CN109589407A - 用于结直肠癌靶向治疗的介孔钌纳米粒子及其制备方法和应用 - Google Patents
用于结直肠癌靶向治疗的介孔钌纳米粒子及其制备方法和应用 Download PDFInfo
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- CN109589407A CN109589407A CN201811296201.5A CN201811296201A CN109589407A CN 109589407 A CN109589407 A CN 109589407A CN 201811296201 A CN201811296201 A CN 201811296201A CN 109589407 A CN109589407 A CN 109589407A
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Abstract
本发明公开了一种用于结直肠癌靶向治疗的介孔钌纳米粒子及其制备方法和应用。该方法包括如下步骤:(1)将三氯化钌溶解到高氯酸溶液中,然后加入非离子表面活性剂,混合均匀,得到混合溶液I;(2)将氨基修饰的胶体二氧化硅纳米粒子加入到混合溶液I中,超声混合均匀,得到混合溶液II;(3)将硼氢化钠溶液加入到混合溶液II中,超声进行反应,待反应结束后水洗、离心,得到中间产物;(4)将中间产物分散到氢氟酸溶液中,然后水洗、干燥,得到用于结直肠癌靶向治疗的介孔钌纳米粒子。本发明制备的钌纳米粒子比表面积大,可负载钌配合物和偶联双特异性抗体,用于靶向抗结直肠癌联合光热和免疫治疗。
Description
技术领域
本发明属于纳米药物技术领域,特别涉及一种用于结直肠癌靶向治疗的介孔钌纳米粒子及其制备方法和应用。
背景技术
结肠直肠癌(CRC)是世界上第三大常见的恶性肿瘤和第四大癌症死亡原因,2012年约有140万新病例产生和近70万人死亡。CRC的发病率分布差异很大,超过三分之二的病例和约60%的死亡是发生在人类发展指数(HDI)高或非常高的国家。现在,许多中高度人类发展指数国家,特别是东欧,亚洲和南美洲,都发现了CRC发病率和死亡率的迅速上升,HDI非常高的国家的发病率高达HDI低的国家的6倍。鉴于时间特征和人口统计预测,到2030年,CRC的全球发病率预计将增加60%,超过220万新病例和110万癌症死亡。
肿瘤的发生发展是一个涉及多因子、多步骤的复杂的生物学过程,具有高度复杂的调控网络和多种逃避凋亡的机制。因此,采用单一方法治疗肿瘤的疗效常常不佳,近年来,为了改善新型抗癌疗法的治疗效果,基于纳米颗粒的肿瘤靶向药物递送策略受到广泛关注。在临床数据的持续整合和药物的不断优化下,单一的治疗方法(如化疗,放射或光热疗法)的疗效已被发现是非常有限的,因此需要利用更全面的方法来巧妙构建出同时具有靶向和免疫应答性的药物递送系统,将这些优化后的方法整合到癌症治疗中,并达到最佳的治疗效果。采用多种治疗手段联用或多种药物联合治疗(combination therapy)是当前临床抗肿瘤治疗的常规模式。FDA(食品药品监督管理局)近年来更是积极倡导开发新型的药物联合治疗肿瘤的临床方案。
