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

我们以前发现AHPP对黄嘌呤氧化酶（XO）表现出有效的抑制作用。AHPP作为药物制剂的困难在于水溶性差、分子量低、体内t1/2短、对病变部位没有靶向能力，为了解决这些问题，我们合成了AHPP与含有AHPP的SMA（苯乙烯-马来酸共聚物）胶束的PEG缀合物。结果表明：（1）聚合AHPP的体外XO抑制活性约为游离AHPP的80%，且效果令人满意。(2)在肝脏缺血再灌注（I/R）模型的体内评价中，聚合物AHPP显示出显著的预防I/R诱导的组织（肝脏）毒性的效果。(3)口服PEG-AHPP在脂质形成中导致自发性高血压大鼠的血压降低至正常范围。(4)一次口服给药后，抗高血压作用甚至持续超过24小时。

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.