CN112843250A - 一种用于肿瘤铁死亡-气体协同治疗的纳米药物及其制备方法 - Google Patents
一种用于肿瘤铁死亡-气体协同治疗的纳米药物及其制备方法 Download PDFInfo
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- CN112843250A CN112843250A CN202110112716.0A CN202110112716A CN112843250A CN 112843250 A CN112843250 A CN 112843250A CN 202110112716 A CN202110112716 A CN 202110112716A CN 112843250 A CN112843250 A CN 112843250A
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Abstract
本发明公开了一种用于肿瘤铁死亡‑气体协同治疗的纳米药物,包括可生物降解的中空介孔有机硅纳米粒、装载于中空介孔有机硅纳米粒的羰基铁类化合物和小分子药物。本发明还公开了一种用于肿瘤铁死亡‑气体协同治疗的纳米药物的制备方法以及作为制备肿瘤治疗药物的应用。本发明制备方法操作简单,可重复大批量制备。本发明的纳米药物通过引入硫‑硫键,与肿瘤微环境中过表达的谷胱甘肽反应,使中空介孔有机硅骨架断裂,从而释放所负载的小分子药物并造成整个纳米药物的降解;通过负载羰基铁类化合物,与肿瘤微环境中过量的过氧化氢响应可释放CO并实现铁死亡,实现气体治疗和铁死亡的协同作用。
Description
技术领域
本发明涉及纳米药物技术领域,尤其涉及一种用于肿瘤铁死亡-气体协同治疗的纳米药物及其制备方法和应用。
背景技术
目前癌症常用的治疗手段有外科手术、放射治疗和化疗等,传统的治疗手段常会存在毒副作用大,难以精准给药等缺陷、且不可避免地对体内正常细胞造成不同程度的损害,不利于长期治疗。随着纳米技术的发展,纳米材料在医药领域受到了关注,诸多研究人员利用纳米材料可通过EPR效应在肿瘤部位聚集以及良好的生物相容性,来实现肿瘤靶向治疗,依托于纳米材料的治疗方法如光动力治疗、光热治疗等陆续出现,开发新的治疗方法也逐渐引起重视。
一氧化碳(CO)气体是一种无色无味的有毒气体,其在生命体内承担着一定的生理作用,如血管内皮细胞的生长、器官移植等,进一步的研究表明,通过改变细胞内CO含量,可对细胞的线粒体造成损伤,致使细胞失活,进而实现对肿瘤细胞的抑制生长进而实现肿瘤治疗。因此,构筑一种具有良好的生物相容性并可释放CO气体的纳米药物递送系统,应用在靶向肿瘤治疗成为一个重要研究的方向。
铁死亡是由Stockwell在2012年提出的一种新的细胞死亡方式,该死亡方式具有一定的铁依赖性和脂质过氧化物依赖性,通过改变细胞内铁元素的浓度,可以调节细胞内的死亡通路,实现铁死亡治疗效果。研究证明将含有铁元素的纳米材料引入细胞内可以诱发铁死亡,因此,在保证纳米材料可降解的前提下,精准的递送含铁的纳米材料,实现肿瘤治疗具有很大的挑战性。
公开号为CN108567980A的专利申请公开了一种光动力诱导的CO释放方法,通过将近红外光响应型、可用于光动力治疗的光敏剂和CO释放分子CORM-401混合,在近红外光的照射下,进行CO释放方法,构建了CO可控释放。但是,该纳米药物需要外源刺激,缺乏气体释放特异性,降解性不高,临床上应用受限。
公开号为CN1100433145A的专利申请公开了一种肿瘤靶向的纳米药物及应用和制备方法,所述的纳米药物包括具有介孔孔道的介孔硅纳米颗粒和装载于所述介孔硅纳米颗粒的介孔孔道中的过渡金属氧化物及过渡金属羰基化合物;通过原位还原法将酸响应纳米药物二氧化锰负载于介孔二氧化硅孔道上,再通过纳米灌注法将气体一氧化碳释放前药十二羰基三铁共载于介孔二氧化硅孔道上。该方法合成的纳米药物负载量不高,且锰离子本身具有较大的毒性,不利于临床的应用。