利用纳米技术,不仅能够实现多种诊断剂和治疗剂有效载荷的这种前所未有的能力,而且还可以实现在同一封装体系中跨越复杂的生物屏障完成特定位点的药物递送。多功能集成纳米平台将肿瘤成像、肿瘤靶向、化学疗法、免疫疗法和光热疗法(PTT)等不同特性结合在一体化系统中,从而实现有效的抗肿瘤反应。中空介孔纳米材料,由于制备工艺简单、载药量高、药物释放行为可控、具有多官能化能力等优点,已作为各种诊断剂、治疗剂、靶向配体(如DOX、PTX、siRNA、转铁蛋白、抗体)的递送载体显示出巨大的潜力。但是广泛使用的介孔二氧化硅材料自身并不具有特殊的光敏感特性,在光热治疗中仍需另外负载光敏剂。钌纳米颗粒(RuNPs)是一种新兴的无机金属纳米材料,不仅具有高光热转换率、价态和多重氧化态的性质,并且已证实了其作为光热试剂在低剂量下即可以对癌细胞产生有效作用,在药物输送和治疗领域具有广阔的应用前景。
许多纳米尺寸的药物在体内产生效能很低主要是由于其药物递送效率低。为了准确地将载有药物的钌纳米粒子递送至肿瘤部位,需要将基于EPR效应的肿瘤被动靶向和特异性抗体诱导的肿瘤主动靶向结合起来以达到预期效果。抗体的应用不仅可以增强药物靶向积累,而且可以刺激机体产生免疫应答。最近《Nature》上报道的理论指出,自然杀伤(NK)细胞具有强大的溶细胞功能以提供宿主防御,在肿瘤的免疫监视中起着至关重要的作用。当先天免疫和适应性免疫系统都不能阻止肿瘤生长时,NK细胞及其受体仍然可以作为许多治疗方法的靶点。为了同时识别活化的NK细胞受体和肿瘤抗原,通过基因转化和蛋白质工程技术,开发了具有两个不同识别位点的双特异性抗体(BsAb)。能与CD16稳定结合的BsAb已被应用于不同类型肿瘤的临床试验中,例如抗乳腺癌的anti-HER2/anti-CD16、抗霍奇金淋巴瘤的anti-CD30/anti-CD16、抗恶性肿瘤的anti-EPCAM/anti-CD16。因此,设计出了一种新型双特异性抗体SS-Fc,一端可以特异性识别癌胚抗原(anti-CEA arm),另一个端可以结合NK细胞受体(anti-CD16arm)。结果证明,两个位点的结合可以识别NK细胞和结直肠癌细胞抗原,从而诱导产生针对过度表达这些抗原的肿瘤的细胞毒性。此外,抗体修饰的纳米粒子可以通过实体瘤的强渗透性和靶向分布在肿瘤部位实现药物大量积累,最终有助于纳米粒子发挥其抗肿瘤性能。
至今未发现有关合成均匀的中空介孔结构金属钌纳米粒子,使其功能化用于结直肠癌的光热和免疫联合治疗的相关报道。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足,提供一种用于结直肠癌靶向治疗的介孔钌纳米粒子的制备方法。
本发明的另一目的在于提供所述方法制备得到的用于结直肠癌靶向治疗的介孔钌纳米粒子。
本发明的再一目的在于提供所述用于结直肠癌靶向治疗的介孔钌纳米粒子的应用。
本发明的目的通过下述技术方案实现:一种用于结直肠癌靶向治疗的介孔钌纳米粒子的制备方法,包括如下步骤:
(1)将三氯化钌(RuCl3)溶解到高氯酸溶液中,然后加入非离子表面活性剂,混合均匀,得到混合溶液I;
(2)将氨基修饰的胶体二氧化硅纳米粒子(AFSN)加入到步骤(1)中得到的混合溶液I中,超声混合均匀,得到混合溶液II;
(3)将硼氢化钠溶液加入到步骤(2)中得到的混合溶液II中,超声进行反应,待反应结束后水洗、离心,得到中间产物;
(4)将步骤(3)中得到的中间产物分散到氢氟酸溶液中(以去除二氧化硅模板),然后水洗、干燥,得到用于结直肠癌靶向治疗的介孔钌纳米粒子。
步骤(1)中所述的高氯酸溶液的浓度优选为0.5mmol/L~0.2mol/L;优选为0.2mol/L。
步骤(1)中所述的高氯酸溶液中的高氯酸与三氯化钌的摩尔比为0.7~1:1;优选为1:1。
步骤(1)中所述的非离子表面活性剂优选为普兰尼克F127(Pluronic F127)。
步骤(1)中所述的非离子表面活性剂和三氯化钌的质量比为10:5~6;优选为50:25~29.04;更优选为50:29.04。
步骤(1)中所述的混合优选为采用涡旋的方式进行混合。
所述的涡旋的时间优选为1~3min。
步骤(2)中所述的氨基修饰的胶体二氧化硅纳米粒子(AFSN)的粒径为100nm;其通过采用ATPES在甲苯中氨基化获得;优选为通过如下步骤制备得到:
(i)将无水乙醇、氨水和水搅拌混合均匀,得到混合溶液III;然后将正硅酸乙酯和无水乙醇混合均匀,得到混合溶液IV;再将混合溶液IV滴加到混合溶液III中,在密闭条件下进行反应,洗涤、离心,得到二氧化硅粒子;
(ii)将步骤(i)得到的二氧化硅粒子和3-氨丙基三乙氧基硅烷(APTES)加入到甲苯中进行反应,待反应结束后洗涤、干燥,得到氨基修饰的胶体二氧化硅纳米粒子(AFSN)。
步骤(i)中所述的氨水为含氨25%~28%的水溶液。
步骤(i)中所述的无水乙醇、氨水、水、正硅酸乙酯和无水乙醇的体积比为19~20:1.7:0.5~1:1.34:6.7;优选为19.65:1.7:0.61:1.34:6.7。
步骤(i)中所述的搅拌的时间10~20min;优选为20min。
步骤(i)中所述的密闭条件优选为通过如下方式实现:采用聚氯乙烯薄膜密封瓶口。
步骤(i)中所述的反应的时间为10~15h;优选为10h。
步骤(i)中所述的洗涤为采用无水乙醇进行洗涤;优选为采用无水乙醇洗涤3次以上。
步骤(i)中所述的二氧化硅粒子的粒径为100nm。
步骤(ii)中所述的二氧化硅粒子的添加量优选为按每毫升3-氨丙基三乙氧基硅烷配比0.1g二氧化硅粒子计算。
步骤(ii)中所述的3-氨丙基三乙氧基硅烷与甲苯的体积比为1:10。
步骤(ii)中所述的反应的条件为:80℃下冷凝回流12h~15h;优选为:80℃下冷凝回流12h。
步骤(ii)中所述的洗涤为依次采用无水乙醇和水进行洗涤;优选为依次采用无水乙醇和水各洗涤三次以上。
步骤(2)中所述的氨基修饰的胶体二氧化硅纳米粒子与所述三氯化钌的质量比为3:29.4~30;优选为3:29.04。
步骤(3)中所述的硼氢化钠溶液的浓度优选为0.1mol/L。
步骤(3)中所述的硼氢化钠溶液中的硼氢化钠与所述三氯化钌的摩尔比优选为5:1。
步骤(3)中所述的反应的条件为:在35~37℃、50~70Hz条件下超声反应4h;优选为:在35℃、50Hz条件下超声反应4h;更优选为:在35℃水浴条件下、50Hz超声反应4h。
步骤(3)中所述的水洗的次数为3次以上。
步骤(4)中所述的氢氟酸溶液的浓度为质量百分比20~40%;优选为质量百分比20%。
步骤(4)中所述的分散的时间为12h~15h;优选为12h。
步骤(4)中所述的干燥的优选条件为:室温下干燥2天以上。
所述的用于结直肠癌靶向治疗的介孔钌纳米粒子制备光热材料或制备抗癌药物中的应用。
所述的抗癌药物优选为抗结直肠癌药物。
一种功能化纳米复合物,包括上述用于结直肠癌靶向治疗的介孔钌纳米粒子、钌配合物和双特异性抗体。
所述的钌配合物为具有荧光性质的钌配合物;优选为钌配合物[Ru(bpy)2(tip)]2+(RBT)。
所述的双特异性抗体优选为SS-Fc。
所述的功能化纳米复合物的制备方法,为以钌配合物作为具有荧光和抗肿瘤药物,用PEG修饰,并偶联双特异性抗体,得到功能化纳米复合物;具体包括如下步骤:
(A)将上述用于结直肠癌靶向治疗的介孔钌纳米粒子加入到钌配合物溶液中,混合均匀,洗涤,离心,得到负载钌配合物的纳米粒子;
(B)将步骤(A)中得到的负载钌配合物的纳米粒子重悬于去离子水中,然后加入双官能化聚乙二醇(SH-PEG-COOH),避光搅拌反应,待反应结束后洗涤、离心,得到PEG修饰后的负载钌配合物的纳米粒子;
