CN114869909B - 一种基于自由基的抗肿瘤治疗剂及其制备方法和应用 - Google Patents
一种基于自由基的抗肿瘤治疗剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种基于自由基的抗肿瘤治疗剂及其制备方法和应用,属于医药技术领域。所述治疗剂,包括ZIF‑8纳米颗粒,在所述ZIF‑8纳米颗粒内部负载有异烟肼,高锰酸钾通过还原反应形成二氧化锰附着在ZIF‑8颗粒表面,在所述二氧化锰层外表面吸附有透明质酸。本发明的抗肿瘤治疗剂可在肿瘤微环境刺激下释放出Mn2+,实现化学动力学治疗,并结合由异烟肼与被还原成Mn4+发生化学反应所产生的•OH进一步增强治疗效果,实现更高效的抗肿瘤治疗。
Description
技术领域
本发明属于医药技术领域,具体涉及一种以异烟肼为增强剂的抗肿瘤治疗剂及其制备方法和应用。
背景技术
恶性肿瘤严重威胁人类的健康和生命,尽管恶性肿瘤的治疗技术在不断地更新,但其长期生存率并没有得到明显改善,而肿瘤预后的复发是造成后期生存率降低的主要原因。当前临床上尚无针对恶性肿瘤术后复发的有效治疗方案。因此,预防或阻断肿瘤的复发提高临床疗效和患者生存率的关键挑战。近年来,化学动力学疗法(CDT)成为广受关注的一项治疗手段,它是基于纳米材料的良好催化活性,催化芬顿及类芬顿反应,在肿瘤内产生有毒的羟基自由基,导致不可逆的线粒体破坏、DNA链断裂以及蛋白和膜的氧化,由于无需施加外源性能量场,避免了光源组织穿透深度的限制和放疗X射线所引起的副作用。这类具有逻辑响应的内源性治疗策划,高效利用肿瘤微环境,最终产物为生物安全的金属离子,避免了传统药物长期滞留体内的潜在毒性。而异烟肼是近几年来发现可自身被催化产生•OH,可用来选择性提高治疗药物的效果。
因此,本发明设计在Mn2+催化H2O2产生•OH的基础上,通过外源增加ROS含量,以达到内外源同时产生杀死癌细胞的目的。
发明内容
本发明的目的是提供一种内源和外源双管齐下增加ROS且合成方法简单的抗肿瘤治疗剂。
本发明的另一目的是提供上述抗肿瘤治疗剂的制备方法及其应用。
为了实现上述目的,本发明采用了如下技术方案:
一种纳米治疗剂,包括ZIF-8纳米颗粒,在所述ZIF-8纳米颗粒内部负载有异烟肼,高锰酸钾会通过还原反应形成二氧化锰附着在ZIF-8颗粒表面,再通过物理吸附将透明质酸(HA)包裹在INH@ZIF-8@MnO2表面。
肿瘤细胞微酸环境会导致ZIF-8分解并释放出异烟肼(INH)和Mn2+;Mn2+与肿瘤细胞内的H2O2发生类芬顿反应(Fenton-like reaction)产生羟基自由基(•OH),同时释放的Mn2+会在谷胱甘肽存在下还原成Mn4+,INH会与Mn4+催化生成羟基自由基(•OH)。透明质酸则可以增加药物的靶向性能,让抗癌药物能目的性地进入肿瘤部位。
上述抗肿瘤治疗剂的制备方法,包括以下步骤:
步骤1,将异烟肼和锌盐的混合甲醇溶液,与2-甲基咪唑的甲醇溶液混合,搅拌反应,离心收集产物,洗涤后得到负载有异烟肼的ZIF-8纳米颗粒INH@ZIF-8;
步骤2,将高锰酸钾水溶液滴加在INH@ZIF-8的水溶液中,室温下搅拌反应,离心收集产物,洗涤后得到包裹有二氧化锰层的ZIF-8纳米颗粒INH@ZIF-8@MnO2;
步骤3,将INH@ZIF-8@MnO2和透明质酸加至水中,室温搅拌反应,离心收集产物,洗涤后得到所述纳米治疗剂INH@ZIF-8@MnO2@HA。
上述抗肿瘤治疗剂在制备治疗肿瘤的药物中的应用。
有益效果:本发明通过将ZIF-8作为载体,高效担载异烟肼(INH),构建得到一种具有化学动力学治疗及化疗作用协同治疗剂。本发明的治疗剂具有ROS响应性的特性,利用芬顿反应原理产生过量的ROS,破坏肿瘤细胞内蛋白质、脂质和DNA等生物大分子。采用上述协同治疗剂是一种无创、绿色的肿瘤治疗方式;本发明的治疗剂可实现靶向药物输送的化学疗法及化学动力学疗法等多模式协同治疗,实现更高效的抗肿瘤治疗;此外,本发明的治疗剂合成步骤比较简单,且产率较高;进一步地,由于合成方法简单,成本较低,因而适合大规模生产。