发明内容
本发明提供了一种用于肿瘤铁死亡-气体协同治疗的纳米药物,该纳米药物不需要外源刺激,具有谷胱甘肽响应降解性、过氧化氢响应释放一氧化碳并实现铁死亡的特性,纳米药物负载率高。
一种用于肿瘤铁死亡-气体协同治疗的纳米药物,包括可生物降解中空介孔有机硅纳米粒、装载于中空介孔有机硅纳米粒的羰基铁类化合物和小分子药物。
所述的可生物降解的中空介孔有机硅纳米粒为具有硫-硫键的中空介孔有机硅纳米粒;作为优选,所述的可生物降解的中空介孔有机硅纳米粒为含有四硫键的中空介孔有机硅。
硫-硫键分布在可生物降解的中空介孔有机硅纳米粒的骨架中,硫-硫键可以响应肿瘤微环境中过量的谷胱甘肽,相互作用并发生断裂,实现降解的同时释放出羰基铁类化合物和小分子药物。
含有四硫键的中空介孔有机硅的高比表面积为载药提供了可能,通过调节负载配比,可以较大地发挥负载能力,保证载药充足的同时也不会浪费过多原料。
同时可生物降解的中空介孔有机硅具有高比表面积,大的空腔结构和多介孔通道,对于各种疏水性小分子药物可以通过范德华力的相互作用或者表面吸附作用实现高负载效果。
所述羰基铁类化合物为五羰基铁、十二羰基铁、二壬羰基铁或羰基铁硫簇化合物。
羰基铁类化合物可与肿瘤微环境中过量的过氧化氢反应产生CO气体和大量的铁离子,其中CO气体可攻击线粒体,导致线粒体失活,直接造成细胞死亡;而铁离子则可与过氧化氢反应引发芬顿反应,产生大量的羟基自由基,在肿瘤细胞中生成脂质过氧化物引发铁死亡,进而实现铁死亡和气体治疗的协同作用。
所述的小分子药物为铁死亡诱导剂,如铂类化合物。
铁死亡诱导剂可直接攻击肿瘤细胞的细胞核使其死亡,同时激活肿瘤细胞内产生大量的还原型辅酶(Ⅱ)和氧化酶(NOX),而NOX可以诱导细胞内氧气生成大量超氧阴离子,超氧阴离子又会被超氧化物歧化酶催化产生过氧化氢,该过程中产生的过氧化氢继续和铁离子进行反应,发生芬顿反应并产生羟基自由基,进而促进脂质过氧化物的产生,造成铁死亡。
作为优选,所述的用于肿瘤铁死亡-气体协同治疗的纳米药物,在其表面选择性修饰蛋白质类物质、脂质类物质或亲水性高分子。
所述的蛋白类物质为还原性牛血清白蛋白、人血清白蛋白、牛血清白蛋白或具有靶向肿瘤细胞表面过表达的整合素蛋白的靶向蛋白质。蛋白类物质具有较好的生物相容性和可降解性,在细胞内可以实现完全降解。
作为优选,所述的蛋白质类物质为还原性牛血清白蛋白。
利用还原性牛血清白蛋白修饰中空介孔有机硅孔道使得小分子药物不会提前释放,同时还原性牛血清白蛋白通过硫-硫键桥接于中空介孔有机硅表面,在肿瘤微环境中也可以实现谷胱甘肽响应断裂,从而加快药物释放。
作为优选,所述的具有靶向肿瘤细胞表面过表达的整合素蛋白的靶向蛋白质为环(精氨酸-甘氨酸-天冬氨酸)。靶向蛋白质与纳米药物上的氨基、羧基进行反应,接枝在纳米药物上,进而赋予纳米药物肿瘤靶向的特性。
所述的脂质类物质为肿瘤细胞的细胞膜,肿瘤细胞的细胞膜可以实现同源肿瘤细胞靶向,同时也具备较好的生物相容性和可降解性。
所述的亲水性高分子为聚乙二醇或聚乳酸-羟基乙酸,极佳的亲水性使得高分子材料可以在生物体内持续循环,高分子材料良好的生物相容性则保证了纳米药物在生物体内可以实现完全代谢和降解。
作为优选,所述的用于肿瘤铁死亡-气体协同治疗的纳米药物的粒径为30~100nm,空腔大小为5~20nm,介孔大小为2~5nm。
以负载中空介孔有机硅的羰基铁类化合物和小分子药物的中空介孔有机硅总质量计,所述羰基铁类化合物的负载率为10%-80%,所述的小分子药物的负载率为2%-20%。
