title: RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature.
abstract: During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration (GUIDE), Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Kai
authors.initials: K
authors.lastname: Temming
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Kok
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000378:metabolism; D011092:Polyethylene Glycols / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C097260:F 4614; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C507107:PEI-g-PEG-RGD; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C109961:doxorubucin cysteinyl-aspartyl-cysteinyl-arginyl-glycyl-aspartyl-cycsteinyl-phenylalanyl-cysteine conjugate; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin