CN116549420A - 一种抗胃癌的仿生纳米顺铂制剂及其制备方法 - Google Patents
一种抗胃癌的仿生纳米顺铂制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种抗胃癌的仿生纳米顺铂制剂及其制备方法。属于医药技术领域。本发明采用纳米颗粒共负载顺铂与自噬抑制剂，通过二者的协同作用增强胃癌及转移性胃癌的治疗作用。该纳米平台由顺铂、自噬抑制剂和可降解的聚合物PLGA(聚乳酸‑羟基乙酸共聚物)及具有胃癌同源靶向的胃癌细胞膜四个模块组成。首先，提取纯化获得胃癌细胞膜；其次，通过乳化‑挥发方法制备PLGA双载药纳米颗粒(药物为：顺铂和自噬抑制剂，如3‑MA)；最后，在双载药纳米颗粒表面修饰胃癌细胞膜，使纳米药物具有胃癌靶向性。
Description
技术领域
本发明涉及医药技术领域，更具体的说是涉及一种抗胃癌的仿生纳米顺铂制剂及其制备方法。
背景技术
顺铂(cisplatin，DDP)是一种广谱抗癌药，已经广泛在临床中使用，起到了良好的抗瘤作用。近十年来采用5－FU联合铂类化疗药或免疫治疗等综合治疗使消化道治疗的五年生存率可达到40％。但由于顺铂的毒副作用，尤其是其直接对肾小管的毒性作用而引起的肾功能衰竭，限制了顺铂广泛的临床应用。
根据细胞增殖周期的理论，消化道肿瘤切除后，由于细胞增殖压力释放，此时大量的G0期癌细胞(此期于癌细胞对所有化疗药都不敏感)进入细胞增殖周期G1，G2期(此期癌细胞对化疗药较敏感)，而且此肿瘤细胞成对数生长(此期也称为肿瘤抽细胞对数生长期)，加上由于手术打击使病人全身免疫力下降，肿瘤组织疯狂生长，如果此时适当的化疗药介入，可以恰时遏制肿瘤的生长而取得治疗作用。反之，由于各种原因在此时没有给予恰当的辅助治疗，错过了这个所谓＂肿瘤最佳辅助治疗的窗口期＂，其结果可想而知。
顺铂化疗仍然是临床上治疗肿瘤切除手术后化疗的主要药物。腹腔热灌注化疗常用药顺铂，是第1个铂类药物，又名顺-双氯双氨络铂，是周期非特异性抗肿瘤药物，注射后广泛分布于腹腔内，且由于它优良的腹膜侵袭性，使其对腹腔种植转移达到良好的效果。化疗药物的腹腔注射不仅使腹腔药物浓度达到很高，还可通过门脉系统再吸收散布到外周循环达到兼顾全身化疗的作用。顺铂极少通过血液屏障，在人体内主要通过肾脏排泄，有较严重的肾脏和神经毒性，严重时可致急性肾功能衰竭，所以全身药物剂量达100mg以上就要注意全身水化，以降低对肾脏的毒副作用。DDP是目前肿瘤化疗的主要药物，对睾丸癌、骨肉瘤、卵巢癌、乳腺癌、肺癌(小细胞肺癌和非小细胞肺癌)、头颈部癌、胃癌、膀胱癌、恶性淋巴瘤和软组织肉瘤有较好疗效。但DDP在杀伤肿瘤细胞的同时对人体正常细胞也造成很大伤害，毒性反应主要包括肾毒性、消化道毒性、骨髓抑制、神经毒性和耳毒性等，反应严重时导致中断治疗。长期使用顺铂会造成耐药性，这也严重阻碍了其治疗效果和临床转化。其中，自噬诱导是肿瘤对顺铂产生耐药性的常见原因之一。
综上，顺铂化疗的最大瓶颈是：(1)在体内没有特异靶向性，毒副作用大；(2)极易耐药。
纳米载药体系能够有效发挥材料对药物的保护作用，协助药物跨越黏膜屏障，通过高通透性和滞留(Enhancedpermeability andretention,EPR)效应增强药物在靶点部位的累积，改变药物在体内的分布，减少系统性毒性，目前已成为现代药物研究的重要方向。
综上，如何提供一种靶向性高、不易耐药的顺铂纳米制剂是本领域技术人员亟需解决的问题。
发明内容
有鉴于此，本发明提供了一种抗胃癌的仿生纳米顺铂制剂及其制备方法。本发明利用纳米球或微球递送系统通过缓释和控释来克服顺铂的自身缺陷，同时负载自噬抑制剂3-甲基腺嘌呤(3-methyladenine,3-MA)降低顺铂的耐药性，达到对顺铂化疗增敏的目的。