附图说明
图1为实施例1中INH@ZIF-8@MnO2@HA纳米材料的SEM照片(a)和TEM照片(b)。
图2为实施例1的INH@ZIF-8的纳米颗粒粒径分布图(a)、INH@ZIF-8@MnO2的纳米颗粒粒径分布图(b)、Zeta图(c)和红外谱图(d)。
图3为实施例1的ZIF-8、INH、INH@ZIF-8@MnO2在500 μg/mL谷胱甘肽下反应降解25μg/mL 罗丹明B在660 nm处出峰的紫外光谱图(a),不同浓度的INH@ZIF-8@MnO2在pH=4环境和500 μg/mL谷胱甘肽下反应降解25 μg/ml 罗丹明B在660 nm处出峰的紫外光谱图(b)。
图4为实施例1的100 μg/mL INH@ZIF-8@MnO2在不同浓度GSH环境中降解10 μg/mL罗丹明B在660 nm处出峰的紫外光谱图(a)和100 μg/mL INH@ZIF-8@MnO2在不同浓度GSH环境中降解10 μg/mL 罗丹明B随时间变化在660 nm处出峰的紫外光谱图的统计(b)。
图5为实施例1的600 μg/mL INH@ZIF-8@MnO2在不同pH值的环境中降解50 μg/mL罗丹明B在660 nm处出峰的紫外光谱图(a)和600 μg/mL INH@ZIF-8@MnO2在不同pH值的环境中降解50 μg/mL 罗丹明B随时间变化在660 nm处出峰的紫外光谱图的统计(b)。
图6为实施例1中不同浓度的ZIF-8、ZIF-8@MnO2、INH@ZIF-8@MnO2的细胞毒性。
具体实施方式
本发明提供了一种内源和外源双管齐下增加ROS的抗癌治疗剂,包括具有球形结构的ZIF-8纳米颗粒和结构内负载的异烟肼以及包裹在ZIF-8结构外的MnO2和透明质酸。
具体地,所述INH@ZIF-8@MnO2纳米颗粒是直径约为100 nm的球形结构。
上述抗癌治疗剂的制备方法包括以下步骤:
步骤1,采用常温搅拌法制作INH@ZIF-8;
步骤2,采用化学键结合方法将MnO2接在INH@ZIF-8表面形成INH@ZIF-8@MnO2;
步骤3,采用物理吸附法将透明质酸(HA)吸附到INH@ZIF-8@MnO2的表面,得到具有靶向性的INH@ZIF-8@MnO2@HA。
上述制备方法得到的抗癌治疗剂,包括具有球形结构的ZIF-8纳米颗粒和结构内负载的INH,通过化学键修饰 INH@ZIF-8表面的MnO2以及能给治疗剂具有靶向性而负载的透明质酸。
所述INH@ZIF-8@MnO2@HA纳米颗粒是直径约为100 nm,且INH作为增加ROS的增强剂。
本发明提供了一种内源和外源双管齐下增加ROS的抗癌治疗剂,本发明的INH@ZIF-8@MnO2@HA可以通过内外源提供ROS来提高肿瘤内ROS的含量到达杀死肿瘤的效果。所述抗癌治疗剂纳米材料含有ZIF-8会在肿瘤微酸环境下迅速分解,释放出Mn2+、INH。其中MnO2中的Mn2+可以与细胞内过表达的H2O2发生类芬顿反应生成有毒的•OH;而INH可在Mn2+、GSH、O2存在反应生成•OH,不仅可以消耗肿瘤内的氧气,而且也实现外源提给ROS系统,从而抑制癌细胞的增值。因此,本发明的抗癌治疗剂实现了外源供给ROS与化学动力学的协同治疗理念。
上述制备得到的内源和外源双管齐下增加ROS的抗癌治疗剂能够作为治疗肿瘤的制剂的应用。
所述的治疗肿瘤的抑制剂在所述的肿瘤微环境响应释放•OH和抗癌药物。
可以理解的,所述内源和外源双管齐下增加ROS的抗癌治疗理念能够抑制肿瘤细胞生长并杀死癌细胞,因此,本发明的协同治疗剂是一种无创、高效、低毒、绿色的肿瘤治疗方式。
本发明的抗癌治疗剂的制备方法,其合成原料价格低廉且制备工艺简单、易于大规模生产。此外,利用本发明制备方法得到的治疗剂具有外源增强剂,大幅度提升的治疗剂的治疗效果,且治疗剂具有良好的靶向性能。