本发明的纳米药物通过引入硫-硫键,与肿瘤微环境中的过表达的谷胱甘肽反应,使得中空介孔有机硅骨架断裂,从而释放其所负载的小分子药物并造成整个纳米药物的降解。中空介孔有机硅搭载的十二羰基合三铁以及铁死亡诱导剂,在载体中空介孔有机硅降解后释放,一方面可以促进肿瘤细胞内过氧化氢的产生,另一方面与肿瘤细胞内的过氧化氢反应,产生CO气体,同时,释放出大量铁离子,铁离子与细胞内过氧化氢发生羟基自由基反应,生成大量的羟基自由基,造成肿瘤细胞铁死亡,进而实现铁死亡和气体治疗的协同作用。
本发明还提供了一种用于肿瘤铁死亡-气体协同治疗的纳米药物的制备方法,制备方法简单,制得的用于肿瘤铁死亡-气体协同治疗的纳米药物能够响应肿瘤微环境中过量的谷胱甘肽,实现降解的同时释放负载的小分子药物,负载率高。
一种用于肿瘤铁死亡-气体协同治疗的纳米药物的制备方法,包括:
(1)采用模板法将硅酸四乙酯及具有硫-硫键桥接的硅前驱体合成得到内核为硅酸四乙酯水解所得的介孔二氧化硅、外壳为硅酸四乙酯与含硫-硫键的介孔硅前驱体共同水解的有机介孔二氧化硅,通过碱性溶液对上述有机介孔二氧化硅进行蚀刻,将内核中的介孔二氧化硅蚀刻掉,得到以硫-硫键及硅氧键为骨架的中空介孔有机硅;
(2)将步骤(1)中得到的以硫-硫键及二氧化硅为骨架的中空介孔有机硅与带有巯基的硅烷偶联剂混合搅拌,得到巯基修饰的中空介孔有机硅;
(3)将羰基铁类物质与小分子药物负载于步骤(2)得到巯基修饰的中空介孔有机硅中;制备得到用于肿瘤铁死亡-气体协同治疗的纳米药物。
作为优选,步骤(1)中,所述模板法所用的模板剂为十六烷基三甲基溴化铵(CTAB)、十六烷基三甲基氯化铵(CTAC)。
所述的含有硫-硫键桥接的有机硅前驱体为[3-(三乙氧基甲硅烷)丙基]四硫化物。
所述的碱性溶液为氨水溶液或碳酸钠溶液。
作为优选,步骤(2)中,所述硅烷偶联剂为3-巯基丙基三甲氧基硅烷。
作为优选,步骤(3)中,所述的巯基修饰的中空介孔有机硅与羰基铁类物质的投料量的质量比为5.0~1.0:8.0;负载羰基铁类物质的纳米药物载体与小分子药物的投料量的质量比为8.0~1.0:3.0。
此时负载的羰基铁类物质和小分子药物载药效果与经济效益可以达到相对较好的结果,保证药物载药效率达到较大时,不会浪费过多原料。
作为优选,所述的羰基铁类化合物为五羰基铁、十二羰基铁、二壬羰基铁或羰基铁硫簇化合物。
所述的小分子药物为铁死亡诱导剂,如铂类化合物。
所述的用于肿瘤铁死亡-气体协同治疗的纳米药物与蛋白质类物质、脂质类物质或亲水性高分子进行选择性修饰,得到修饰后的用于肿瘤铁死亡-气体协同治疗的纳米药物。
所述的蛋白类物质为还原性牛血清白蛋白、人血清白蛋白、牛血清白蛋白或具有靶向肿瘤细胞表面过表达的整合素蛋白的靶向蛋白质;作为优选,所述的蛋白类物质为还原性牛血清白蛋白,还原性牛血清白蛋白为牛血清白蛋白和硼氢化钠还原所得。
还原性牛血清白蛋白具有良好的生物相容性,而且在生物体内可以完全降解,没有毒副作用。
所述的具有靶向肿瘤细胞表面过表达的整合素蛋白的靶向蛋白质为环(精氨酸-甘氨酸-天冬氨酸)。
所述的脂质类物质为肿瘤细胞膜;作为优选,所述的脂质类物质为人脑胶质瘤细胞的细胞膜。
所述的人脑胶质瘤细胞的细胞膜由脂质体挤出器进行提取得到,具有良好的生物降解性。
所述的亲水性高分子为聚乙二醇或聚乳酸-羟基乙酸。
本发明还提供了一种用于肿瘤铁死亡-气体协同治疗的纳米药物作为制备肿瘤治疗药物的应用。
本发明中所涉及的肿瘤为食管鳞癌(K150细胞系)、人源乳腺癌(MCF-7细胞系)或人脑胶质瘤(U87-MG细胞系),本发明的纳米药物作为治疗药物对上述癌细胞进行使用。
同现有技术相比,本发明的有益效果体现在:
(1)本发明制备的纳米药物通过引入硫-硫键,与肿瘤微环境中过表达的谷胱甘肽反应,使得中空介孔有机硅骨架断裂,从而释放所负载的小分子药物并造成整个纳米药物的降解。
(2)本发明制备的纳米药物通过负载羰基铁类化合物,在肿瘤微环境中过量的过氧化氢响应,释放CO并实现铁死亡,实现气体治疗和铁死亡的协同作用。
