Anti-neovascular therapy using novel peptides homing to angiogenic vessels.
Cancer chemotherapy targeted to angiogenic vessels is expected to cause indirect tumor regression through the damage of the neovasculature without the induction of drug resistance. To develop a tool for neovasculature-specific drug delivery, we isolated novel peptides homing to angiogenic vessels formed by a dorsal air sac method from a phage-displayed peptide library. Three distinct phage clones that markedly accumulated in murine tumor xenografts presented PRPGAPLAGSWPGTS-, DRWRPALPVVLFPLH- or ASSSYPLIHWRPWAR-peptide respectively. After the determination of the epitope sequences of these peptides, we modified liposomes with epitope penta-peptides. Liposome modified with APRPG-peptide showed high accumulation in murine tumor xenografts, and APRPG-modified liposome encapsulating adriamycin effectively suppressed experimental tumor growth. Finally, specific binding of APRPG-modified liposome to human umbilical endothelial cells, and that of PRP-containing peptide to angiogenic vessels in human tumors, i.e., islet cell tumor and glioblastoma, were demonstrated. The present study indicates the usefulness of APRPG-peptide as a tool for anti-neovascular therapy, a novel modality of cancer treatment.
Oku
Naoto
N
Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. oku@u-shizuoka-ken.ac.jp
Asai
Tomohiro
T
Watanabe
Koh
K
Kuromi
Koichi
K
Nagatsuka
Mayumi
M
Kurohane
Kohta
K
Kikkawa
Hironori
H
Ogino
Koichi
K
Tanaka
Michinori
M
Ishikawa
Dai
D
Tsukada
Hideo
H
Momose
Masanobu
M
Nakayama
Jun
J
Taki
Takao
T
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D008081:Liposomes / Q000378:metabolism; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D019151:Peptide Library; D010455:Peptides / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000098:blood supply* / Q000473:pathology; D014055:Tomography, Emission-Computed
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D008222:Lymphokines; D019151:Peptide Library; D010455:Peptides; D004317:Doxorubicin