title: Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide.
abstract: Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs.
authors: Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Shingo
authors: S
authors: Hatakeyama
authors: Kazuhiro
authors: K
authors: Sugihara
authors: Toshiaki K
authors: TK
authors: Shibata
authors: Jun
authors: J
authors: Nakayama
authors: Tomoya O
authors: TO
authors: Akama
authors: Naoaki
authors: N
authors: Tamura
authors: Shuk-Man
authors: SM
authors: Wong
authors: Andrey A
authors: AA
authors: Bobkov
authors: Yutaka
authors: Y
authors: Takano
authors: Chikara
authors: C
authors: Ohyama
authors: Minoru
authors: M
authors: Fukuda
authors: Michiko N
authors: MN
authors: Fukuda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000737:chemistry / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D045325:HCT116 Cells; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D007275:Injections, Intravenous; D000077146:Irinotecan; D008163:Luminescent Measurements / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
chemical_list: C417561:Alexa 488 hydrazide; D017305:Annexin A1; D002241:Carbohydrates; D006834:Hydrazines; D010455:Peptides; D000077146:Irinotecan; D002166:Camptothecin