下面结合附图和具体实施例对本发明作进一步详细说明,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
实施例1
(1)制备INH@ZIF-8
将0.42g的六水合硝酸锌、100 mg的异烟肼、20 mL甲醇加到100 mL的圆底烧瓶中,短暂超声处理,将0.925 g 2-甲基咪唑、20 mL甲醇加到50 mL的圆底烧瓶中,也短暂超声处理。待两种溶液准备就绪后,迅速将2-甲基咪唑甲醇溶液倒入含异烟肼、硝酸锌的甲醇溶液中。剧烈搅拌24 h。反应结束后,产物通过高速离心收集,用去离子水和无水乙醇洗涤3次。最后将得到的白色产物分散在10 mL无水乙醇中。
所述六水合硝酸锌、异烟肼、甲醇和2-甲基咪唑皆为制备常用的化学原料,均可直接从试剂网上订购。
所述反应的最佳转速为1200 rpm,反应时间为24 h。所述得到的INH@ZIF-8纳米球直径约为100 nm左右。
(2)制备INH@ZIF-8@MnO2
将500 μg/mL 的高锰酸钾水溶液取500 μL滴加到浓度为10 mg/mL INH@ZIF-8的4mL 水溶液中,转速为800 rpm,搅拌12 h。反应结束后,产物通过高速离心收集,用无水乙醇洗涤3次。最后将得到的褐色产物分散在10 mL无水乙醇中。
所述的修饰MnO2的方法是最为简单的,也最方便的方法。
所述反应的最佳转速为800 rpm,反应时间为12 h。所述得到的INH@ZIF-8@MnO2纳米球直径约为100 nm左右。
(3)制备INH@ZIF-8@MnO2@HA
10 mg INH@ZIF-8@MnO2与5 mg HA溶于5 mL去离子水中,转速为800 rpm,室温搅拌24 h。反应结束后,产物通过高速离心收集,用无水乙醇洗涤3次。最后将得到的褐色产物分散在10 mL无水乙醇中。
所述的HA为制备常用的化学原料,可直接从试剂网上订购。且最终产物INH@ZIF-8@MnO2@HA其纳米尺寸依旧在100 nm 左右。
性能测试:
1、INH@ZIF-8@MnO2纳米颗粒的形貌测定
图1是实施例1制备的INH@ZIF-8@MnO2纳米颗粒的SEM图(a)、INH@ZIF-8@MnO2纳米颗粒的TEM图(b)。
通过扫描电镜图和透射电镜图可以看出INH@ZIF-8@MnO2的纳米尺寸大概在100nm左右,从图(b)可以看出MnO2成功长在ZIF-8的表面。
2、INH@ZIF-8、INH@ZIF-8@MnO2的粒径、电位和红外测定
图2(a)中能够观察到合成的INH@ZIF-8纳米球直径为100 nm ± 5 nm,且分散均匀。图2(b)能够观察到合成的INH@ZIF-8@MnO2纳米颗粒直径为150 ± 5 nm,且分散均匀。图2(c)可以通过Zeta电位的变化观察到每个步骤负载的情况。图2(d)可以看出制备的ZIF-8、INH@ZIF-8、INH@ZIF-8@MnO2都在3100、2900 cm-1出现ZIF-8的特殊峰,说明基础框架为ZIF-8,另外INH@ZIF-8@MnO2在415 cm-1处出现Mn-O特殊峰,说明MnO2成功修饰在INH@ZIF-8的表面。
3、测定INH@ZIF-8@MnO2产生•OH性能测定
测量在3 mL磷酸缓冲溶液(pH 4.5)中进行,第一组溶液含有330 μg/mL ZIF-8和330 μg/mL INH、500 μg/mL GSH和罗丹明B (25 μg/mL) ;第二组溶液含有330 μg/mL Mn2+、330 μg/mL INH、500 μg/mL GSH和罗丹明B (25 μg/mL);第三组溶液含有实施例1所制备的330 μg/mL INH@ZIF-8@MnO2、500 μg/mL GSH和罗丹明B (25 μg/mL),在37°C下持续6小时。罗丹明B会羟基自由基作用使体系吸光度降低,用紫外-可见光谱仪观察吸收光谱,会在660nm的吸光度下出现明显的吸收峰,得到图3(a)。说明实施例1中制备的纳米离子其产生•OH的能力最强。
