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

M E M Dolman1, Stefan Harmsen, Ebel H E Pieters

  • 1Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

International Journal of Nanomedicine
|February 16, 2012
PubMed
Abstract

Insights

A novel kidney-targeted sunitinib conjugate shows promise for treating renal fibrosis by improving drug delivery and reducing toxicity. Further studies are needed to optimize its antifibrotic effects.

Area of Science:

  • Nephrology
  • Pharmacology
  • Oncology

Background:

  • Activated proximal tubular cells are key drivers of renal fibrosis.
  • Investigating sunitinib and a kidney-targeted conjugate for antifibrotic potential in tubulointerstitial fibrosis.

Purpose of the Study:

  • To evaluate the efficacy of a kidney-targeted sunitinib conjugate in attenuating fibrogenic events.
  • To assess the safety and renal accumulation of the conjugate.

Main Methods:

  • A sunitinib analog (17864) was conjugated to lysozyme via a platinum-based linker.
  • Pharmacological activity was tested in human kidney proximal tubular cells (HK-2).
  • Renal accumulation and antifibrotic effects were studied in a mouse unilateral ureteral obstruction (UUO) model.

Main Results:

  • The 17864-lysozyme conjugate inhibited tyrosine kinase activity and showed sustained renal drug levels for up to 3 days.
  • Renal drug levels were significantly higher (28-fold AUC) compared to sunitinib malate.
  • While high-dose sunitinib malate caused toxicity, a single dose of 17864-lysozyme was safe but lacked antifibrotic effects in the UUO model.

Conclusions:

  • Sunitinib, a multikinase inhibitor, may benefit fibrotic diseases if safety and sustained renal drug levels are improved.
  • Kidney-targeted delivery strategies, like the one presented, are crucial for enhancing the therapeutic window of such agents.
Keywords:
drug deliveryfibrosisplatinum linkersunitinib

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