(3)本发明制备的纳米药物具有MRI成像功能,在肿瘤诊断与治疗中具有较好的应用前景。
(4)本发明制备方法中所涉及的设备及原料均廉价易得,且操作简单,可重复大批量制备。
附图说明
图1为实施例1制备的包裹有介孔有机硅的介孔硅纳米粒子MSN@MON的透射电镜照片;
图2为实施例1制备的经氨水蚀刻后中空介孔有机硅(HMON)的透射电镜照片;
图3为实施例1制备的MSN@MON、HMON和HMON@FeCO/CDDP的等温吸脱附曲线,其中:图a为MSN@MON等温吸脱附曲线,图b为HMON等温吸脱附曲线,图c为HMON@FeCO/CDDP等温吸脱附曲线;
图4为实施例3制备的HFePt NPs的透射电镜照片;
图5为实施例1制备的MSN@MON和实施例3制备的HFePt NPs的DLS粒径分布图;
图6为实施例1制备的MSN@MON、HMON和HMON-SH及实施例3制备的HMON@FeCO/CDDP-rBSA和HFePt NPs的Zeta电位图;
图7为药物性能评价实验1中实施例1、实施例4、实施例5和实施例6制备得到的HMON对十二羰基合三铁的负载效率图;
图8为药物性能评价实验2中HMON@FeCO/CDDP在体外PBS环境中释放CO效果图;
图9为药物性能评价实验3中HFePt NPs的ESR图;
图10为药物性能评价实验4中HFePt NPs降解效果图;
图11为药物性能评价实验5中HFePt NPs的MRI效果图;
图12为药物性能评价实验6中HMON、HMON@FeCO/CDDP和HFePt NPs在K150细胞中的细胞毒性效果图;
图13为药物性能评价实验7中实施例3制备的HFePt NPs在U87-MG细胞中孵育不同时间后的脂质过氧化物产生效果图。
具体实施方式
通过下面实施例对本发明做进一步的阐述,下述说明仅为解释本发明,并不对其内容进行限定。
实施例中的十六烷基三甲基氯化铵、十二羰基合三铁、顺铂、牛血清白蛋白购自上海阿拉丁公司。
实施例1制备用于肿瘤铁死亡-气体协同治疗的纳米药物
1.合成含有四硫键的中空介孔有机硅纳米颗粒
称取0.1g三乙醇胺(TEA)、0.5g十六烷基三甲基氯化铵(CTAC)于50mL烧瓶中,加入22mL水,超声使之分散均匀后置于80℃油浴锅内,搅拌;待体系温度稳定后,向其中滴加1.0mL的硅酸四乙酯(TEOS)作为硅源,反应1小时得到介孔硅内核;之后向体系中滴加0.5mLTEOS,1.0mL双[3-(三乙氧基甲基硅烷)丙基]四硫化物(BTES)的均匀混合溶液,其中BTES可作为硅源;继续反应3h后停止反应,使用乙醇洗涤并离心数次,至上清液透明无色,弃上清,所得沉淀物即为MSN@MON;将制得的MSN@MON分散于盐酸/乙醇溶液中,80℃下冷凝回流数次,以除去模板剂CTAC;将除完模板的MSN@MON加水分散均匀,取10mL MSN@MON乳白状水溶液于50mL烧瓶中,加入5mL氨水溶液及20mL水,于95℃油浴锅中进行搅拌,3h后停止反应,离心,弃去上清,所得白色沉淀即为HMON。
所述中空介孔有机硅纳米颗粒粒径为40-60nm,空腔尺寸5-15nm,介孔大小为2nm-5nm,且该中空介孔有机硅骨架中含有的四硫键,可响应GSH实现降解。
2.负载十二羰基铁/顺铂的HMON
先将含100mg HMON的乙醇溶液与100uL的3-巯基丙基三甲氧基硅烷在50度油浴锅中混合均匀,持续搅拌1天后,离心,所得沉淀即为已接枝巯基的HMON(HMON-SH);取含有20mg HMON-SH的水溶液与32mg/mL的十二羰基合三铁/四氢呋喃溶液在70度下搅拌2小时,得到的纳米药物记为HMON@FeCO。
将32mg/mL的十二羰基合三铁/四氢呋喃溶液与HMON-SH的反应产物分散在10mL去离子水中,取2mL溶液0.5mg/mL的20mL顺铂/水溶液进行反应,室温下搅拌24小时,之后离心弃掉上清,取沉淀物,即得到用于肿瘤铁死亡-气体协同治疗的纳米药物(HMON@FeCO/CDDP)。
