title: Organ- and cell-type specific delivery of kinase inhibitors: a novel approach in the development of targeted drugs.
abstract: During the past years, we have explored the cellular delivery of kinase inhibitors. Kinase inhibitors have selectivity for specific kinases but they lack cellular selectivity. This is exemplified by recent reports on cardiotoxicity of kinase inhibitors used in cancer treatment. We postulate that targeted cellular delivery of kinase inhibitors can improve their safety/toxicity profiles, as will be exemplified by recent published studies. Cell specific delivery of therapeutics is a quickly growing area of investigation. This innovative strategy employs carrier molecules that bind to receptors exposed on the surface of cell types involved in disease processes. Binding and receptor mediated internalization of the carrier facilitates local accumulation of the product in target cells. Upon systemic administration, this may create local drug depots in specific organs, while other tissues are avoided, thus favoring enhanced localized drug efficacy and reduced side-effects. Synthesis of targeted kinase inhibitor-carrier conjugates was achieved using a new approach, in which kinase inhibitors were bound to a platinum(II) atom, the so-called Universal Linkage System (ULS). We review this novel linkage chemistry and demonstrate the applicability of ULS for drug targeting approaches aiming at angiogenic endothelial cells, hepatic stellate cells, and kidney tubular cells. We will review important issues like drug release mechanism, safety of the linker, and pharmacokinetics of the products in animals. Finally, we review the pharmacological efficacy of the cellular targeted drug conjugates in experimental animal models, especially in renal and liver fibrosis models.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, University of Groningen, The Netherlands.
authors.forename: Kai
authors.initials: K
authors.lastname: Temming
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Fretz
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Kok
mesh_terms: D004337:Drug Carriers; D016503:Drug Delivery Systems; D006801:Humans; D008081:Liposomes; D008360:Mannosephosphates / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D017671:Platinum Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D011092:Polyethylene Glycols / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D008360:Mannosephosphates; D009842:Oligopeptides; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D047428:Protein Kinase Inhibitors; C027693:mannose-6-phosphate; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid