Abstract
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 language | English |
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Pages (from-to) | 1455-1462 |
Number of pages | 8 |
Journal | Biochemical Pharmacology |
Volume | 73 |
Issue number | 9 |
DOIs | |
Publication status | Published - 1-May-2007 |
Keywords
- liver fibrosis
- drug targeting
- hepatic stellate cell
- selective delivery
- cytostatic drugs
- mannose-6-phosphate/insulin-like
- growth factor II receptor
- MANNOSE 6-PHOSPHATE
- IN-VIVO
- SELECTIVE DELIVERY
- MYCOPHENOLIC-ACID
- LIVER FIBROSIS
- ALBUMIN
- RECEPTOR
- DRUG
- HETEROGENEITY
- EXPRESSION