聚异丙基丙烯酰胺微凝胶新型血管栓塞剂的实验研究

发布时间：2018-07-21 16:28

【摘要】：第一部分空白和载阿霉素聚异丙基丙烯酰胺微凝胶的制备和表征目的：制备空白和载阿霉素聚异丙基丙烯酰胺微凝胶并了解其物理特性。材料和方法：以聚异丙基丙烯酰胺为基质,分别采用改良的沉淀聚合法和物理混合负载法制备空白和载阿霉素聚异丙基丙烯酰胺微凝胶。并对其进行表征检测,考察两者的粘滞度、流动性、载药量和相变特性。结果：空白和载阿霉素聚异丙基丙烯酰胺微凝胶的粘滞度和流动性良好,易经2.7F微导管推注；聚异丙基丙烯酰胺微凝胶具有负载阿霉素的能力,具有体外缓慢释放药物特性,144小时释药80%,且性能稳定。结论：使用改良制备工艺制备出的聚异丙基丙烯酰胺微凝胶具有优良流动性,粘滞度适中,导管内可操控性能好,药物负载稳定,可作为抗肿瘤药物的良好载体,亦可作为一种新型的液体型血管栓塞剂使用。第二部分空白和载聚异丙基丙烯酰胺微凝胶栓塞兔肾动脉的实验研究目的：探讨聚异丙基丙烯酰胺微凝胶栓塞血管的可行性、可操控性和生物兼容性,考察聚异丙基丙烯酰胺微凝胶栓塞的中长期栓塞效果,评价其栓塞持久性。材料和方法：建立30只健康兔右侧肾脏栓塞模型,分别应用空白和载阿霉素的聚异丙基丙烯酰胺微凝胶进行右侧肾动脉栓塞。分别于1周、1个月、2个月和3个月四个时间点进行复查,造影检查评价血管再通及新生侧枝血管形成情况,病理学检查评价栓塞的持久性和药物缓释性,探讨其中长期栓塞效果和载药可行性。结果：阿霉素可由血管内逐渐向周围扩散,空白聚异丙基丙烯酰胺微凝胶可栓塞肾脏末梢小动脉,仅可引起轻度炎症反应,无异物肉芽组织形成且血管壁无损伤作用。3个月的随访考察期内,栓塞牢固且持久,无血管再通和侧枝循环形成。结论：聚异丙基丙烯酰胺微凝胶具有良好的血管栓塞作用,具有较低的溶胶粘度、较快温度响应速度、较好的触变性、良好生物相容性和药物载体等特点,作为一种新型的液体栓塞剂用于载药研究和介入栓塞实验研究是可行的和安全有效的。第三部分载阿霉素聚异丙基丙烯酰胺微凝胶栓塞兔肝VX2瘤的实验研究目的：观察载阿霉素聚异丙基丙烯酰胺微凝胶对兔肝VX2瘤生长的影响,评价其抗肿瘤治疗效果。材料和方法：建立40只兔肝VX2瘤移植性肝癌模型,行MR检查证实后,随机分为四组。经兔股动脉逆行插管,超选择插管至肿瘤部位后分别进行以下治疗方案：A组：经导管注入载阿霉素聚异丙基丙烯酰胺微凝胶(IBi-D)约0.4ml(n=10)；B组：经导管注入空白聚异丙基丙烯酰胺微凝胶(IB)约0.4ml (n=10);C组：经导管灌注阿霉素总量为5mg/kg稀释后的盐酸阿霉素(DOX)0.4ml (n=10);D组：经导管注入生理盐水(NS)0.4ml (n=10);在治疗前1天和治疗后7天分别进行MRI扫描检查,分别测得术前平均肿瘤体积V1和术后平均肿瘤体积V2,比较肿瘤变化率V2/V1,并于第二次MRI检查后处死实验动物,进行病理学检查。然后在影像学和病理学两个角度综合评价肿瘤生长率和肿瘤坏死程度。同时,治疗后观察实验动物的生存情况。结果：载阿霉素聚异丙基丙烯酰胺微凝胶可通过导管进入肿瘤靶区,栓塞肿瘤血管和供血小动脉；栓塞治疗前,兔肝VX2瘤体积间无显著差异(P0.05,ANOVA法)。栓塞后1周各组肿瘤平均生长率分别为A组90.82%±19.34,B组120.71%±33.24,C组331.45%±32.54和D组381.50%±33.17,组间两两比较存在显著性差异(P0.05,Bonferroni法)。载阿霉素聚异丙基丙烯酰胺微凝胶栓塞组与空白聚异丙基丙烯酰胺微凝胶栓塞组比较,空白组在肿瘤旁交界区内有较多残存的活性肿瘤细胞。与盐酸阿霉素和生理盐水灌注对照组比较,空白和载阿霉素聚异丙基丙烯酰胺微凝胶栓塞组,肿瘤坏死范围更广、坏死程度更高。结论：载阿霉素聚异丙基丙烯酰胺微凝胶具有良好的栓塞作用,可明显抑制兔肝VX2瘤生长,具有较好的治疗作用。
[Abstract]:Preparation and characterization of the first part of the blank and the adriamycin - containing polyisopropylacrylamide microgels

