替拉扎明Hepasphere药物洗脱微球制备及其在生物体内药物释放特性研究  

Preparation and Pharmacokinetics Study of Tirapazamine-Loaded Hepasphere Microspheres

作　　者：李林 梁斌 刘一鸣 张欣[1] 张鸿森 郑传胜[1] LI Lin;LIANG Bin;LIU Yiming(Department of Radiology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei Province 430022,P.R.China)

机构地区：[1]华中科技大学同济医学院附属协和医院放射科,武汉430022

出　　处：《临床放射学杂志》2021年第1期146-151,共6页Journal of Clinical Radiology

摘　　要：目的采用机械吸附及离子交换的方法制备替拉扎明(TPZ)Hepasphere药物洗脱微球,并研究其在肝癌动物模型体内的药物释放特性。方法采用空白洗脱栓塞微球Hepasphere、生理盐水、TPZ及稀盐酸混合的方法制备TPZ Hepasphere药物洗脱微球,之后建立30只兔VX2肝癌模型,接受TPZ Hepasphere药物洗脱微球经导管肝动脉栓塞处理,分别于栓塞后5 min、10 min、15 min、20 min、30 min、45 min、1 h、2 h、4 h、1天、3天和7天静脉血取样;再分别于栓塞后1 h、2 h、4 h、1天、3天和7天每次处死5只动物,采取肿瘤和瘤周正常肝实质标本,采用高效液相色谱分析法(HPLC)检测其中的TPZ及其代谢物SR4317、SR4330的浓度。结果刚混合时,微球及TPZ的溶液呈浑浊的红色,静置50 min后可见载有TPZ的深红色微球沉积于注射器底部。动物血浆内TPZ药物浓度于栓塞后5 min到达峰值,术后第7天血浆内仍可检测到其药物浓度,为峰值浓度的7.12%;血浆内SR4317浓度术后第1天降至极低水平;各时间点血浆内SR4330浓度均极低。肿瘤组织内TPZ浓度于术后1 h达峰值,术后第7天肿瘤组织内仍可检测到其较高的药物浓度,为峰值浓度的28.79%;SR4317术后1 h其浓度达到峰值,术后第七天下降到峰值浓度的34.85%;SR4330术后1天降至极低水平。各个时间点肿瘤内TPZ及其代谢物浓度均明显高于瘤周肝实质。结论TPZ Hepasphere药物洗脱微球具有制备简单、载药性能良好的优点,其栓塞肝癌动物模型后微球内药物缓慢释放,可以长时间使肿瘤内保持较高的药物浓度。Objective To prepare the tirapazamine(TPZ)-loadedHepaspheremicrospheresby the mechanism of ion-exchange and mechanical adsorption and investigate the pharmacokinetics of TACE with the TPZ-loaded Hepasphere microspheres in rabbit VX2 tumor model.Methods The TPZ-loaded Hepasphere microspheres were prepared by mixed TPZ powder,normal saline,diluted hydrochloric acid and the blank drug-eluting Hepasphere microspheres.After inducing a VX2 tumor in the liver,30 rabbits were treated with intra-arterial administration of HepaSpheres microspheres loaded with TPZ.The blood samples were collected at various time points(5,10,15,20,30,45 minutes,1,2,4 hours and 1,3,7 days after the surgery).Rabbits were euthanized and samples from the tumor,peritumoral liver parenchyma were obtained at 1,2,4 hours and at 1,3,or 7 days after treatment.(5 animals at each time point).TPZ and its metabolite concentration analysis were performed via high-pressure liquid chromatography(HPLC).Results The mixture was dark red at the beginning,butafter 50 minutes the microspheres separated from thesupernatant and turned into red spheres depositing at the bottom of the syringe.The peak plasma TPZ concentration was observed at 5 minutes.7.12%of the peak concentration was still detectable at 7 days after treatment.The plasma SR4317 concentration had declined to negligible levels in 1 day;The plasma SR4330 concentration was very low at each time.The peak intratumoral TPZ concentration was observed at 1 hour,it remained detectable 7 daysafter treatment which was about 28.79%of the peak concentration.The intratumoral SR4317 concentration peaked at 1 hour at it was still detectable at 7 days after treatment which was about 34.85%of the peak concentration.The peak SR4330 concentration declined to negligible level with in 1 day.Compared with the peritumoral liver parenchyma,the tumor had significantly higher TPZ and its metabolite concentration at each time point.Conclusion It is easy to prepare the TPZ-loaded Hepasphere microspheres and the microspheres show

关 键 词：替拉扎明 Hepasphere微球 离子交换 机械吸附 VX2肿瘤 药物释放 

分 类 号：R943[医药卫生—药剂学] R969[医药卫生—药学]