Pharmacokinetics of a hepatic stellate cell-targeted doxorubicin construct in bile duct-ligated rats

Rick Greupink, Catharina Reker-Smit, Johannes H. Proost, Anne-miek van Loenen Weemaes, Marjolijn de Hooge, Klaas Poelstra, Leonie Beljaars*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background/aims: Inhibition of hepatic stellate cell (HSC) proliferation is a relevant strategy to inhibit liver fibrosis. Coupling of antiproliferative drugs to the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA) may lead to cell-selective inhibition of HSC proliferation. We coupled the antiproliferative drug doxorubicin (DOX) to this drug carrier and investigated the pharmacokinetics of this construct in a rat model of liver fibrosis, as well as in cultured HSC.

Methods/results: M6PHSA-DOX was cleared from the plasma in a biphasic manner. Upon i.v. injection of 4 mu g kg(-1) (tracer), 2 and 20 mg kg(-1), the clearance in the distribution phase of drug disposition (CLd) significantly decreased from 9.7 +/- 0.7 to 4.7 +/- 2.3 and 1.0 +/- 0.1 ml kg(-1) min(-1), respectively. This indicates that saturation of clearance mechanisms occurs in this phase of drug disposition, likely reflecting saturable receptor-mediated uptake in the target cells. Gamma-camera studies revealed that the majority of the conjugate accumulated in the liver within 5 min, and immunohistochemical double-staining of liver sections demonstrated co-localization of the construct with HSC-markers. Simulation of the release of DOX from the carrier, after cellular uptake by HSC, showed that a gradual release of the drug takes place over a 9 h period. Studies in cultured HSC illustrated that after 24 h incubation with the conjugate, DOX was associated with the cell nucleus.

Conclusions: The rapid distribution of M6PHSA-DOX from the blood to HSC, in combination with the expected gradual release of DOX within these cells, make this construct a promising tool for achieving sustained and selective inhibition of HSC proliferation. (c) 2006 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)1455-1462
Number of pages8
JournalBiochemical Pharmacology
Issue number9
Publication statusPublished - 1-May-2007


  • liver fibrosis
  • drug targeting
  • hepatic stellate cell
  • selective delivery
  • cytostatic drugs
  • mannose-6-phosphate/insulin-like
  • growth factor II receptor
  • DRUG

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