title: Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells.
abstract: BACKGROUND
  Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis.
  
  
  METHODS
  A kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice.
  
  
  RESULTS
  The 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects.
  
  
  CONCLUSIONS
  Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: M E M
authors.initials: ME
authors.lastname: Dolman
authors.forename: Stefan
authors.initials: S
authors.lastname: Harmsen
authors.forename: Ebel H E
authors.initials: EH
authors.lastname: Pieters
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Marie
authors.initials: M
authors.lastname: Lacombe
authors.forename: Bálint
authors.initials: B
authors.lastname: Szokol
authors.forename: László
authors.initials: L
authors.lastname: Orfi
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Kok
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000737:chemistry / Q000493:pharmacokinetics; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D000077210:Sunitinib
chemical_list: D004337:Drug Carriers; D007211:Indoles; D009944:Organoplatinum Compounds; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D009113:Muramidase; D000077210:Sunitinib