(C)将步骤(B)中得到的PEG修饰后的负载钌配合物的纳米粒子重悬于去离子水中,并调节pH至6.0,然后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基磺基琥珀酰亚胺钠盐(Sulfo-NHS)进行反应,待反应结束后调节pH至7.0,再加入双特异性抗体,在避光条件下继续反应,最后加入猝灭试剂终止反应,洗涤、离心,得到功能化纳米复合物(HMRu@RBT-SS-Fc)。
步骤(A)中所述的用于结直肠癌靶向治疗的介孔钌纳米粒子与钌配合物的质量比为2:1。
步骤(A)中所述的混合均匀优选为通过如下方式实现:先在50Hz的条件下超声处理1h,然后在避光条件下、400rpm/min搅拌24h。
步骤(A)中所述的钌配合物优选为钌配合物[Ru(bpy)2(tip)]2+(RBT)。
步骤(B)中所述的双官能化聚乙二醇的分子量为4000~6000;优选为5000。
步骤(B)中所述的双官能化聚乙二醇的用量为按每毫克所述用于结直肠癌靶向治疗的介孔钌纳米粒子配比1μM双官能化聚乙二醇计算。
步骤(B)中所述的搅拌的条件为:400rpm/min搅拌2~3h;优选为:400rpm/min搅拌2h。
步骤(C)中所述的PEG修饰后的负载钌配合物的纳米粒子与双特异性抗体的质量比4~5:1;优选为4:1。
步骤(C)中所述的双特异性抗体优选为SS-Fc。
步骤(C)中所述的反应时间为10~20min;优选为15min。
步骤(C)中所述的继续反应的条件为:400rpm/min搅拌反应2~3h;优选为:常温下、400rpm/min搅拌反应2h。
步骤(C)中所述的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)的添加量为按其在反应体系中的终浓度为2mM计算。
步骤(C)中所述的N-羟基磺基琥珀酰亚胺钠盐(Sulfo-NHS)的添加量为按其在反应体系中的终浓度为5mM计算。
步骤(C)中所述的猝灭试剂优选为甘氨酸。
所述的甘氨酸的用量为按其在最终反应体系中的终浓度为40mM计算。
所述的功能化纳米复合物在制备光热材料或制备抗结直肠癌症药物中的应用。
本发明相对于现有技术具有如下的优点及效果:
1、本发明以氨基官能化的胶体二氧化硅粒子(AFSN)作为硬模板,以非离子表面活性剂(Pluronic F127)作为软模板,以三氯化钌(RuCl3)作为原料,以硼氢化钠(NaBH4)作为还原剂促进钌的沉积,添加高氯酸(HClO4)以控制Ru的还原电位,用氢氟酸(HF)除去二氧化硅模板,得到中空介孔钌纳米粒子。该纳米粒子可负载钌配合物和偶联双特异性抗体。
2、本发明以钌配合物(RBT,[Ru(bpy)2(tip)]2+)作为具有荧光和抗肿瘤效果的药物,用PEG修饰,并偶联双特异性抗体(SS-Fc,anti-CD16and anti-CEA),可制得功能化纳米复合物。本发明制备的钌纳米粒子结构新颖,比表面积大,均匀的孔道以及内部中空结构能使客体物质(如抗肿瘤药物)有效装载。
3、本发明的功能化纳米复合物在808nm近红外光照射下可以有效释放RBT以产生ROS,迅速升温达到光热消融肿瘤目的,并募集自然杀伤细胞(NK cells),从而触发免疫应答,最终导致细胞的坏死和凋亡。此外,功能化纳米粒子可以有效增强细胞吸收,肿瘤渗透,细胞毒性,在肿瘤位点的实现精准靶向积累和治疗效果,可用于靶向抗结直肠癌联合光热和免疫治疗。
4、本发明的功能化纳米复合物具有近红外敏感的光热效果,可以利用负载的钌配合物(RBT)的荧光来定位肿瘤部位,结合纳米尺寸EPR效应的被动靶向和特异性抗体的主动靶向可以实现功能化纳米粒子在肿瘤部位的高度积累,从而引发结直肠癌细胞凋亡,具有体内联合治疗异位结直肠癌的作用。该功能化纳米复合物发光热和免疫联合治疗可有效治疗结直肠癌,可应用于制备抗结直肠癌联合治疗的药物中。
5、本发明制备过程新颖,产物体系简单,操作简单,方法简易,产品可直接保存和使用,制备的功能化纳米粒子在未来的多重联合抗癌疗法中具有巨大的潜力。
附图说明
图1是双模版法合成中空介孔钌纳米粒子过程中不同时间点的透射电镜图。
图2是中空介孔钌纳米粒子的高倍透射电镜图和元素分析结果图;其中,图A是中空介孔钌纳米粒子的高倍透射电镜图;图B是各元素分析结果。
图3是纳米钌、功能化纳米复合物的热红外成像图和光热升温曲线图;其中,图A是纳米钌、功能化纳米复合物的热红外成像图;图B是光热升温和降温曲线;图C是不同浓度的功能化纳米复合物的光热升温曲线;图D是功能化纳米复合物的光热稳定性循环升温曲线;图E是功能化纳米复合物在近红外光照射后的原子力显微镜图像。
图4中功能化纳米复合物在有无近红外光照下诱导结肠癌细胞CT26凋亡的结果图;其中,图A是功能化纳米复合物在有无近红外光照下诱导结肠癌细胞CT26凋亡的流式细胞分析图;图B、C是流式分析结果的量化图。
图5中功能化纳米复合物在异位结肠癌荷瘤小鼠的体内治疗结果图;其中,图A是不同治疗组的异位结肠癌荷瘤小鼠的肿瘤体积曲线;图B是荷瘤小鼠的体重变化曲线;图C是剥离出的肿瘤实物图;图D是肿瘤的重量。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。下列实施例中所用原料的纯度只要达到化学纯以上即可,来源均可从市场购得。
实施例1:中空介孔钌纳米粒子的制备
(1)量取173μL高氯酸(HClO4),用蒸馏水定容至10mL配制成0.2mol/L的高氯酸储存液;同时称取37.83mg硼氢化钠(NaBH4),用蒸馏水定容至10mL配制成0.1mol/L的硼氢化钠储存液。
(2)氨基修饰的胶体二氧化硅粒子的制备:将19.65mL无水乙醇、0.61mL水、1.7mL氨水(含氨25%~28%的水溶液)磁力搅拌约20min成均匀的溶液,再缓慢地滴加1.34mL正硅酸乙酯和6.7mL无水乙醇的混合溶液,滴加完后,用聚氯乙烯薄膜密封瓶口,反应10h,用无水乙醇洗涤3次离心分离后,即得到粒径为100nm的单分散二氧化硅粒子。将0.5006g二氧化硅粒子(100nm)、5mL 3-氨丙基三乙氧基硅烷(APTES)加入到50mL甲苯中,于80℃下冷凝回流12h,反应结束后依次采用无水乙醇和水连续洗3次,45℃下干燥24h,得到氨基修饰的胶体二氧化硅纳米粒子(AFSN)。
(3)中空介孔钌纳米粒子的双模板法合成:将29.04mg三氯化钌(RuCl3)溶解于7.0mL高氯酸储存液(0.2mol/L)中,加入50mg普兰尼克F127(Pluronic F127)后涡旋1~3min使其充分溶解。加入3.0mg氨基修饰的胶体二氧化硅纳米粒子(AFSN),超声处理使其均匀分散。完全溶解后,加入7.0mL硼氢化钠储存液(0.1mol/L),在50Hz条件下超声反应4h,利用循环水使水浴温度保持在35℃。反应结束后,水洗3次离心分离产物,置于20%(w/w)氢氟酸(HF)溶液中分散12h。除去二氧化硅模板后,水洗数次,室温下干燥2天,得到中空介孔钌纳米粒子(HMRu NPs;简称为HMRu)。该纳米粒子能在室温下稳定存在,容易保存。
(4)在步骤(3)中反应的不同点(0.5h、1h、1.5h、2h、3h、4h)取纳米粒子溶液滴于铜网上,干燥后通过Hitachi H-7650型透射电子显微镜(TEM)观察制得的纳米粒子,结果如图1所示。观察到在反应过程中,钌种子逐渐覆盖在氨基改性的二氧化硅颗粒上,并随着时间推移进一步积累成多孔钌壳。
(5)利用氢氟酸去除二氧化硅模板后,如图2所示,所获得的中空介孔钌纳米粒子的透射电子显微镜(TEM)显示其为均匀单分散的颗粒,粒径在110nm左右。高分辨率透射电子显微镜(HTEM)图像清楚地显示了该纳米粒子的晶格条纹约为0.26nm,平均壳厚度约为13nm,具有明确的中空介孔结构。均匀的孔道以及内部中空结构能使客体物质(如抗肿瘤药物)有效装载。通过EX-250系统能量色散谱(EDX)测量了制得的纳米粒子某一区域内的元素组成,数据进一步证实了中空介孔钌的成功制备和二氧化硅模板的充分去除。
实施例2:功能化纳米复合物的制备
(1)称取11mg具有荧光性质的钌配合物(RBT,[Ru(bpy)2(tip)]2+),用PBS缓冲液定容至10mL配制成钌配合物储存液;其中,具有荧光性质的钌配合物参考如下文献(Wang C,Yu Q,Yang L,et al.Ruthenium(II)polypyridyl complexes stabilize the bcl-2promoter quadruplex and induce apoptosis of Hela tumor cells[J].Biometals,2013,26(3):387-402.)获得。称取25mg中空介孔钌纳米粒子(实施例1制得),用PBS缓冲液定容至10mL配制成钌纳米粒子储存液。
(2)钌配合物的负载和PEG的修饰:取2mL 2.5mg/mL钌纳米粒子储存液,加入到1mL1.1mg/mL钌配合物储存液中,随后将混合物在50Hz的条件下超声处理1h,分散均匀后,在黑暗中以400rpm/min的恒定速度磁力搅拌24h。充分分散后,用PBS缓冲液洗涤3次后离心后,重悬在10mL去离子水中。随后加入5μM双官能化聚乙二醇(SH-PEG-COOH,即Hetero-bi-functionalized PEG(ThiolPoly(Ethylene Glycol)-Carboxymethyl,Mw=5000,购于北京华威锐科化工有限公司),再次以400rpm/min恒定速度温和搅拌2小时,将所得产物离心洗涤并重悬在去离子水中备用(50μg/mL)。钌配合物的包封率为13.9%。
(3)双特异性抗体的偶联:取2mL上述步骤(2)中得到的溶液,并控制其酸碱度(pH值)为6.0,在此条件下依次加入终浓度为2mM的1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)和终浓度为5mM的N-羟基硫代琥珀酰亚胺钠盐(Sulfo-NHS),在室温下充分反应15min。随后将溶液调节至pH=7.0,加入25μL1mg/mL的双特异性抗体(SS-Fc,anti-CD16andanti-CEA;参考文献获得:Li J,Zhou C,Dong B,et al.Single domain antibody-basedbispecific antibody induces potent specific anti-tumor activity[J].Cancerbiology&therapy,2016,17(12):1231-1239.),严格控制溶液处在避光条件中,常温下以400rpm/min的恒定速度磁力搅拌2h。双特异性抗体充分偶联后,加入终浓度为40mM甘氨酸作为猝灭试剂使反应终止,所得产物经两次离心洗涤后,得到功能化功能化纳米复合物(HMRu@RBT-SS-Fc),然后将其分散在1mL PBS中用于后续应用。双特异性抗体的包封率为6.6%。该功能化纳米复合物能在室温下稳定存在,容易保存。
实施例3:纳米钌、纳米复合物的光热效果评估
取实施例1制备得到的中空介孔钌纳米粒子(配置成5μg/mL的溶液)和实施例2制备得到的功能化纳米复合物(配置1、5、10、20μg/mL的溶液),在300mW cm-2的光强度下用808nm的近红外光(NIR)照射5分钟检测其光热效果,以PBS缓冲液为阴性对照。近红外光照射过程中,利用测温仪每隔1分钟测量溶液温度,监测其温度变化,并用FLIR E8型红外热成像仪拍摄直观的热像图。如图3所示,可以观察到中空介孔钌纳米粒子和功能化纳米复合物均显示出卓越的光热效果,温度可迅速升至50℃。此外,对中空介孔钌纳米粒子、功能化纳米复合物溶液反复进行四个周期的近红外辐照,监测其温度变化并用原子力显微镜(AFM)观察纳米粒子形态的变化,如图3所示,即使在经过的多次NIR近红外照射后,纳米颗粒仍显示出优异的光热稳定性和单分散球形态,结果表明,纳米钌和纳米复合物可作为优异的光热纳米试剂,有效地将激光能量转化为局部热能量。
实施例4:功能化纳米复合物引发的细胞凋亡测定
(1)选用癌胚抗原阳性的鼠源结直肠癌细胞CT26作为实验细胞株,以评估潜在的细胞毒性和凋亡作用,本实验中CT26细胞购自ATCC公司,培养条件为添加了10%(v/v)牛血清的DMEM培养基,5%(v/v)CO2,37℃条件下。为评价光热效果,将CT26细胞分为无近红外激光照射组(NIR off)和有近红外激光照射组(NIR on)。使用Annexin V-Alexa Fluor 488/PI凋亡检测试剂盒(四正柏生物技术有限公司,中国),通过流式细胞术检测细胞凋亡。
(2)取对数生长期的癌胚抗原阳性CT26细胞用0.1%(w/v)胰蛋白酶溶液消化制成细胞悬浮液,以1×105细胞/孔的细胞浓度接种于12孔板中,在超净工作台上放置40min,添加1mL培养基,置于培养箱中培养24小时,待细胞贴壁后,用不同配方处理细胞(10μg/mL的HMRu、1.6μg/mL的RBT、0.7μg/mL的SS-Fc、HMRu+RBT+SS-Fc(10μg/mL的HMRu、1.6μg/mL的RBT、0.7μg/mL的SS-Fc)、10μg/mL的HMRu@RBT-SS-Fc),共培养6小时后,有近红外激光照射组在300mW cm-2的光强度下用808nm的近红外光(NIR)照射5分钟,再培养18小时。
(3)将上述共孵育的贴壁CT26细胞,用0.1%(w/v)胰蛋白酶消化后,取5×105~1×106个细胞/ml,以1000rpm转速在4℃下离心10分钟后,弃去上清液,加入1ml冷的PBS缓冲液,轻轻震荡使细胞悬浮,重复洗涤3次。将细胞重悬于200μL Binding Buffer中,加入10μLAlexa Fluor 488轻轻混匀,避光室温反应15分钟,加入300μL Binding Buffer(总反应体积500μL)以及5μL PI(碘化丙啶),在1小时内上机在流式细胞仪(BD Biosciences,美国)上进行荧光分析。如图4所示,我们发现HMRu,HMRu+RBT+SS-Fc和HMRu@RBT-SS-Fc组显示出了近红外敏感的抗肿瘤效应,而游离RBT和游离SS-Fc组几乎没有差异,这种差异归因于光热效应或者RBT的毒性或者两者的协同作用。
实施例5:功能化纳米复合物的小鼠体内治疗效果
