Anti-neovascular therapy by liposomal drug targeted to membrane type-1 matrix metalloproteinase.
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.
Kondo
Masami
M
Department of Medical Biochemistry and COE Program in the 21st Century, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Japan.
Asai
Tomohiro
T
Katanasaka
Yasufumi
Y
Sadzuka
Yasuyuki
Y
Tsukada
Hideo
H
Ogino
Koichi
K
Taki
Takao
T
Baba
Kazuhiko
K
Oku
Naoto
N
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001088:Arabinonucleotides / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000201:enzymology; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008081:Liposomes; D008297:Male; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000201:enzymology; D010712:Phosphatidic Acids / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport; D015996:Survival Rate; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014471:Umbilical Veins / Q000378:metabolism / Q000473:pathology
D020533:Angiogenesis Inhibitors; D001088:Arabinonucleotides; D008081:Liposomes; C507096:Mmp14 protein, mouse; D010712:Phosphatidic Acids; C114869:dpp-cndac; C031599:dipalmitoylphosphatidic acid; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14