Anti-neovascular therapy by liposomal DPP-CNDAC targeted to angiogenic vessels.
We previously reported 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, is quite useful for cancer therapy. On the other hand, for anti-neovascular therapy, we recently isolated peptides homing to angiogenic vessels from a phage-displayed random peptide library, and observed that peptide-modified liposomal adriamycin strongly suppressed tumor growth, perhaps through damaging angiogenic endothelial cells. In the present study, we modified DPP-CNDAC-liposomes with one of the angiogenic homing peptides, APRPG, and examined their antitumor activity. Three doses of APRPG-modified DPP-CNDAC-liposomes (15 mg/kg as CNDAC) strongly inhibited tumor growth compared with the same number of doses of unmodified DPP-CNDAC-liposomes. The life span was increased 31.8%, with one completely cured mouse out of the six mice treated. Since the accumulation of liposomes in the tumor tissue was not so much different between APRPG-liposomes and non-modified liposomes, the enhanced therapeutic efficacy may be explained as the alteration of targets, i.e. APRPG-modified DPP-CNDAC-liposomes caused tumor growth suppression through damage of angiogenic endothelial cells. Anti-neovascular therapy promises no drug resistance, and should be effective against essentially any kind of solid tumor; and thus the present results demonstrate another benefit of the therapy, namely, high efficacy of cancer treatment.
Asai
Tomohiro
T
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Shimizu
Kosuke
K
Kondo
Masami
M
Kuromi
Koichi
K
Watanabe
Koh
K
Ogino
Koichi
K
Taki
Takao
T
Shuto
Satoshi
S
Matsuda
Akira
A
Oku
Naoto
N
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D010712:Phosphatidic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D008081:Liposomes; D009842:Oligopeptides; D010712:Phosphatidic Acids; D003561:Cytarabine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine; C031599:dipalmitoylphosphatidic acid