The antiproliferative drug doxorubicin inhibits liver fibrosis in bile duct-ligated rats and can be selectively delivered to hepatic stellate cells in vivo
The antiproliferative drug doxorubicin inhibits liver fibrosis in bile duct-ligated rats and can be selectively delivered to hepatic stellate cells in vivo
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DOI：
10.1124/jpet.105.099499
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发表时间：
2006-05-01
影响因子：
3.5
通讯作者：
Poelstra, K
中科院分区：
文献类型：
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作者：
Greupink, R;Bakker, HI;Poelstra, K
肝星状细胞（HSC）增殖是肝纤维化的关键事件，因此，抗增殖药物的药理学干预可能会产生抗纤维化作用。本文研究了三种细胞生长抑制剂对体外培养的大鼠肝星状细胞的增殖抑制作用。随后，在体内评价了最有效药物的抗纤维化潜力。作为克服药物相关毒性的策略，我们还研究了如何通过将其与HSC选择性药物载体甘露糖-6-磷酸修饰的人血清白蛋白（M6 PHSA）缀合来将这种药物特异性地递送到HSC。我们研究了顺铂、苯丁酸氮芥和阿霉素（DOX）对培养的HSC中5-溴-2 '-脱氧尿苷掺入的影响，发现DOX是最有效的药物。胆管结扎（BDL）大鼠在BDL后第3 - 10天每天静脉注射0.35 mg/kg DOX治疗，使肝切片中α-平滑肌肌动蛋白染色面积从8.5 +/-0.8%减少到5.1 +/- 0.9%（P +/- 0.01）和胶原染色面积从13.1 +/- 1.3至8.9 +/- 1.5%（P +/- 0.05）。将DOX偶联至M6 PHSA，并研究该构建体（M6 PHSA-DOX）的器官分布。静脉内给药后20分钟，50 +/-6%的剂量存在于肝脏中，并且观察到M6 PHSA-DOX与HSC标志物的共定位。此外，体外研究显示M6 PHSA-DOX与活化的HSC的选择性结合。此外，M6 PHSA-DOX在体外强烈减弱HSC增殖，表明活性药物在摄取缀合物后释放。DOX抑制BDL大鼠的肝纤维化，并且这种药物的HSC选择性靶向是可能的。这可能为抗增生药物用于抗纤维化目的提供前景。
Hepatic stellate cell (HSC) proliferation is a key event in liver fibrosis; therefore, pharmacological intervention with antiproliferative drugs may result in antifibrotic effects. In this article, the antiproliferative effect of three cytostatic drugs was tested in cultured rat HSC. Subsequently, the antifibrotic potential of the most potent drug was evaluated in vivo. As a strategy to overcome drug-related toxicity, we additionally studied how to deliver this drug specifically to HSC by conjugating it to the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA). We investigated the effect of cisplatin, chlorambucil, and doxorubicin (DOX) on 5-bromo-2'-deoxyuridine incorporation in cultured HSC and found DOX to be the most potent drug. Treatment of bile duct-ligated (BDL) rats with daily i.v. injections of 0.35 mg/kg DOX from day 3 to 10 after BDL reduced alpha-smooth muscle actin-stained area in liver sections from 8.5 +/- 0.8 to 5.1 +/- 0.9% (P +/- 0.01) and collagen-stained area from 13.1 +/- 1.3 to 8.9 +/- 1.5% (P +/- 0.05). DOX was coupled to M6PHSA, and the organ distribution of this construct (M6PHSA-DOX) was investigated. Twenty minutes after i.v. administration, 50 +/- 6% of the dose was present in the livers, and colocalization of M6PHSA-DOX with HSC markers was observed. In addition, in vitro studies showed selective binding of M6PHSA-DOX to activated HSC. Moreover, M6PHSA-DOX strongly attenuated HSC proliferation in vitro, indicating that active drug is released after uptake of the conjugate. DOX inhibits liver fibrosis in BDL rats, and HSC-selective targeting of this drug is possible. This may offer perspectives for the application of antiproliferative drugs for antifibrotic purposes.