分析结果:
图1为实施例1制备的MSN@MON的透射电镜照片,由图1可以明显观察到MSN@MON的介孔结构,其粒径大小在30~80nm;
图2为实施例1制备的HMON的透射电镜照片,由图2可知,HMON具有明显的中空结构,说明蚀刻成功,其中空空腔大小在5~15nm。
图3为实施例1制备的MSN@MON、HMON和HMON@FeCO/CDDP的氮气等温吸脱附曲线,由图3可知,等温吸脱附曲线从a到b的变化说明了HMON的成功合成,吸脱附曲线类型由IV型变为V型,说明空腔结构的出现;从b到c的变化可以看出HMON载药之后并不影响材料的结构变化,可推测大部分顺铂类药物附着于介孔孔道的内部或空腔内外表面,结合相应的比表面积变化则可以说明纳米药物的成功负载。
实施例2负载羰基铁类化合物为二壬羰基铁,其它同实施例1
取16mg二壬羰基铁(Fe2(CO)9)溶于20mL四氢呋喃中,加入20mg的HMON-SH,在70度油浴锅中进行搅拌,持续反应2小时后,停止反应,离心,得到负载二壬羰基铁的中间体HMON@Fe2(CO)9,进行下一步反应。
实施例3对HMON@FeCO/CDDP进行还原性牛血清白蛋白及RGD修饰
首先利用1mol的硼氢化钠溶液将40mg/mL的牛血清白蛋白水溶液进行还原,该反应在冰浴条件下进行,之后得到40mg/mL的还原性牛血清白蛋白水溶液;取5mL HMON-SH@FeCO/CDDP分散液,加入2.5mL还原性牛血清白蛋白水溶液和10mL去离子水,50度下搅拌反应2小时,离心,弃去上清,得到HMON-SH@FeCO/CDDP-rBSA纳米颗粒,加水定容至5mL,待用。
取5mL HMON-SH@FeCO/CDDP-rBSA溶液,加入活化剂N-羟基琥珀酰亚胺(NHS)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC),再加入100uL cRGD2进行接枝,得到HMON-SH@FeCO/CDDP-rBSA-RGD2,即经还原性牛血清白蛋白和RGD修饰后的纳米药物(HFePtNPs)。
分析结果:
图4为实施例3制备的HFePt NPs的透射电镜照片,由图4可知,纳米粒子表面附着一层致密物质,说明该纳米粒子成功载药后修饰还原性牛血清白蛋白成功,所得HFePt NPs为理想中的纳米粒子,且整体纳米粒子的尺寸仍保持在30~80nm,因而可进入肿瘤细胞内,并在生物体中可以实现肿瘤组织部位聚集。
图5为实施例1制备的MSN@MON和实施例3制备的HFePt NPs的DLS粒径分布图,由图5可知,MSN@MON和HFePt NPs的粒径分布差别不大,即修饰rBSA前后不影响纳米粒子的粒径大小,且该粒径分布图与之前的透射电镜图相吻合,粒径大多分布在50nm附近。
图6为实施例1制备的MSN@MON、HMON、HMON-SH以及实施例3制备的HMON@FeCO/CDDP-rBSA和HFePt NPs的Zeta电位图,由图6可知,MSN@MON、HMON、HMON-SH、HMON@FeCO/CDDP-rBSA和HFePt NPs都成功合成;
实施例4十二羰基合三铁的加入量不同,其它同实施例3。
取20mg的HMON-SH与含有16mg的十二羰基合三铁的20mL THF溶液在70℃油浴锅中加热搅拌2h,将所得产物进行离心,取沉淀分散在水中,定量。取含有10mg HMON@FeCO的水溶液与20mL的0.5mg/mL的顺铂水溶液进行常温搅拌,持续反应24小时,之后离心弃去上清,取沉淀分散在5mL水溶液中。之后步骤与实施例3中相同,取5mL的已负载顺铂/十二羰基合三铁的溶液,加入还原性牛血清白蛋白进行反应2小时后,离心,取沉淀分散后接枝RGD2,接枝RGD2步骤参照实施例3,从而得到HMON-SH@FeCO/CDDP-rBSA-RGD2,即HFePt NPs-2纳米药物。
