New miceller agent for antioxidation therapy based on XO inhibition using AHPP

我们先前发现AHPP对黄嘌呤氧化酶(XO)有很强的抑制作用。针对AHPP水溶性差、相对分子质量低、体内t1/2短、对病变部位无靶向作用等问题，我们合成了AHPP与含AHPP的SMA胶束的聚乙二醇偶联物。结果发现：(1)两种聚合物AHPP的体外XO抑制活性均约为游离AHPP的80%，且效果令人满意。(2)肝脏I/R模型体内评价显示，聚合物AHPP对I/R所致组织(肝)毒性有明显的保护作用。(3)自发性高血压大鼠口服聚乙二醇AHPP可使血压降至正常范围。(4)一次口服降压作用持续24小时以上。

We had previously discovered that AHPP exhibited a potent inhibitory effect against xanthine oxidase (XO). The difficulty to make AHPP as pharmaceutical agent resides in poor water solubility and low MW that has short in vivo t1/2 and no targeting capacity to the diseased site.To solve these problems we synthesized PEG-conjugate of AHPP and SMA (styrene-co-maleic acid) micelles containing AHPP. As the results, we found (1) XO inhibitory activity in vitro of both polymeric AHPP showed about 80% of that of free AHPP, and satisfactory. (2) In vivo evaluation of ischemia-reperfusion (I/R) model of liver, the polymeric AHPP showed significant effect preventing I/R induced tissue (liver) toxicity. (3) Oral administration of PEG-AHPP in lipid formation in the spontaneously hypertensive rats resulted in lowering of blood pressure to normal range. (4) The antihypertensive effect lasted even more than 24 hr after one oral administration.