Objective : To prepare a blank and contain adriamycin - polyisopropylacrylamide micro - gel and to understand its physical properties . Materials and Methods : Polyisopropylacrylamide was used as the base material to prepare the blank and the adriamycin - containing polyisopropylacrylamide micro - gel by the modified precipitation polymerization method and the physical mixed loading method respectively . The characterization and detection were carried out to investigate the viscosity , fluidity , drug loading and phase change characteristics of both .

Results : The viscosity and fluidity of the blank and the adriamycin - containing polyisopropylacrylamide microgels were good , which was easy to be injected by a 2.7F microcatheter .
The polyisopropylacrylamide micro - gel has the capability of loading adriamycin , and has the characteristics of slow release of drug in vitro , 80 % of drug release in 144 hours , and stable performance .

Conclusion : The poly ( isopropylacrylamide ) micro - gel prepared by modified preparation process has good fluidity , moderate viscosity , good control performance in the catheter , stable drug load , and can be used as a good carrier of anti - tumor drug and can be used as a novel liquid type vascular embolism agent .

Experimental study of second part blank and poly ( isopropylacrylamide ) microgel embolization in rabbit renal artery

Objective : To investigate the feasibility , controllability and biocompatibility of poly ( isopropylacrylamide ) micro - gel embolism blood vessels .

Materials and Methods : 30 healthy rabbit right renal embolism models were established , and the right renal artery embolization was performed in 1 week , 1 month , 2 months and 3 months respectively .

Results : ADM could diffuse gradually around the blood vessel , and the blank polyisopropylacrylamide microemulsion could embolize the small artery of the renal distal tip , which could cause mild inflammatory reaction , no foreign body granulation tissue formed and no damage to the vessel wall . During the 3 - month follow - up visit , the embolism was firm and durable , no blood vessel re - conduction and collateral circulation were formed .

Conclusion : Poly ( isopropylacrylamide ) micro - gel has good blood vessel embolization effect , and has the characteristics of low sol viscosity , rapid temperature response speed , good thixotropic property , good biocompatibility and drug carrier , etc . As a new liquid embolic agent , it is feasible and safe to study drug - carrying and interventional embolization .

Experimental study on the third part of adriamycin - containing poly ( isopropylacrylamide ) micro - gel embolism in rabbit liver VX2 tumor

Objective : To observe the effect of adriamycin - containing poly ( isopropylacrylamide ) micro - gel on the growth of rabbit liver VX2 tumor and evaluate its anti - tumor effect .

Materials and Methods : 40 rabbits with hepatic VX2 tumor transplantation were established . After MR examination , four groups were randomly divided into four groups : group A : injection of adriamycin - loaded polyisopropylacrylamide ( IBi - D ) by catheter injection about 0.4 ml ( n = 10 ) ;
Group B : Injection of empty polyisopropylacrylamide ( IB ) by catheter was about 0.4 ml ( n = 10 ) ; C group : 0.5 mg / kg of adriamycin ( n = 10 ) diluted by catheter and 0.4 ml ( n = 10 ) in saline ( NS ) . After 1 day of treatment and 7 days after treatment , the tumor growth rate and tumor necrosis degree were evaluated .
There was no significant difference between VX2 tumor volume before and after embolization ( P0.05 , ANOVA ) . The average growth rate of tumor was 90.82 % 卤 19.34 in group A , 120.71 % 卤 33.24 in group B , 335.45 % 卤 32.54 in group C , 381.50 % 卤 33.17 in group D , and there was significant difference between the two groups ( P0.05 ) . Compared with the blank polyisopropylacrylamide microgel embolism group , there were more active tumor cells in the blank group . Compared with the control group of adriamycin and physiological saline , the blank and the adriamycin - containing polyisopropylacrylamide were compared with the control group , and the tumor necrosis area was wider and the necrosis degree was higher .

Conclusion : The adriamycin - containing poly ( isopropylacrylamide ) micro - gel has good embolization effect , and can obviously inhibit the growth of rabbit liver VX2 tumor , and has good therapeutic effect .
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R943;R965

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