Anti-neovascular therapy by liposomal drug targeted to membrane type-1 matrix metalloproteinase

Int J Cancer. 2004 Jan 10;108(2):301-6. doi: 10.1002/ijc.11526.


Because membrane type-1 matrix metalloproteinase (MT1-MMP) is expressed specifically on the angiogenic endothelium as well as tumor cells, an agent possessing the ability to bind to this molecule might be useful as a tool for active targeting of tumor angiogenic vessels. Based on the sequences of peptide substrates of MT1-MMP, which had been determined by using a phage-displayed peptide library, we examined the binding ability of peptide-modified liposomes for endothelial cells and targeting ability for tumor tissues by positron emission tomography (PET). Liposomes modified with stearoyl-Gly-Pro-Leu-Pro-Leu-Arg (GPLPLR-Lip) showed high binding ability to human umbilical vein endothelial cells and accumulated in the tumor about 4-fold more than did the unmodified liposomes. Because we reported previously that liposomalized 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (DPP-CNDAC), a hydrophobized derivative of the novel antitumor nucleoside CNDAC, strongly suppressed tumor growth when delivered in liposomes modified with another angiogenic homing peptide, we examined the antitumor activity of DPP-CNDAC entrapped in GPLPLR-Lip. DPP-CNDAC/GPLPLR-Lip showed significant tumor growth suppression compared to DPP-CNDAC/unmodified liposomes. These results suggest that DPP-CNDAC-liposomes modified with MT1-MMP-targeted peptide are useful for cancer anti-neovascular therapy (ANET), namely, tumor growth suppression by damage to angiogenic endothelial cells.

Publication types

  • Comparative Study

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Arabinonucleotides / therapeutic use*
  • Colonic Neoplasms / blood supply*
  • Colonic Neoplasms / enzymology
  • Drug Delivery Systems
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Humans
  • Liposomes
  • Male
  • Matrix Metalloproteinase 14
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / antagonists & inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / enzymology
  • Phosphatidic Acids / chemistry
  • Phosphatidic Acids / metabolism
  • Protein Transport
  • Survival Rate
  • Treatment Outcome
  • Tumor Cells, Cultured / transplantation
  • Umbilical Veins / metabolism
  • Umbilical Veins / pathology


  • Angiogenesis Inhibitors
  • Arabinonucleotides
  • Liposomes
  • Mmp14 protein, mouse
  • Phosphatidic Acids
  • dpp-cndac
  • dipalmitoylphosphatidic acid
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 14