为了实现上述目的，本发明采用如下技术方案：
一种抗胃癌的仿生纳米顺铂制剂，包括顺铂纳米粒和胃癌细胞膜，且二者的质量比为100:1；
所述顺铂纳米粒包括如下质量份数的组分：顺铂20～30份、自噬抑制剂20～30份、聚乳酸-羟基乙酸共聚物100～210份和聚乙烯醇10～15份。
所取得的有益效果：本发明采用纳米颗粒共负载顺铂与自噬抑制剂，通过二者的协同作用增强胃癌及转移性胃癌的治疗作用。且在纳米颗粒表面修饰胃癌细胞膜，一方面，可以显著提高胃癌细胞对纳米药物的吸附和吸收，另一方面，由于细胞膜通常高表达CD47，又叫“别吃我”蛋白，可以阻碍免疫系统对纳米药物的清除，从而延长纳米药物在体内的滞留时间，更大发挥疗效。而药物到达靶部位(胃癌)后，顺铂的释放可以帮助清除腹腔内残留的肿瘤细胞，自噬抑制剂的释放可以抑制肿瘤细胞的保护性自杀，增敏顺铂的疗效。
进一步的，一种抗胃癌的仿生纳米顺铂制剂，包括顺铂纳米粒和胃癌细胞膜，且二者的质量比为100:1；
所述顺铂纳米粒包括如下质量份数的组分：顺铂20份、自噬抑制剂20份、聚乳酸-羟基乙酸共聚物100份和聚乙烯醇10份。
进一步的，所述自噬抑制剂为3-MA、氯喹。
进一步的，所述胃癌细胞膜是由与病人具有相同分型的胃癌细胞中提取分离的。
进一步的，所述聚乙烯醇的脱乙酰度为85％以上。
一种抗胃癌的仿生纳米顺铂制剂的制备方法，包括如下步骤：
(1)将顺铂和3MA溶于DMSO中，超声溶解，作为内水相；
(2)将聚乳酸-羟基乙酸共聚物溶解于二氯甲烷中，作为油相；
(3)将内水相与油相混合，涡旋30秒，冰上超声，形成乳液1；
(4)溶解1％的聚乙烯醇作为外水相；
(5)乳液1加入外水相，高压匀质乳化3分钟，形成乳液2；
(6)向乳液2中继续加入外水相和水，通风橱中磁力搅拌4～6小时；
(7)用超纯水离心洗涤，即得到顺铂纳米粒溶液；
(8)提取胃癌细胞膜；
(9)将顺铂纳米粒和胃癌细胞膜加入超纯水超声混匀，然后用手持探头式匀浆机冰上超声3分钟。
进一步的，胃癌细胞膜的提取分离方法为：收集胃癌组织，加入胶原酶，在37℃、震荡(500RPM)消化，提取单个胃癌细胞。之后按照细胞膜蛋白与细胞浆蛋白提取试剂盒(产品编号:P0033，碧云天生物技术有限公司)的产品说明书提取细胞膜。
经由上述的技术方案可知，与现有技术相比，本发明取得的有益效果为：
(1)为了减轻其毒副作用，本发明提出了将顺铂用生物纳米材料(胃癌细胞膜)包裹(已证实用癌细胞膜作为纳米包裹的生物材质无致癌性)；其主要目的是减少化疗药物顺铂的毒副作用，提高与癌细胞的靶向融合而产生特定的靶向抗癌作用。
(2)通过纳米技术构建靶向纳米递送系统，可以将顺铂化疗药靶向递送到胃癌部位，而对其他组织器官不会造成毒副作用，而纳米颗粒同时还有缓释作用，药物的持续缓慢释放，可以达到长时间维持一定血药浓度以杀伤癌细胞的效果。
(3)顺铂引起的胃癌细胞自噬，是顺铂耐药的主要机制，因此，我们在纳米颗粒里同时负载了自噬抑制剂，抑制细胞自噬，达到彻底清缴腹腔中胃癌细胞的目的。
(4)利用胃癌细胞膜蛋白对胃癌细胞的同源靶向性，可以显著增加纳米粒对胃癌细胞的靶向性，从而更精准的将化疗药物送入细胞。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1为本发明的抗胃癌的仿生纳米顺铂制剂的制备工艺流程图；
图2为本发明实验1中抗胃癌的仿生纳米顺铂制剂的表征结果；
图3为本发明实验2中不同药物对胃癌细胞自噬的影响结果；
图4为本发明实验3中对胃癌的靶向性结果；其中，A为胃癌细胞与没有修饰和细胞膜修饰的纳米粒共孵育1小时后，活细胞成像结果；B为流式细胞仪检测10000个细胞内的荧光强度结果；C为对图B的统计学分析；