实施例5十二羰基合三铁的加入量不同,其它同实施例3
对所得HMON-SH进行定量,取20mg的HMON-SH与含有8mg的十二羰基合三铁的20mLTHF溶液在70℃油浴锅中加热搅拌2h,将所得产物进行离心,取沉淀分散在水中,定量。取含有10mg HMON@FeCO的水溶液与20mL的0.5mg/mL的顺铂水溶液进行常温搅拌,持续反应24小时,之后离心弃去上清,取沉淀分散在5mL水溶液中。之后步骤与实施例3中相同,取5mL的已负载顺铂/十二羰基合三铁的溶液,加入还原性牛血清白蛋白进行反应2小时后,离心,取沉淀分散后接枝RGD2,得到HMON-SH@FeCO/CDDP-rBSA-RGD2,即HFePt NPs-3纳米药物。
实施例6十二羰基合三铁的加入量不同,其它同实施例3
取20mg的HMON-SH与含有4mg的十二羰基合三铁的20mLTHF溶液在70℃油浴锅中加热搅拌2h,将所得产物进行离心,取沉淀分散在水中,定量。取含有10mg HMON@FeCO的水溶液与20mL的0.5mg/mL的顺铂水溶液进行常温搅拌,持续反应24小时,之后离心弃去上清,取沉淀分散在5mL水溶液中。之后步骤与实施例3中相同,取5mL的已负载顺铂/十二羰基合三铁的溶液,加入还原性牛血清白蛋白进行反应2小时后,离心,取沉淀分散后接枝RGD2,得到HMON-SH@FeCO/CDDP-rBSA-RGD2,得到HFePt NPs-4纳米药物。
实施例7对HMON@FeCO/CDDP修饰的蛋白质类物质为牛血清白蛋白,其它同实施例3
取20mg的HMON-SH与含有32mg的十二羰基合三铁的20mL THF溶液在70℃油浴锅中加热搅拌2h,将所得产物进行离心,取沉淀分散在水中,定量。取含有10mg HMON@FeCO的水溶液与20mL的0.5mg/mL的顺铂水溶液进行常温搅拌,持续反应24小时,之后离心弃去上清,取沉淀分散在5mL水溶液中,取5mL的HMON@FeCO/CDDP的溶液,加入12.5mL 8mg/mL的牛血清白蛋白进行反应2小时后,离心,取沉淀分散后接枝RGD2,得到包封牛血清白蛋白并接枝RGD的负载十二羰基合三铁和顺铂的中空介孔有机硅纳米药物。
实施例8对HMON@FeCO/CDDP修饰的蛋白质类物质为人脑胶质瘤细胞的细胞膜
首先进行人脑胶质瘤细胞的细胞膜的提取。将细胞培养瓶中的细胞消解下来,制成细胞悬液,1000rpm下离心5min,取沉淀分散在膜蛋白提取缓冲液中,用移液器吹打均匀,随后放置于冰上冰浴15min。将冰浴后的细胞悬液置于超声破碎仪下,超声15min,使细胞充分裂解,收集细胞裂解液于离心管中;将细胞裂解液在2000rpm下离心10min,之后小心收集上清液至新的离心管中;再在20000rpm下离心1h,收集细胞膜沉淀,置于-20度冰箱保存待用。
取HMON@FeCO/CDDP溶液5mL,与5mL细胞膜悬液混合充分,利用脂质体挤出器通过400nm的聚碳酸酯多孔膜挤出7-10次,从而获得U87-MG细胞膜包被的纳米药物。
药物性能评价:
1.中空介孔有机硅对于十二羰基合三铁的负载率评价
不同浓度的十二羰基铁负载率的计算方法为:将所得产物经王水消解后利用ICP-OES测定Fe元素浓度,进而反推产物中十二羰基合三铁的量,根据产物质量,负药率即负载药物量/产物质量;负载效率可根据负载药物量/投料量计算。以负载中空介孔有机硅的羰基铁类化合物和小分子药物的中空介孔有机硅总质量计,实施例1中所述羰基铁类化合物的负载率为75%,所述的小分子药物的负载率为11%。实施例3、实施例4、实施例5和实施例6制备得到的HFePt NPs负载率见图7。
