尿激酶免疫脂质体靶向溶栓治疗兔肺动脉血栓栓塞

目的 观察以抗纤维蛋白D-二聚体单克隆抗体(DDmAb)为靶向装置的血栓靶向尿激酶(urokinase,UK)免疫脂质体(liposome,Lip)的溶栓效果.方法 新西兰大白兔32只,随机分为4组,每组8只,每只兔均采用自体血栓栓子颈静脉注入法建立急性肺动脉血栓栓塞模型.各组经股静脉输入不同溶栓剂进行溶栓治疗,通过观察右心室压变化及比较肺内残留栓子评价各组溶栓疗效.4组分别为阴性对照组(输入TBS缓冲液),阳性对照组(输入15万IU/kg UK),UK-Lip组(输入3万IU/kg尿激酶脂质体,反相蒸发法制备),DDmAb-UK-Lip组(输入3万IU/kg尿激酶免疫脂质体,戊二醛交联法连接UK-Lip和DDmAb制备).结果 栓塞后各组右心室压均明显升高(P均<0.01),平均升高(6.75±6.82)mm Hg(1 mm Hg=0.133 kPa).阴性对照组溶栓结束时右心室压[(40.15±11.22)mm Hg]与溶栓即刻[(41.67±14.23)mm Hg]相比下降轻微,阳性对照组和DDmAb-UK-Lip组降到与正常近似[阳性对照组和DDmAb-UK-Lip组溶栓结束时与栓塞前右心室压分别为(34.71±8.67)mm Hg比(33.98±9.32)mm Hg和(30.65±6.67)mm Hg比(30.77±6.85)mm Hg,P均>0.05],UK-Lip组情况居于阴性对照组和阳性对照组及DDmAb-UK-Lip组之间.阳性对照组及DDmAb-UK-Lip组栓子溶解最充分,残留柃子数近似(P>0.05),UK-Lip组栓子部分溶解,阴性对照组栓子未溶解.阳件对照组的心、肝、肾组织明显出血,其他组内脏未见明显病理学改变.结论 DDmAb-UK-Lip治疗急性肺动脉血栓栓塞的尿激酶用量仪为单独应用尿激酶的1/5即达到相似的溶栓效果,且不良反应较少,以DDmAb-UK-Lip进行靶向溶栓可能是肺动脉血栓栓塞的一种理想溶栓方式.

Thrombolysis of rabbit's pulmonary embolism with thrombus-targeted urokinase immune liposome

Objective To develop thrombus-targeted urokinase immune iiposome through incorporating D-dimer monoclonal antibody (DDmAb) to liposome and observe the thrombolytic efficiency in a rabbit pulmonary thromboembolism (PE) model. Methods Reverse-phase evaporation method was used to develop targeted urokinase immune liposome by coupling DDmAb to urokinase liposome (liposomal-encapsalated urokinase) with glutaraldehyde. The PE models were induced by injecting 4 autologous emboli (2 mm×5 mm) through jugular vein catheter into pulmonary arteries. New Zealand white rabbits (n=32) were randomized into four groups: A group (TBS), B group (150 000 IU/kg UK), C group (30 000 IU/kg urokinase liposome) and D group (30 000 IU/kg urokinase immune liposome). The right ventricular pressure and the emboli size in pulmonary arteries were determined. Results The right ventricular pressure increased significantly in PE rabbits (P<0.01), the average value is (6.75±6.82)mm Hg(1 mm Hg= 0.133 kPa). Eighty minutes post various treatments, right ventricular pressure remained unchanged as post PE in group A [(40.15±11.22) mm Hg vs. (41.67±14.23) mm Hg], decreased to baseline level in group BandD [(34.71±8.67)mm Hg vs. (33.98±9.32)mm Hg, (30.65±6.67)mm Hg vs. (30.77± 6.85)mm Hg, all P>0.05], decreased but not returned to normal value in group C. Residual emboli size remained unchanged in group A and partly reduced in group C and more significantly reduced in group B and D. Hemorrhage of heart, kidney and liver was evidenced in group A but not in other groups. Conclusion Acute PE could be successfully treated by the thrombus-targeted ttrokinase immune liposome with D-dimer monoclonal antibody.