图5为本发明实验4中药物对胃癌细胞的杀伤效果评价。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明所需药剂为常规实验药剂，采购自市售渠道；未提及的实验方法为常规实验方法，在此不再一一赘述。
实施例1
(1)称取20mg顺铂和20mg 3MA于1ml DMSO(二甲亚砜)中，超声溶解，作为内水相。
(2)称取100mg PLGA溶解于5ml二氯甲烷中，作为油相。
(3)将内水相与油相混合，涡旋30秒，冰上超声，形成乳液1。
(4)溶解1％的PVA作为外水相。
(5)乳液1加入20ml外水相，高压匀质乳化3分钟，形成乳液2。
(6)向乳液2中加入30ml外水相，20ml水，通风橱中磁力搅拌4～6小时，挥发掉有机溶剂。
(7)用超纯水离心洗涤三次，以去除多余的PVA，即得到顺铂纳米粒溶液。
(8)收集胃癌组织，加入胶原酶，在37℃、震荡(500RPM)消化，提取单个胃癌细胞。之后按照细胞膜蛋白与细胞浆蛋白提取试剂盒(产品编号:P0033，碧云天生物技术有限公司)的产品说明书提取细胞膜。
(9)制备的顺铂纳米粒及提取的细胞膜冷冻干燥后，按照100mg顺铂纳米粒加入1mg胃癌细胞膜的比例混合，加入超纯水超声混匀，然后用手持探头式匀浆机冰上超声3分钟。
实验1
检测指标：粒径分布和扫描电镜。
检测对象：顺铂-3MA纳米粒、实施例1制备的抗胃癌的仿生纳米顺铂制剂。
顺铂-3MA纳米粒制备方法：
(1)称取20mg顺铂和20mg 3MA于1ml DMSO(二甲亚砜)中，超声溶解，作为内水相。
(2)称取100mg PLGA溶解于5ml二氯甲烷中，作为油相。
(3)将内水相与油相混合，涡旋30秒，冰上超声，形成乳液1。
(4)溶解1％的PVA作为外水相。
(5)乳液1加入20ml外水相，高压匀质乳化3分钟，形成乳液2。
(6)向乳液2中加入30ml外水相，20ml水，通风橱中磁力搅拌4～6小时，挥发掉有机溶剂。
(7)用超纯水离心洗涤三次，以去除多余的PVA，即得到顺铂-3MA纳米粒溶液。
长期保存，冷冻干燥；短期保存，在4℃冰箱。
检测结果如图2所示。
粒径分布结果表明，纳米球粒径大概分布在250nm，细胞膜修饰后约为550nm。扫描电镜显示呈规则的球形，纳米粒包裹胃癌细胞膜形成抗胃癌的仿生纳米顺铂制剂后，分散更好。
实验2
不同药物对胃癌细胞自噬的影响
将胃癌细胞种植在共聚焦专用培养皿内，培养基中加入相同浓度(2.5微克/ml)的不同药物后共同培养24小时，移去培养基，PBS洗2遍，使用细胞自噬染色检测试剂盒(购自碧云天生物生物科技有限公司，产品编号C3018S)染色，上机检测前，加入DAPI(自带荧光淬灭剂)，采用激光共聚焦进行成像。
药物分组如下：
正常对照组；
顺铂原药组；
3-MA组；
顺铂纳米粒组；
顺铂-3MA纳米粒组(制备方法同实验1)；
顺铂纳米粒制备方法：
(1)称取20mg顺铂于1ml DMSO(二甲亚砜)中，超声溶解，作为内水相。
(2)称取100mg PLGA溶解于5ml二氯甲烷中，作为油相。
(3)将内水相与油相混合，涡旋30秒，冰上超声，形成乳液1。
(4)溶解1％的PVA作为外水相。
(5)乳液1加入20ml外水相，高压匀质乳化3分钟，形成乳液2。
(6)向乳液2中加入30ml外水相，20ml水，通风橱中磁力搅拌4～6小时，挥发掉有机溶剂。
(7)用超纯水离心洗涤三次，以去除多余的PVA，即得到顺铂纳米粒溶液。
长期保存，冷冻干燥；短期保存，在4℃冰箱。
结果如图3所示。