由图7可知,通过改变十二羰基合三铁的投料量,随着药物浓度的增加,负药率出现一定的升高趋势,而负载效率则相应的有所下降。当调节使用16mg的十二羰基合三铁溶于20mL的四氢呋喃时,与20mg的中空介孔有机硅进行药物负载反应,也即按照实施例1进行反应所得产物,可以同时保证负药率和负载效率都处于相对较大的值,从而兼顾载药量和负载效率。
2.对实施例1所制备的用于肿瘤铁死亡-气体协同治疗的纳米药物HMON@FeCO/CDDP进行CO性能验证
取一定量0.5mL的HMON@FeCO/CDDP分散于磷酸缓冲液(PBS)中,加入一定量的过氧化氢和一氧化碳探针以及反应所必须的氯化钯;其中过氧化氢可以与HMON@FeCO/CDDP反应产生CO,而CO可以还原二价钯得到零价钯,零价钯可以催化一氧化碳探针产生荧光。另设置空白对照组。
图8为药物性能评价实验2中HMON@FeCO/CDDP在体外PBS环境中释放CO效果图,由图8可知,荧光峰谱在516nm左右峰强出现了明显的变化,说明了HMON@FeCO/CDDP可以产生CO。
3.对实施例3制备得到的HFePt NPs进行体外产生ROS验证
设置2组实验,分别取一定量的实施例3制备得到HFePt NPs样品,稀释至一定浓度,一组实验设置为空白组,即不加任何其他材料;另一组则加入一定量的谷胱甘肽和过氧化氢,其中HFePt NPs样品浓度均为40ug/mL;谷胱甘肽浓度为10mM;过氧化氢浓度为100uM;反应数分钟后,立刻分别取300uL样品溶液与20uL的DMPO相混合测定ESR。
图9为药物性能评价实验1中HFePt NPs的ESR图,由图9可知,谱图中有明显的羟基自由基峰,说明HFePt NPs与谷胱甘肽和过氧化氢反应并产生羟基自由基。
4.对实施例3制备得到的HFePt NPs进行降解性评价
取0.5mL的HFePt NPs分别加入20mL的缓冲溶液(pH均为7.4),然后分别进行不同处理(加入或者不加入过氧化氢/GSH),然后在不同的时间节点取出一定量的液体进行TEM表征。
图10为药物性能评价实验2中HFePt NPs降解效果图,由图10可知,加入过氧化氢和GSH组的TEM降解效果明显优于不进行任何处理的实验组,从而表明该纳米药物对于GSH具有较好的响应降解效果,而从加入过氧化氢处理的实验来看,可以推测,该纳米药物与过氧化氢产生的CO气体从某种程度上可以促进体系的崩塌和整个纳米药物的降解。
5.对实施例3制备得到的HFePt NPs进行体外MRI效果评价
取1mL的实施例3制备的HFePt NPs加水逐级稀释为不同浓度分别为0ug/mL、3.125ug/mL、6.25ug/mL、12.5ug/mL、25ug/mL、50ug/mL,分散均匀,然后将溶液置于1.5TMRI成像仪下进行测试,T1成像和T2成像效果见图11。
由图11可知,HFePt NPs具有较好的MRI成像效果。
6.对实施例1和实施例3制备得到的HMON、HMON@FeCO/CDDP、HFePt NPs进行细胞毒性效果评价
测定HMON、HMON@FeCO/CDDP、HFePt NPs对K150肿瘤细胞的毒性效果。将K150细胞接种于96孔板中,每个孔中种5000-10000个细胞,在二氧化碳培养箱中培养24小时后,将一系列含有不同浓度材料的培养基替换原有的培养基,继续培养24小时之后,吸弃培养基,加入一定量的MTT和完全培养基,再放入培养箱中孵育4小时后,加入DMSO,充分震荡使晶体完全溶解后,利用酶标仪测定不同孔中的吸光度值。
图12为药物性能评价实验6中HMON、HMON@FeCO/CDDP、HFePt NPs在K150细胞中的细胞毒性效果图,由图12可知,随着HFePt NPs浓度的不断增加,细胞的存活率是逐渐下降的,也即说明HFePt NPs的毒性是随着HFePt NPs的浓度逐渐增加的,当HFePt NPs浓度低于100ug/mL时,HFePt NPs具有较好的生物相容性。