测量在3 mL磷酸缓冲溶液(pH 4.5)中进行,该溶液含有实施例1所制备的不同浓度INH@ZIF-8@MnO2 (93.75、187.5、375、750、1500、3000 μg/mL)、GSH (500 μg/mL)和罗丹明B (25 μg/mL),在37°C下持续6小时。罗丹明B会羟基自由基作用使体系吸光度降低, 用紫外-可见光谱仪观察吸收光谱,会在660 nm的吸光度下出现明显的吸收峰,得到图3(b)。说明实施例1中制备的纳米粒子随着浓度的增加其产生•OH逐渐增大。
4、不同GSH浓度下INH@ZIF-8@MnO2产生•OH性能测定
测量在3 mL磷酸缓冲溶液(pH 4.5)中进行,该溶液含有不同浓度GSH(0、100、400、500 μg/mL)、实施例1所制备的INH@ZIF-8@MnO2 (100 μg/mL)和罗丹明B (10μg/mL),在37°C下持续9小时。罗丹明B会羟基自由基作用使体系吸光度降低, 用紫外-可见光谱仪观察吸收光谱,会在660 nm的吸光度下出现明显的吸收峰,得到图4(a)。说明实施例1中制备的纳米粒子随着GSH含量的增加,其产生•OH的能力也逐渐增大。
测量在3 mL磷酸缓冲溶液(pH 4.5)中进行,该溶液含有不同浓度GSH(0、100、400、500 μg/mL)、实施例1所制备的INH@ZIF-8@MnO2 (100 μg/mL)和罗丹明B (10 μg/mL),在37°C下不同时间点(0、1、2、3、8、9 h)分别取660 nm处的吸光度数值,得到图4(b)。说明实施例1中制备的纳米粒子随着时间的增加,其产生•OH的能力也逐渐增大。
5、不同pH下INH@ZIF-8@MnO2产生•OH性能测定
测量在3 mL不同pH值(pH=7.4、6.5、4)的磷酸缓冲溶液中进行,该溶液含有相同浓度GSH (500 μg/mL)、实施例1所制备的INH@ZIF-8@MnO2 (600 μg/mL)和罗丹明B (50 μg/mL),在37°C下持续24小时。罗丹明B会羟基自由基作用使体系吸光度降低, 用紫外-可见光谱仪观察吸收光谱,会在660 nm的吸光度下出现明显的吸收峰,得到图5(a)。说明实施例1中制备的纳米粒子在酸性的条件下其产生•OH的能力最强。
测量在3 mL不同pH值(pH=7.4、6.5、4)的磷酸缓冲溶液中进行,该溶液含有相同浓度GSH (500 μg/mL)、实施例1所制备的INH@ZIF-8@MnO2 (600 μg/mL)和罗丹明B (50μg/mL),在37°C下不同时间点(0、1、2、3、4、5、12、24h)分别取660 nm处的吸光度数值,得到图5(b)。说明实施例1中制备的纳米粒子随着时间的增加,其在酸性条件下分解的速度增加,产生•OH的能力最强。
6、不同浓度ZIF-8、INH@ZIF-8、ZIF-8@MnO2、INH@ZIF-8@MnO2的细胞活性
通过使用MTT 测定法测定Hela细胞的细胞生存力。将细胞以104个/孔的密度接种到96孔细胞培养板中,并在5% CO2下于37 °C孵育12 h。然后,将加药组以每孔50 μL的ZIF-8、INH@ZIF-8、ZIF-8@MnO2、INH@ZIF-8@MnO2分散在DMEM中,其浓度不同(5、10、20、40、80和160 µg/mL)被添加到每个孔。加药后在5% CO2下于37℃在孵育48h。孵育后,去除旧培养基,并用PBS洗涤细胞孔以去除未摄取的颗粒,然后添加100 µL新鲜培养基。然后向每个孔中加入10 µL过滤灭菌的MTT试剂(PBS中5 mg/mL),并将板在37℃下孵育。再孵育4 h后,除去培养基,并通过添加DMSO溶解沉淀的甲瓒晶体。使用酶标仪在450 nm处测量每个孔中溶解的甲瓒晶体的吸收值。以未加药处理的细胞作为对照组,其细胞活性记为100 %,计算出各浓度下的细胞存活率。所有样品均一式三份制备。
通过图6的细胞毒性的结果可以看出,ZIF-8的细胞活性均在95%以上;INH@ZIF-8的细胞活性均低于ZIF-8的细胞活性,这是因为INH@ZIF-8中的INH被释放出来会与本身癌细胞内的Mn4+反应生成有毒的羟基自由基,从而降低了细胞活性。ZIF-8@MnO2比INH@ZIF-8的细胞活性稍低是因为肿瘤内的过表达H2O2会与Mn2+发生类芬顿反应生成羟基自由基。INH@ZIF-8@MnO2的细胞活性是最低的,这是因为我们从外界提供了充足的Mn2+,使得INH在肿瘤微环境中获得充足的Mn4+进而发生化学反应产生羟基自由基,同时Mn2+也会和肿瘤过表达的H2O2发生类芬顿反应,通过外源内源提供的ROS来抑制肿瘤的生长,从而达到杀死肿瘤的目的。
本发明提供的内源和外源双管齐下增加ROS的抗癌治疗剂以ZIF-8作为基础框架并在ZIF-8结构内吸附异烟肼,然后再结构外部修饰MnO2和透明质酸。其中ZIF-8是通过常温反应的方法制备,具有单分散性且尺寸分布均一。其次,物理吸附的异烟肼可以与肿瘤内锰离子反应生成有毒•OH,再进一步,通过形成配位键将MnO2修饰到INH@ZIF-8的表面,不仅可作为化学动力学治疗,也可为异烟肼提供充足的锰离子元素。最后在物理吸附透明质酸,增加抗癌治疗剂的靶向效果。因此本发明的纳米粒子可以结合ROS响应、化学动力学治疗二者协同作用,实现高效抗肿瘤治疗。
Claims (4)
1.纳米治疗剂在制备肿瘤治疗药物中的应用,其特征在于,所述纳米治疗剂采用以下步骤制备:
步骤1,将异烟肼和锌盐的混合甲醇溶液,与2-甲基咪唑的甲醇溶液混合,室温下搅拌反应,离心收集产物,洗涤后得到负载有异烟肼的ZIF-8纳米颗粒INH@ZIF-8;
所述异烟肼的用量为100mg,锌盐六水合硝酸锌的用量为0.42g,2-甲基咪唑的用量为0.925g;
步骤2,将500 μL 500 μg/mL的高锰酸钾水溶液滴加在4mL 10mg/mL的INH@ZIF-8的水溶液中,室温下搅拌反应,离心收集产物,洗涤后得到附着有二氧化锰的ZIF-8纳米颗粒INH@ZIF-8@MnO2;
步骤3,将10mg INH@ZIF-8@MnO2和5mg透明质酸加至5mL水中,室温下搅拌反应,离心收集产物,洗涤后得到所述纳米治疗剂INH@ZIF-8@MnO2@HA。
2. 根据权利要求1所述的应用,其特征在于:步骤1中搅拌反应的转速为1200 rpm,反应时间为24 h。
3. 根据权利要求1所述的应用,其特征在于:步骤2中搅拌反应的转速为800 rpm,反应时间为12 h。
4. 根据权利要求1所述的应用,其特征在于:步骤3中搅拌反应的转速为800 rpm,反应时间为24 h。
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CN110075106A (zh) * | 2019-05-13 | 2019-08-02 | 华中科技大学 | 一种抗肿瘤药物及异烟肼在制备抗肿瘤药物中的应用 |
CN111253581A (zh) * | 2020-01-19 | 2020-06-09 | 浙江大学 | 一种增强化学动力治疗与饥饿治疗联合的金属有机框架材料、制备方法及应用 |
US11124897B1 (en) * | 2020-09-17 | 2021-09-21 | King Abdulaziz University | Biodegradable core-shell fibrous scaffolds for controlled oxygen and drug release |
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