图3中可以看出，顺铂原药和顺铂纳米粒都会诱导胃癌细胞自噬，而加入3-MA后，会显著抑制顺铂诱导的细胞自噬。自噬抑制剂3-MA的引入是为了抑制顺铂造成的胃癌细胞自噬，从而减少胃癌细胞对顺铂的耐药性。
实验3
实施例1制备的抗胃癌的仿生纳米顺铂制剂对胃癌细胞的靶向性
由于纳米颗粒本身没有荧光，香豆素6(C6)被同时负载到纳米颗粒内作为纳米颗粒的荧光标志物。
Cis是顺铂的缩写，CM是胃癌细胞膜的缩写，CM@Cis-3MA-C6-NPs是胃癌细胞膜包裹的负载顺铂、3-MA和C6的仿生纳米粒。
将相同浓度(1微克/ml)的没有修饰的顺铂纳米粒(Cis-C6-NPs)及胃癌细胞膜修饰的仿生纳米顺铂(CM@Cis-3MA-C6-NPs)分别与胃癌细胞共同孵育1小时后，弃去培养基，PBS洗三遍，培养板中加入1ml PBS，采用活细胞成像仪，观察纳米颗粒与细胞的结合情况。
结果如图4所示。
图4中可以看出，仿生纳米顺铂制剂可以在短时间内更好的进入胃癌细胞，这可能是由于仿生纳米顺铂制剂对胃癌细胞的同源靶向性。
实验4
药物对胃癌细胞的杀伤效果评价
实验方法：8000个/孔的密度种植胃癌细胞到96孔板内，将不同浓度的药物加入培养基(图中标示的浓度为终浓度)与细胞共同孵育24小时，48小时，或72小时后，采用细胞活性检测试剂盒(CCK8)检测细胞的活性。
结果如图5所示。
由图5可以看出，药物干预72小时后，顺铂和3MA双载药纳米粒(Cis-3MA-NPs)能显著抑制胃癌细胞增殖，并对其呈浓度依赖的杀伤效果。
自噬抑制剂3-MA的加入，可以改善胃癌细胞对顺铂的耐药性，增加其敏感性，显著提高了顺铂的杀伤效率。
本说明书中各个实施例采用递进的方式描述，每个实施例重点说明的都是与其他实施例的不同之处，各个实施例之间相同相似部分互相参见即可。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (6)
1.一种抗胃癌的仿生纳米顺铂制剂，其特征在于，包括顺铂纳米粒和胃癌细胞膜，且二者的质量比为100:1；
所述顺铂纳米粒包括如下质量份数的组分：顺铂20～30份、自噬抑制剂20～30份、聚乳酸-羟基乙酸共聚物100～210份和聚乙烯醇10～15份。
2.如权利要求1所述的一种抗胃癌的仿生纳米顺铂制剂，其特征在于，包括顺铂纳米粒和胃癌细胞膜，且二者的质量比为100:1；
所述顺铂纳米粒包括如下质量份数的组分：顺铂20份、自噬抑制剂20份、聚乳酸-羟基乙酸共聚物100份和聚乙烯醇10份。
3.如权利要求1或2任一所述的一种抗胃癌的仿生纳米顺铂制剂，其特征在于，所述自噬抑制剂为3-MA、氯喹。
4.如权利要求1或2任一所述的一种抗胃癌的仿生纳米顺铂制剂，其特征在于，所述胃癌细胞膜是由与病人具有相同分型的胃癌细胞中提取分离的。
5.如权利要求1或2任一所述的一种抗胃癌的仿生纳米顺铂制剂，其特征在于，所述聚乙烯醇的脱乙酰度为85％以上。
6.权利要求1或2任一所述的一种抗胃癌的仿生纳米顺铂制剂的制备方法，其特征在于，包括如下步骤：
(1)将顺铂和3MA溶于DMSO中，超声溶解，作为内水相；
(2)将聚乳酸-羟基乙酸共聚物溶解于二氯甲烷中，作为油相；
(3)将内水相与油相混合，涡旋30秒，冰上超声，形成乳液1；
(4)溶解1％的聚乙烯醇作为外水相；
(5)乳液1加入外水相，高压匀质乳化3分钟，形成乳液2；
(6)向乳液2中继续加入外水相和水，通风橱中磁力搅拌4～6小时；
(7)用超纯水离心洗涤，即得到顺铂纳米粒溶液；
(8)提取胃癌细胞膜；
(9)将顺铂纳米粒和胃癌细胞膜加入超纯水超声混匀，然后用手持探头式匀浆机冰上超声3分钟。
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