 Jul;35(20):5347-5358. doi: 10.1016/j.biomaterials.2014.03.036. Epub 2014 Apr 13.


A novel therapeutic strategy combining mTOR inhibitor rapamycin (RAPA) and doxorubicin (DOX)-loaded cyclic octapeptide liposomes for targeting integrin α3 was expected to combat the triple-negative breast cancer (TNBC). RAPA was loaded into PEG-PCL polymer micelles (M-RAPA) to realize solubilization. Flow cytometry analysis and laser confocal microscopy were used to evaluate the in vitro cellular uptake. The in vivo tumor targeting and bio-distribution were investigated by living fluorescence imaging. As the results, LXY modification significantly enhanced the cellular uptake of liposomal DOX in integrin α3 overexpressed TNBC cells (MDA-MB-231) in vitro and accordingly improved the tumor accumulation of liposomes in vivo. When used alone or in combination with LXY-LS-DOX, M-RAPA could greatly inhibit the expression of HIF-1α protein, which is always highly expressed in malignant cancers and involved in tumor angiogenesis, proliferation, therapeutic resistance and poor prognosis. Meanwhile, the improved efficacy of combined targeted therapy with LXY-LS-DOX and M-RAPA was demonstrated by the in vitro cytotoxicity against model TNBC cells and in vivo anti-tumor activity against mouse bearing TNBC model. These results suggested that the targeted combinational therapy based on LXY-LS-DOX and M-RAPA systems may provide a rational strategy to improve therapeutic outcomes of TNBC.

Keywords: Combined therapy; Liposomal doxorubicin; Rapamycin; Targeting delivery; Triple-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / pharmacology
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Integrin alpha3 / genetics
  • Integrin alpha3 / metabolism*
  • Liposomes
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Micelles
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Polyethylene Glycols / pharmacology
  • Polymers / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Triple Negative Breast Neoplasms / therapy*


  • Antibiotics, Antineoplastic
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Integrin alpha3
  • Liposomes
  • Micelles
  • Polymers
  • Protein Kinase Inhibitors
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Doxorubicin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus