CN112430330B - Pda-pei修饰物、含其的抗食管癌药及其制备 - Google Patents

Pda-pei修饰物、含其的抗食管癌药及其制备 Download PDF

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CN112430330B
CN112430330B CN202011073865.2A CN202011073865A CN112430330B CN 112430330 B CN112430330 B CN 112430330B CN 202011073865 A CN202011073865 A CN 202011073865A CN 112430330 B CN112430330 B CN 112430330B
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张琨
李敬安
马珊珊
白雨鑫
开昆仑
邢衢
李檀
关方霞
李庆华
张彦婷
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Abstract

本发明提供了聚多巴胺聚乙烯亚胺修饰物。本发明还提供了含其的抗食管癌药。本发明还提供了其制备方法及其抗食管癌用途。本发明的聚多巴胺聚乙烯亚胺修饰物，其制备可包括：通过迈克尔加成和席夫碱反应，将聚乙烯亚胺接枝在聚多巴胺上。本发明的制备方法简单易操作，无需昂贵复杂的设备，工艺成本较低，效果显著。本发明的聚多巴胺聚乙烯亚胺修饰物可促进食管癌细胞凋亡或坏死，抗食管癌效果亦比较好，可显著弥补载药食管癌支架载药量有限、载药涂层抗癌功能不足等缺点，赋予支架持续的抗癌疗效。

Description

PDA-PEI修饰物、含其的抗食管癌药及其制备
技术领域
本发明涉及一种聚多巴胺聚乙烯亚胺修饰物、其制备方法及其抗食管癌用途。
背景技术
自Frimberger于1983年首次成功采用自膨式金属支架治疗食管恶性狭窄以来，经过临床适应和改进，治疗食管癌的支架类型主要包括裸金属支架、覆膜支架、载药支架与粒子支架等。裸金属支架无法抑制肿瘤细胞的生长和炎症的发生，选用覆膜支架虽然有效阻止肿瘤向腔内生长，但不能控制肿瘤生长并容易发生支架的移位，且端部易引起再狭窄。粒子支架对手术水平要求较高、放射性粒子是否需要回收目前还存在疑议。载药支架存在的问题主要体现在以下两个方面：(1)支架表面的药物装载量有限，随着药物的释放，装载量逐渐减少，药物的有效浓度逐渐降低为零，最终导致杀伤肿瘤细胞的功能丧失；(2)逐渐暴露的材料基底不仅不能有效阻抗细胞，反而可能会因支架材料良好的细胞相容性促进肿瘤细胞、肌成纤维细胞、上皮细胞等生长，这也是影响支架长期疗效的重要因素。
因此，在食管支架材料表面引入稳定性较好的阻抗细胞(如肿瘤细胞、肌成纤维细胞、上皮细胞)的功能底层，赋予支架持续抑制肿瘤长入、组织增生与炎症进程的功能是当前食管支架研发中亟需解决的瓶颈问题。
聚乙烯亚胺(本文亦称PEI)是一种细胞毒性物质，但有文献报道其共聚后毒性显著降低。目前未见报道PEI与聚多巴胺(本文亦称PDA)共聚，可显著抗食管癌的专利或其他文献。
发明内容
本发明独辟蹊径，克服了现有技术的偏见，坚持探索聚乙烯亚胺修饰物，意外发现，聚多巴胺的聚乙烯亚胺修饰物，其抗食管癌效果比较好。
一方面，本发明涉及聚多巴胺的聚乙烯亚胺修饰物用于制备促进食管癌细胞凋亡或坏死的促进剂的用途，该促进剂可为抗食管癌的药物，如药用支架。
另一方面，本发明涉及制备所述聚多巴胺的聚乙烯亚胺修饰物的方法，包括：通过迈克尔加成和席夫碱反应，将聚乙烯亚胺接枝在聚多巴胺上。
任选地，所述用于接枝的聚乙烯亚胺的分子量为1.8×103-7×104，如为1.8×103、104、2.5×104或7×104。
任选地，所述用于接枝的聚多巴胺以沉积在支架材料表面的形式提供,支架材料可为常用的组织工程材料，如医用的不锈钢、镍钛合金或镁合金。
任选地，所述接枝反应包括：将聚乙烯亚胺配成0.5-2mg/ml的水溶液，聚多巴胺浸泡在该聚乙烯亚胺水溶液中进行所述接枝反应。
任选地，所述接枝反应的温度为20-40℃,如为37℃。
任选地，所述接枝反应的时间为0.5-3天，如为24h。
任选地，所述聚多巴胺由多巴胺在有氧、pH8-9的条件下聚合得到，反应可在氧气存在下直接进行，pH可为8.5，比如使用Tris(三羟甲基氨基甲烷)缓冲液。
任选地，所用多巴胺与所述聚乙烯亚胺的质量比为1:1。
任选地，所述多巴胺的浓度为0.5-2mg/ml。
任选地，所述聚多巴胺的制备包括将支架材料浸泡在多巴胺溶液中，反应温度可为20-30℃,如为25℃，反应时间可为0.5-3天，如为48h。
再一方面，本发明涉及前述方法制得的修饰物。
本发明的有益效果主要为：
在现有技术教导PEI共聚会显著降低其效果的情况下，本发明偏见，坚持探索聚乙烯亚胺修饰物，意外发现，聚多巴胺的聚乙烯亚胺修饰物，其粗糙度、润湿性能好，抗食管癌效果亦比较好，可显著弥补载药食管癌支架载药量有限、载药涂层抗癌功能不足等缺点，赋予支架持续的抗癌疗效。另外，本发明的制备方法简单易操作，无需昂贵复杂的设备，工艺成本较低，效果显著。
附图说明
图1为各样品表面原子力图粗糙度值对比。
图2为各样品表面胺基定量结果(*p<0.05,mean±SD,n＝3)。
图3为各样品表面水接触角测量结果，分别用图3-1至3-6表示。
具体实施方式
下面具体描述本发明，如无特别说明，所用材料或方法均为常规方法。
一、实施例：
聚多巴胺的聚乙烯亚胺修饰物的制备方法，包括：
在抛光的不锈钢317LSS(1cm×1cm)表面沉积多巴胺聚合薄膜：将多巴胺溶解在pH值8.5的Tris缓冲液中，多巴胺的浓度为2mg/ml,浸没材料，25℃下聚合沉积48h，反应完毕后吸除残余反应液，用去离子水洗净未聚合的分子，干燥得到表面沉积有PDA膜的材料(本文命名为PDA支架)待用；
通过迈克尔加成和席夫碱反应将PEI接枝在多巴胺聚合薄膜表面：分别将分子量为1.8×103DA、1×104DA、2.5×104DA、7×104DA的PEI溶解于去离子水中，依次制备得到浓度为2mg/ml的PEI水溶液PEI-1、PEI-2、PEI-3、PEI-4(按溶质PEI的分子量，由小到大命名)；将A步所得沉积有多巴胺聚合薄膜的PDA支架,分别浸没在前述PEI溶液中，37℃反应24h，反应完毕后吸除残余反应液，用去离子水洗净未固定的PEI分子，分别制得聚多巴胺的聚乙烯亚胺修饰物支架PDA/PEI-1、PDA/PEI-2、PDA/PEI-3、PDA/PEI-4(PDA/PEI-1指PDA支架与PEI-1溶液反应所得支架，其余类推)。
二、性能检测试验
以A步所用原料不锈钢317LSS、A步所得PDA支架为对照，分别检测支架PDA/PEI-1、PDA/PEI-2、PDA/PEI-3、PDA/PEI-4的性能，各样品原子力图片及粗糙度值对比如图1所示，材料表面的胺基密度数据对比如图2所示，支架材料表面水接触角如图3所示。
食管癌试验例：
将1cm×1cm的317LSS,PDA和不同PDA/PEI样品紫外灭菌后分别置于24孔板中，加入一定量的食管癌Eca109肿瘤细胞悬液，于37℃、5％CO2条件下静态培养4h、1d、3d后，使用AO/PI双染细胞凋亡检测试剂盒进行荧光染色，倒置荧光显微镜下观察样品表面Eca109肿瘤细胞的生长情况。其中，细胞核完整的绿色荧光为活细胞，细胞核染色质浓缩的绿色荧光为早期细胞凋亡，细胞核染色质浓缩的橙色荧光为晚期细胞凋亡，红色荧光为坏死细胞，通过细胞计数计算细胞的凋亡率与坏死率，定量评价修饰层的抗肿瘤细胞生长情况，统计见表1和2，下面重点描述食管癌试验结果。
表1 317LSS,PDA和不同PDA/PEI样品表面Eca109肿瘤细胞的凋亡率
317L SS PDA PDA/PEI-1 PDA/PEI-2 PDA/PEI-3 PDA/PEI-4
4h 0.0％±0.0％ 0.0％±0.0％ 73.4％±6.9％ 94.6±12.7％ 98.0±2.9％ 100.0％±0.0％
1d 0.0％±0.0％ 0.0％±0.0％ 95.4％±10.8％ 99.5±20.3％ 100.0％±1.3％ 100.0％±0.6％
3d 0.0％±0.0％ 0.0％±0.0％ 95.4％±19.1％ 97.6±24.7％ 100.0％±0.0％ 100.0％±0.0％
表2 317LSS,PDA和不同PDA/PEI样品表面Eca109肿瘤细胞的坏死率
317L SS PDA PDA/PEI-1 PDA/PEI-2 PDA/PEI-3 PDA/PEI-4
4h 0.0％±0.0％ 0.0％±0.0％ 5.5％±2.0％ 9.7±4.2％ 79.1±2.9％ 98.4％±0.0％
1d 0.0％±0.0％ 0.0％±0.0％ 10.7％±3.8％ 66.2±22.5％ 96.7％±1.3％ 100.0％±0.0％
3d 0.0％±0.0％ 0.0％±0.0％ 52.7％±10.4％ 70.2±13.1％ 100.0％±0.0％ 100.0％±0.0％

