title: Dendrimer-based macromolecular conjugate for the kidney-directed delivery of a multitargeted sunitinib analogue.
abstract: The development of a macromolecular conjugate of a multitargeted tyrosine kinase inhibitor is described that can be used for renal-specific delivery into proximal tubular cells. A novel sunitinib analogue, that is, 17864, is conjugated to a NH(2) -PAMAM-G3 dendrimer via the platinum (II)-based Universal Linkage System (ULS™). The activity of 17864 is retained after coordination to the ULS linker alone or when coupled to NH(2) -PAMAM-G3. 17864-UlS-NH(2) -PAMAM-G3 is non-toxic to proximal tubular cells in vitro. After intravenous administration to mice, 17864-UlS-NH(2) -PAMAM-G3 rapidly and efficiently accumulates in the kidneys. These results are encouraging for future studies focusing on the development of novel therapeutics for the treatment of renal diseases.
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, Utrecht, The Netherlands.
authors: M E Emmy M
authors: ME
authors: Dolman
authors: Kim M A
authors: KM
authors: van Dorenmalen
authors: Ebel H E
authors: EH
authors: Pieters
authors: Rolf W
authors: RW
authors: Sparidans
authors: Marie
authors: M
authors: Lacombe
authors: Bálint
authors: B
authors: Szokol
authors: László
authors: L
authors: Orfi
authors: György
authors: G
authors: Kéri
authors: Niels
authors: N
authors: Bovenschen
authors: Gert
authors: G
authors: Storm
authors: Wim E
authors: WE
authors: Hennink
authors: Robbert J
authors: RJ
authors: Kok
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050091:Dendrimers / Q000008:administration & dosage* / Q000032:analysis* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage* / Q000032:analysis; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000737:chemistry* / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000032:analysis*
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D047428:Protein Kinase Inhibitors