title: Potent retro-inverso D-peptide for simultaneous targeting of angiogenic blood vasculature and tumor cells.
abstract: The application of tumor targeting ligands for the treatment of cancer holds the promise of enhanced efficacy and reduced toxicity. L-SP5 ((L)(SVSVGMKPSPRP)) is a peptide that recognizes tumor neovasculature but not normal blood vessels (Lee et al., Cancer Res.2007, 67, 10958-65). The current report presents the design and application of D-SP5 ((D)(PRPSPKMGVSVS)), a novel retro-inverso analogue of L-SP5. Peptides D-SP5 and parental L-SP5 are shown to compete for the same target sites of a yet unknown cellular target and possess a dual-targeting bioactivity for both activated endothelial cells (HUVEC) and several tumor cell lines. Cellular uptake experiments showed superior in vitro targeting abilities of D-SP5 compared with L-SP5, such as enhanced internalization into stimulated HUVEC or KB, U87, and SGC tumor cells. A radioligand receptor binding assay revealed a higher cell affinity of D-SP5 in all tested cell lines, with K(d) values for D-SP5 about 2-fold lower than for L-SP5. An up to 3-fold higher maximum binding capacity (B(max)) to cells of D-SP5 was noted. Fluorescein-labeled D-SP5 upon intravenous administration displayed strong association with tumor endothelium. D-SP5-conjugated PEG-DSPE micelles displayed enhanced tumor homing (evidenced by near-infrared in vivo imaging). When loaded with doxorubicin, D-SP5 micelles could markedly suppress tumor growth with higher efficacy than L-SP5 micelles both in vitro and in vivo in KB tumor xenografts. In summary, the data demonstrate that D-SP5 displays higher binding affinities toward tumor endothelium as well as tumor cells and enhanced tumor targeting capability in vitro and in vivo.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Lei
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Cao
authors.initials: C
authors.lastname: Xie
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D010455:Peptides; D010714:Phosphatidylethanolamines; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D004317:Doxorubicin