Claims (8)

1.聚多巴胺的聚乙烯亚胺修饰物用于制备抗食管癌药物的用途，所述修饰物是聚乙烯亚胺接枝在聚多巴胺上的修饰物，通过迈克尔加成和席夫碱反应制得，所述聚多巴胺由多巴胺聚合得到，所述多巴胺与所述聚乙烯亚胺的质量比为1:1，所述多巴胺的浓度为0.5-2mg/ml，所述聚乙烯亚胺的分子量为1.8×103-7×104。
2.如权利要求1所述的用途，其特征是，所述聚乙烯亚胺的分子量为1.8×103、104、2.5×104或7×104。
3.如权利要求1所述的用途，其特征是，所述聚多巴胺由多巴胺在有氧、pH8-9的条件下聚合得到。
4.如权利要求3所述的用途，其特征是，所述pH为8.5。
5.如任一在先权利要求所述的用途，其特征是，所述聚多巴胺以沉积在支架材料表面的形式提供，支架材料为组织工程材料。
6.如权利要求5所述的用途，其特征是，所述支架材料为医用的不锈钢、镍钛合金或镁合金。
7.如权利要求1所述的用途，其特征是，所述接枝是将聚多巴胺浸泡在0.5-2mg/ml的聚乙烯亚胺水溶液中进行接枝反应。
8.如权利要求1所述的用途，其特征是，该药物为药用支架。
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