7.对实施例1所得HMON@FeCO/CDDP纳米药物和实施例3中制备得到的HFePt NPs在细胞内产生铁死亡效果验证
按2*10^5cell/mL的浓度将1mL细胞接种于共聚焦培养皿中,分空白组和实验组,其中实验组加入一定浓度的分散于完全培养基中的HFePt NPs材料,空白组加入不含材料的等量完全培养基,共同孵育一定时间后,进行共聚焦显微镜检测。其中,绿色荧光为铁死亡标志物脂质过氧化物的标识,蓝色荧光为细胞核染色。
图13为实施例1制备的HMON@FeCO/CDDP纳米药物和实施例3制备的HFePt NPs在U87-MG细胞中孵育不同时间后的脂质过氧化物产生效果图,由图13可知,HFePt NPs与细胞共孵育一段时间后,绿色荧光明显增强,说明HFePt NPs与细胞共孵育24小时后,细胞内确实产生了脂质过氧化物,也即发生了铁死亡。
Claims (10)
1.一种用于肿瘤铁死亡-气体协同治疗的纳米药物,其特征在于,包括可生物降解的中空介孔有机硅纳米粒、装载于中空介孔有机硅纳米粒的羰基铁类化合物和小分子药物。
2.根据权利要求1所述的用于肿瘤铁死亡-气体协同治疗的纳米药物,其特征在于,所述的可生物降解的中空介孔有机硅纳米粒为具有硫-硫键的中空介孔有机硅纳米粒。
3.根据权利要求1所述的用于肿瘤铁死亡-气体协同治疗的纳米药物,其特征在于,所述的羰基铁类化合物为五羰基铁、十二羰基铁、二壬羰基铁或者羰基铁硫簇化合物;所述的小分子药物为铁死亡诱导剂。
4.根据权利要求1所述的用于肿瘤铁死亡-气体协同治疗的纳米药物,其特征在于,以负载中空介孔有机硅的羰基铁类化合物和小分子药物的中空介孔有机硅总质量计,所述羰基铁类化合物的负载率为10%-80%,所述小分子化疗药物的负载率为2%-20%。
5.根据权利要求1所述的用于肿瘤铁死亡-气体协同治疗的纳米药物,其特征在于,所述的用于肿瘤铁死亡-气体协同治疗的纳米药物,在其表面选择性修饰蛋白质类物质、脂质类物质或亲水性高分子。
6.根据权利要求5所述的用于肿瘤铁死亡-气体协同治疗的纳米药物,其特征在于,所述的蛋白质类物质为还原性牛血清白蛋白、牛血清白蛋白、人血清白蛋白或具有靶向肿瘤细胞表面过表达的整合素蛋白的靶向蛋白质,所述的脂质类物质为肿瘤细胞的细胞膜,所述的亲水性高分子为聚乙二醇或聚乳酸-羟基乙酸。
7.根据权利要求1-6任一权利要求所述的用于肿瘤铁死亡-气体协同治疗的纳米药物的制备方法,包括:
(1)采用模板法将硅酸四乙酯及具有硫-硫键桥接的硅前驱体合成得到内核为硅酸四乙酯水解所得的介孔二氧化硅、外壳为硅酸四乙酯与含硫-硫键的介孔硅前驱体共同水解的有机介孔二氧化硅,通过碱性溶液对上述有机介孔二氧化硅进行蚀刻,将内核中的介孔二氧化硅蚀刻掉,得到以硫-硫键及硅氧键为骨架的中空介孔有机硅;
(2)将步骤(1)中得到的以硫-硫键及二氧化硅为骨架的中空介孔有机硅与带有巯基的硅烷偶联剂混合搅拌,得到巯基修饰的中空介孔有机硅;
(3)将羰基铁类物质与铁死亡诱导剂负载于步骤(2)得到巯基修饰的中空介孔有机硅中;制备得到用于肿瘤铁死亡-气体协同治疗的纳米药物。
8.根据权利要求7所述的纳米药物制备方法,其特征在于,步骤(3)中,所述的巯基修饰的中空介孔有机硅与羰基铁类物质的投料量的质量比为5.0~1.0:8.0;负载羰基铁类物质的纳米药物载体与小分子药物的投料量的质量比为8.0~1.0:3.0。
9.根据权利要求7所述的用于肿瘤铁死亡-气体协同治疗的纳米药物的制备方法,步骤(3)中,所述的用于肿瘤铁死亡-气体协同治疗的纳米药物与蛋白质类物质、脂质类物质或亲水性高分子进行选择性修饰,得到修饰后的用于肿瘤铁死亡-气体协同治疗的纳米药物。
10.一种如权利要求1-6任一所述的用于肿瘤铁死亡-气体协同治疗的纳米药物作为制备肿瘤治疗药物的应用。
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