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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >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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The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

机译：抗增殖药物阿霉素可抑制胆管结扎大鼠的肝纤维化，并可选择性地体内递送至肝星状细胞

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Hepatic stellate cell (HSC) proliferation is a key event in liver fibrosis;therefore,pharmacological intervention with antiprolif-erative 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.
机译：肝星状细胞（HSC）增殖是肝纤维化的关键事件;因此，抗增生药物的药理干预可能会产生抗纤维化作用。作为克服药物相关毒性的策略，我们另外研究了如何通过将其与HSC选择性药物载体甘露糖6-磷酸酯-缀合来将这种药物特异性地递送至HSC。修饰的人血清白蛋白（M6PHSA）。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。结扎的（BDL）大鼠在第3天至第10天每天静​​脉注射0.35 mg / kg DOX，将肝脏切片中α-平滑肌肌动蛋白染色的面积从8.5 +-0.8降低到5.1 +-0.9％（P <0.01）和胶原蛋白染色面积从13.1 +-1.3到8.9 +-1.5％（P <0.05）。DOX与M6PHSA偶联，研究了该构建体的器官分布（M6PHSA-DOX）。静脉注射后20分钟，50±6剂量百分比存在于肝脏中，并观察到M6PHSA-DOX与HSC标记共定位。此外，体外研究表明M6PHSA-DOX与活化的HSC有选择性结合。此外，M6PHSA-DOX在体外强烈减弱了HSC增殖。 DOX抑制BDL大鼠肝纤维化，并且有可能对该药物进行HSC选择性靶向。这可能为抗增殖药物在抗纤维化方面的应用提供了前景。

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