CN111944757A - 一种工程化卵巢癌体外模型及其应用 - Google Patents
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Abstract
本发明公开了一种工程化卵巢癌体外模型及其应用,属于肿瘤模型领域。本发明的工程化卵巢癌体外模型是由水凝胶包裹卵巢癌细胞制备而成,优选地,所述水凝胶是在巯基化透明质酸和巯基化明胶的混合溶液中加入聚乙二醇双丙烯酸酯交联得到的水凝胶。本发明的工程化卵巢癌体外模型具有恶性肿瘤的典型标志物,耐药性强,是良好的抗肿瘤药物筛选模型。
Description
技术领域
本发明属于肿瘤模型领域。
背景技术
卵巢癌是卵巢肿瘤的一种恶性肿瘤,是指生长在卵巢上的恶性肿瘤,其中90%~95%为卵巢原发性的癌,另外5%~10%为其它部位原发的癌转移到卵巢。由于卵巢癌早期缺少症状,即使有症状也不特异,筛查的作用又有限,因此早期诊断比较困难,就诊时60%~70%已为晚期,而晚期病例又疗效不佳。因此,虽然卵巢癌的发病率低于宫颈癌和子宫内膜癌居妇科恶性肿瘤的第三位,但死亡率却超过宫颈癌及子宫内膜癌之和,高居妇科癌症首位,是严重威胁妇女健康的最大疾患。
与其他癌症类似,卵巢癌也存在耐药性的问题。据报道,80%的卵巢癌患者对基于铂的治疗初步反应是良好的,但患者容易复发,且间隔时间越来越短,最终患者死于铂抵抗的卵巢癌。
细胞模型是研究癌症耐药性和新型抗癌药物药效评价的重要体外模型。目前卵巢癌耐药细胞模型主要为贴壁培养的耐药细胞株,但这样的细胞相对普通不耐药卵巢癌细胞而言不容易获得,多数时候需要通过从耐药病人体内分离,十分不便。
目前缺少一种易于制备的耐药卵巢癌细胞模型。
近年研究表明,细胞外基质(ECM)对肿瘤的进展至关重要。细胞外基质是由蛋白和糖类大分子构成的网络,为细胞的生存及活动提供适宜的场所,并通过信号转导系统影响细胞的形状、代谢、功能、迁移、增殖和分化,将肿瘤细胞置于细胞外基质中培养,可得到更接近体内肿瘤的肿瘤模型。由于天然的细胞外基质存在不同批次质量差异和组成不确定的问题,有人想到用3D水凝胶来替代细胞外基质,模拟肿瘤细胞的体内生理状态,构建相关模型。
Prospero Civita等构建了一种胶质瘤3D水凝胶肿瘤模型,研究胶质瘤细胞与非癌细胞共培养对肿瘤细胞的耐药性的影响。该模型将巯基化透明质酸(thiol-modifiedhyaluronan)与巯基化明胶(thiol-modified gelatin)混合构成液体水凝胶前体,加入1×106个/mL的细胞,加入交联剂聚乙二醇双丙烯酸酯(3400g/mol),形成多聚化的水凝胶将细胞包裹在里面。结果发现,共培养后的肿瘤细胞耐药性增强;但其3D培养的肿瘤细胞与2D培养(普通贴壁培养)的肿瘤细胞对同样的药物(替莫唑胺、氯米帕明或长春新碱)没有耐药性的显著差别【Pre-Clinical Drug Testing in 2D and 3D Human In Vitro Models ofGlioblastoma Incorporating Non-Neoplastic Astrocytes:Tunneling Nano Tubulesand Mitochondrial Transfer Modulates Cell Behavior and Therapeutic Respons,Int.J.Mol.Sci.2019,20,6017】。
目前尚未见关于水凝胶提高肿瘤细胞耐药性的报道。
发明内容
本发明要解决的问题是:提供一种耐药的肿瘤体外模型。
发明人通过研究发现,与水凝胶包裹的胶质瘤细胞不同,水凝胶包裹的卵巢癌细胞出现耐药性。故提供如下技术方案:
