title: Enhanced active targeting via cooperative binding of ligands on liposomes to target receptors.
abstract: To achieve effective active targeting in a drug delivery system, we previously developed dual-targeting (DT) liposomes decorated with both vascular endothelial growth factor receptor-1 (VEGFR-1)-targeted APRPG and CD13-targeted GNGRG peptide ligands for tumor neovessels, and observed the enhanced suppression of tumor growth in Colon26 NL-17 tumor-bearing mice by the treatment with the DT liposomes encapsulating doxorubicin. In this present study, we examined the binding characteristics of DT liposomes having a different couple of ligands, namely, APRPG and integrin αvβ3-targeted GRGDS peptides. These DT liposomes synergistically associated to stimulated human umbilical vein endothelial cells compared with single-targeting (ST) liposomes decorated with APRPG or GRGDS. The results of a surface plasmon resonance assay showed that ST liposomes modified with APRPG or GRGDS peptide selectively bound to immobilized VEGFR-1 or integrin αvβ3, respectively. DT liposomes showed a higher affinity for a mixture of VEGFR-1 and integrin αvβ3 compared with ST liposomes, suggesting the cooperative binding of these 2 kinds of ligand on the liposomal surface. In a biodistribution assay, the DT liposomes accumulated to a significantly greater extent in the tumors of Colon26 NL-17 tumor-bearing mice compared with other liposomes. Moreover, the intratumoral distribution of the liposomes examined by confocal microscopy suggested that the DT liposomes targeted not only angiogenic endothelial cells but also tumor cells due to GRGDS-decoration. These findings suggest that "dual-targeting" augmented the affinity of the liposomes for the target cells and would thus be useful for active-targeting drug delivery for cancer treatment.
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.forename: Yuki Murase
authors.initials: YM
authors.lastname: Nedachi
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Katanasaka
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shimizu
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Maeda
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D018826:CD13 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008024:Ligands; D008081:Liposomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D014018:Tissue Distribution; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D008024:Ligands; D008081:Liposomes; D009842:Oligopeptides; C490869:alanyl-prolyl-arginyl-prolyl-glycine; D004317:Doxorubicin; C049554:glycyl-arginyl-glycyl-aspartyl-serine; D040281:Vascular Endothelial Growth Factor Receptor-1; D018826:CD13 Antigens