Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

M. Dolman, Stefan Harmsen, Ebel H E Pieters, Rolf W. Sparidans, Marie Lacombe, Bálint Szokol, L. Őrfi, G. Kéri, Gert Storm, Wim E. Hennink, Robbert J. Kok

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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-specifc 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)417-433
Number of pages17
JournalInternational Journal of Nanomedicine
Volume7
Publication statusPublished - 2012

Fingerprint

Platinum
Enzymes
Muramidase
Kidney
Ureteral Obstruction
Metabolites
Pharmaceutical Preparations
Toxicity
Catalyst activity
Fibrosis
sunitinib
Protein-Tyrosine Kinases
Drug-Related Side Effects and Adverse Reactions
Intravenous Injections
Area Under Curve
Therapeutics
Pharmacology
Safety

Keywords

  • Drug delivery
  • Fibrosis
  • Platinum linker
  • Sunitinib

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Organic Chemistry
  • Drug Discovery

Cite this

Dolman, M., Harmsen, S., Pieters, E. H. E., Sparidans, R. W., Lacombe, M., Szokol, B., ... Kok, R. J. (2012). Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells. International Journal of Nanomedicine, 7, 417-433.

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells. / Dolman, M.; Harmsen, Stefan; Pieters, Ebel H E; Sparidans, Rolf W.; Lacombe, Marie; Szokol, Bálint; Őrfi, L.; Kéri, G.; Storm, Gert; Hennink, Wim E.; Kok, Robbert J.

In: International Journal of Nanomedicine, Vol. 7, 2012, p. 417-433.

Research output: Contribution to journalArticle

Dolman, M, Harmsen, S, Pieters, EHE, Sparidans, RW, Lacombe, M, Szokol, B, Őrfi, L, Kéri, G, Storm, G, Hennink, WE & Kok, RJ 2012, 'Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells', International Journal of Nanomedicine, vol. 7, pp. 417-433.
Dolman M, Harmsen S, Pieters EHE, Sparidans RW, Lacombe M, Szokol B et al. Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells. International Journal of Nanomedicine. 2012;7:417-433.
Dolman, M. ; Harmsen, Stefan ; Pieters, Ebel H E ; Sparidans, Rolf W. ; Lacombe, Marie ; Szokol, Bálint ; Őrfi, L. ; Kéri, G. ; Storm, Gert ; Hennink, Wim E. ; Kok, Robbert J. / Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells. In: International Journal of Nanomedicine. 2012 ; Vol. 7. pp. 417-433.
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AU - Pieters, Ebel H E

AU - Sparidans, Rolf W.

AU - Lacombe, Marie

AU - Szokol, Bálint

AU - Őrfi, L.

AU - Kéri, G.

AU - Storm, Gert

AU - Hennink, Wim E.

AU - Kok, Robbert J.

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