一种耐药的卵巢癌体外模型,它是由水凝胶包裹卵巢癌细胞制备而成。
如前述的体外模型,所述卵巢癌细胞为SKOV3细胞。
如前述的体外模型,所述水凝胶是在巯基化透明质酸和巯基化明胶的混合溶液中加入聚乙二醇双丙烯酸酯交联得到的水凝胶。
如前述的体外模型,所述巯基化透明质酸与巯基化明胶质量比为3:21~7:9;优选地,所述巯基化透明质酸与巯基化明胶质量比为3:21。
如前述的体外模型,所述体外模型的制备方法包括如下步骤:
1)将1%(m/v)的巯基化透明质酸溶液、3%(m/v)的巯基化明胶溶液按体积比3:7~7:3混匀后,得水凝胶前体,加入卵巢癌细胞;
2)加入聚乙二醇双丙烯酸酯,使聚乙二醇双丙烯酸酯的双键摩尔数与水凝胶前体中巯基总摩尔数之比为1:2,形成水凝胶;
优选地,所述巯基化透明质酸溶液和巯基化明胶溶液体积比为3:7。
如前述的体外模型,所述聚乙二醇双丙烯酸酯为聚乙二醇双丙烯酸酯6000。
前述体外模型在治疗耐药卵巢癌的药物的筛选中的用途。
如前述的用途,所述耐药为耐受阿霉素。
一种工程化卵巢癌体外模型的制备方法,包括如下步骤:
1)将1%(m/v)的巯基化透明质酸溶液、3%(m/v)的巯基化明胶溶液按体积比3:7~7:3混匀后,得水凝胶前体,加入卵巢癌细胞;
2)加入聚乙二醇双丙烯酸酯,使聚乙二醇双丙烯酸酯的双键摩尔数与水凝胶前体中巯基总摩尔数之比为1:2,形成水凝胶。
如前述的方法,所述巯基化透明质酸溶液和巯基化明胶溶液体积比为3:7;
和/或,所述聚乙二醇双丙烯酸酯为聚乙二醇双丙烯酸酯6000;
和/或,所述卵巢癌细胞为SKOV3细胞。
如前述的方法,所述耐药为耐受阿霉素。
本发明的有益效果:
本发明工程化卵巢癌体外模型具有恶性肿瘤的典型标志物,耐药性强,且其制备原料容易获得,利于肿瘤耐药性研究和抗肿瘤药物筛选。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1:SKOV3在工程化卵巢癌体外模型水凝胶内的多细胞球形形态,标尺100μm。
图2:工程化卵巢癌体外模型中的MMP-2、MMP-9、HIF-1α与VEGF-A的免疫荧光染色。
图3:SKOV3细胞在2D和工程化卵巢癌体外模型中摄入载药纳米胶束后的活率统计。
具体实施方式
实施例1工程化卵巢癌体外模型的制备和观察
1.工程化卵巢癌体外模型制备
将1×106的SKOV3细胞包裹于100μl水凝胶(透明质酸和明胶体积比为3:7),具体步骤如下:
分别配制1%(m/v)的巯基化透明质酸、3%(m/v)的巯基化明胶和1010wt%的聚乙二醇双丙烯酸酯(PEGDA)6000/PBS溶液。按照体积比巯基化透明质酸/巯基化明胶为3/7混合均匀后,加入1×106个SKOV3细胞混合均匀,再按r=1/2(r:PEGDA中的双键的摩尔数与混合液中巯基总摩尔数之比)加入PEGDA溶液。待成凝胶后,在体外进行培养。
2.形态观察
体外培养21天,采用倒置相差显微镜观察拍照,可见卵巢癌细胞SKOV3在水凝胶内形成多细胞球(图1)。
实施例2工程化卵巢癌体外模型的肿瘤标志物检测
在实施例1的基础上,将透明质酸和明胶体积比调整为5:5,体外培养21天,用免疫荧光染色技术对恶性肿瘤标志物MMP-2、MMP-9、HIF-1α与VEGF-A进行检测。
结果如图2所示,可见SKOV3细胞形成了多细胞球形形态,其MMP-2、MMP-9、HIF-1α与VEGF-A均呈阳性高表达。
结果表明,本发明的模型能够模拟卵巢癌的恶性肿瘤的特征。
实施例3工程化卵巢癌体外模型的耐药性
本实施例用于比较平面培养(2D培养)的SKOV3细胞和本发明工程化卵巢癌体外模型耐受阿霉素的耐药性。
