Anti-neovascular therapy by use of tumor neovasculature-targeted long-circulating liposome.
For the purpose of cancer anti-neovascular therapy (ANET), we previously isolated 5-mer peptide Ala-Pro-Arg-Pro-Gly (APRPG) that specifically bound to the tumor angiogenic site and observed that APRPG-modified liposomes encapsulating adriamycin were effective for the suppression of tumor in tumor-bearing mice. Since polyethylene glycol (PEG) modification of liposomes endows them with a future of long circulation, we modified liposomes with PEG and APRPG-conjugated distearoylphosphatidylethanolamine (DSPE-PEG-APRPG) and examined the applicability of the liposomes on ANET. Liposomes containing DSPE-PEG-APRPG not only specifically bound to vascular endothelial growth factor-stimulated human umbilical vein endothelial cells in vitro, but also showed long-circulating characteristic and enhanced accumulation in tumor in vivo. Furthermore, adriamycin-encapsulated liposomes modified with APRPG-PEG caused more efficient tumor growth suppression than adriamycin-encapsulated liposomes modified with PEG alone in Colon 26 NL-17 carcinoma-bearing mice, despite not so much different accumulation of both liposomes in the tumor. These data suggest that tumor neovasculature-targeted long-circulating liposomes encapsulating anti-cancer drugs effectively eradicate cancerous cells through damaging of angiogenic endothelial cells. ANET promises no drug resistance and is expected to be effective against essentially any kind of solid tumors. The present results demonstrate the beneficial usage of APRPG-PEG for the active-targeting of drug carriers to angiogenic site in the novel modality of tumor treatment, namely ANET.
Maeda
Noriyuki
N
Department of Medical Biochemistry and COE Program in the 21st Century, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Shizuoka 422-8526, Japan.
Takeuchi
Yoshito
Y
Takada
Miki
M
Sadzuka
Yasuyuki
Y
Namba
Yukihiro
Y
Oku
Naoto
N
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers; D006801:Humans; D008081:Liposomes; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000494:pharmacology; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D004337:Drug Carriers; D008081:Liposomes; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D011092:Polyethylene Glycols; D004317:Doxorubicin