Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

J Clin Invest. 2009 Sep;119(9):2830-42. doi: 10.1172/JCI38842. Epub 2009 Aug 10.


The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Carriers
  • Female
  • Humans
  • Liposomes
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Melitten / administration & dosage*
  • Melitten / pharmacokinetics
  • Melitten / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Nanoparticles / administration & dosage
  • Nanoparticles / ultrastructure
  • Tissue Distribution


  • Antineoplastic Agents
  • Drug Carriers
  • Liposomes
  • Melitten