title: Targeted delivery of anticancer drugs to tumor vessels by use of liposomes modified with a peptide identified by phage biopanning with human endothelial progenitor cells.
abstract: As tumor angiogenic vessels are critical for tumor growth and express different molecules on their surface from those on normal vessels, these vessels are expected to be an ideal target for anticancer drug delivery systems. It was previously reported that endothelial progenitor cells (EPCs) are involved in angiogenesis, tumor growth, and metastasis, and that EPCs show gene expression patterns similar to those of tumor endothelial cells. In the present study, a tumor vessel-targeting peptide, ASSHN, was identified from a phage-display peptide library by in vitro biopanning with human EPCs (hEPCs) and in vivo biopanning using angiogenesis model mice prepared by the dorsal air sac method. Phage clones displaying ASSHN peptide showed a marked affinity for hEPCs in vitro, and also for tumor vessels in vivo. PEGylated liposomes modified with the ASSHN peptide (ASSHN-Lip) were designed and prepared for the delivery of anticancer agents. Confocal images showed that ASSHN-Lip clearly bound to hEPCs in vitro and tumor vessels, and also showed extravasation from the vessels. The administration of doxorubicin-encapsulated ASSHN-Lip into Colon26 NL-17-bearing mice significantly suppressed tumor growth compared with doxorubicin-encapsulated PEGylated liposomes. These results suggest that the delivery of anticancer agents with ASSHN-Lip could be useful for targeted cancer therapy.
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan; Japan Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukuta
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kiyokawa
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakada
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Bessyo-Hirashima
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Fukaya
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hyodo
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Takase
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: oku@u-shizuoka-ken.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D001435:Bacteriophages; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D066026:Endothelial Progenitor Cells / Q000166:cytology*; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry*
chemical_list: D008081:Liposomes; D010455:Peptides; D004317:Doxorubicin
keywords: Active targeting; Anti-neovascular therapy; Cancer; Endothelial progenitor cell; Liposome; Phage-display peptide library