1.方法
2D培养:将5×104/孔的SKOV3细胞铺入24孔板的爬片上,培养3天后,按1mg/ml的最终胶束浓度加入阿霉素纳米胶束(市售)。分别培养60和120min后,细胞活率采用live/Dead染色评价。将爬片用PBS洗3次,加入4μM EthD-III(一种商用死细胞染料,可对死细胞染色)和2μM calcein AM(钙黄绿素,可对活细胞染色)室温放置30min后,再用PBS洗3次后用抗淬灭封片剂封片。
本发明工程化卵巢癌体外模型:将1×106的SKOV3细胞包裹于100μl水凝胶中,操作方法同实施例1,但水凝胶中透明质酸和明胶的体积比分为:7:3、5:5和3:7。培养21天后,按1mg/ml的最终胶束浓度加入阿霉素纳米胶束,分别培养60和120min后用PBS洗3次,加入4μM EthD-III和2μM calcein AM室温放置30min后,再用PBS洗3次后用抗淬灭封片剂封片。
使用激光共聚焦显微镜照相,死细胞染色显示红色,活细胞染色显示绿色。细胞活率=活细胞数/(活细胞+死细胞数)×100%,每个样品计算10张图片的细胞数。
2.结果
工程化卵巢癌体外模型在阿霉素纳米胶束处理后,细胞活率显著高于2D培养细胞;且前者随时间增加并不显著降低,而后者随时间增加而明显降低(图3)。
上述结果表明:本发明的工程化卵巢癌体外模型具有远高于2D培养的卵巢癌细胞的耐药性。
综上,本发明工程化卵巢癌体外模型对抗肿瘤药物的耐药性强,其原料容易获得,可用于肿瘤耐药性研究和抗肿瘤药物筛选。
Claims (10)
1.一种耐药的卵巢癌体外模型,其特征在于:它是由水凝胶包裹卵巢癌细胞制备而成。
2.如权利要求1所述的体外模型,其特征在于:所述卵巢癌细胞为SKOV3细胞。
3.如权利要求1或2所述的体外模型,其特征在于:所述水凝胶是在巯基化透明质酸和巯基化明胶的混合溶液中加入聚乙二醇双丙烯酸酯交联得到的水凝胶。
4.如权利要求3所述的体外模型,其特征在于:所述巯基化透明质酸与巯基化明胶质量比为3:21~7:9;优选地,所述巯基化透明质酸与巯基化明胶质量比为3:21。
5.如权利要求3或4所述的体外模型,其特征在于:所述体外模型的制备方法包括如下步骤:
1)将1%(m/v)的巯基化透明质酸溶液、3%(m/v)的巯基化明胶溶液按体积比3:7~7:3混匀后,得水凝胶前体,加入卵巢癌细胞;
2)加入聚乙二醇双丙烯酸酯,使聚乙二醇双丙烯酸酯的双键摩尔数与水凝胶前体中巯基总摩尔数之比为1:2,形成水凝胶;
优选地,所述巯基化透明质酸溶液和巯基化明胶溶液体积比为3:7;
优选地,所述聚乙二醇双丙烯酸酯为聚乙二醇双丙烯酸酯6000。
6.权利要求1~5任一所述体外模型在治疗耐药卵巢癌的药物的筛选中的用途。
7.如权利要求6所述的用途,其特征在于:所述耐药为耐受阿霉素。
8.一种耐药工程化卵巢癌体外模型的制备方法,其特征在于,包括如下步骤:
1)将1%(m/v)的巯基化透明质酸溶液、3%(m/v)的巯基化明胶溶液按体积比3:7~7:3混匀后,得水凝胶前体,加入卵巢癌细胞;
2)加入聚乙二醇双丙烯酸酯,使聚乙二醇双丙烯酸酯的双键摩尔数与水凝胶前体中巯基总摩尔数之比为1:2,形成水凝胶。
9.如权利要求8所述的方法,其特征在于:所述巯基化透明质酸溶液和巯基化明胶溶液体积比为3:7;
和/或,所述聚乙二醇双丙烯酸酯为聚乙二醇双丙烯酸酯6000;
和/或,所述卵巢癌细胞为SKOV3细胞。
10.如权利要求8或9所述的方法,其特征在于:所述耐药为耐受阿霉素。
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