(1)选用雌性BALB/c小鼠(6周龄,20~22g)作实验动物,小鼠购自广东省医学实验动物中心。动物饲养环境受到严格控制(温度:25±1℃,相对湿度:50±5%,从早上6:00到下午6:00暗/光循环12h)。所有动物实验均按《实验动物管理条例》的标准进行。
(2)在雌性BALB/c小鼠右侧腹股沟处皮下注射CT26细胞(1×106),将荷CT26单侧移植瘤的BALB/c小鼠随机分为7组(每组5只):PBS(5mg/kg);RBT(0.8mg/kg);SS-Fc(0.35mg/kg);HMRu@RBT(5mg/kg)+SS-Fc(0.35mg/kg);HMRu@RBT(5mg/kg)+SS-Fc(0.35mg/kg)+NIR;HMRu@RBT-SS-Fc(5mg/kg);HMRu@RBT-SS-Fc(5mg/kg)+NIR。当肿瘤生长至100~150mm3后,按照上述分组采用尾静脉注射25μL不同配方的制剂。光热治疗组在注射12小时后,用808nm近红外光(300mW cm-2)照射5min。每3天经尾静脉注射1次,共3次治疗。每两天记录肿瘤体积及小鼠体重,连续15天。每只小鼠定期记录体重变化,用数字卡尺监测肿瘤体积,计算公式如下:体积=W2×L/2每只,其中“W”其中和“L”分别表示肿瘤的宽度和长度。治疗结束后,对实验组小鼠实施安乐死,剥离肿瘤,称重。如图5所示,发现HMRu@RBT-SS-Fc+NIR组的抗肿瘤效率得到显著增强,具有约96%的高抑制率,而且在任何实验组中均没有显着的体重减轻。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种用于结直肠癌靶向治疗的介孔钌纳米粒子的制备方法,其特征在于,包括如下步骤:
(1)将三氯化钌溶解到高氯酸溶液中,然后加入非离子表面活性剂,混合均匀,得到混合溶液I;
(2)将氨基修饰的胶体二氧化硅纳米粒子加入到步骤(1)中得到的混合溶液I中,超声混合均匀,得到混合溶液II;
(3)将硼氢化钠溶液加入到步骤(2)中得到的混合溶液II中,超声进行反应,待反应结束后水洗、离心,得到中间产物;
(4)将步骤(3)中得到的中间产物分散到氢氟酸溶液中,以去除二氧化硅模板,然后水洗、干燥,得到用于结直肠癌靶向治疗的介孔钌纳米粒子。
2.根据权利要求1中所述的用于结直肠癌靶向治疗的介孔钌纳米粒子的制备方法,其特征在于,步骤(2)中所述的氨基修饰的胶体二氧化硅纳米粒子通过如下步骤制备得到:
(i)将无水乙醇、氨水和水搅拌混合均匀,得到混合溶液III;然后将正硅酸乙酯和无水乙醇混合均匀,得到混合溶液IV;再将混合溶液IV滴加到混合溶液III中,在密闭条件下进行反应,洗涤、离心,得到二氧化硅粒子;
(ii)将步骤(i)得到的二氧化硅粒子和3-氨丙基三乙氧基硅烷加入到甲苯中进行反应,待反应结束后洗涤、干燥,得到氨基修饰的胶体二氧化硅纳米粒子。
3.根据权利要求2中所述的用于结直肠癌靶向治疗的介孔钌纳米粒子的制备方法,其特征在于:
步骤(i)中所述的氨水为含氨25%~28%的水溶液;
步骤(i)中所述的无水乙醇、氨水、水、正硅酸乙酯和无水乙醇的体积比为19~20:1.7:0.5~1:1.34:6.7;
步骤(i)中所述的搅拌的时间10~20min;
步骤(i)中所述的反应的时间为10~15h;
步骤(i)中所述的洗涤为采用无水乙醇进行洗涤;
步骤(i)中所述的二氧化硅粒子的粒径为100nm;
步骤(ii)中所述的二氧化硅粒子的添加量为按每毫升3-氨丙基三乙氧基硅烷配比0.1g二氧化硅粒子计算;
步骤(ii)中所述的3-氨丙基三乙氧基硅烷与甲苯的体积比为1:10;
步骤(ii)中所述的反应的条件为:80℃下冷凝回流12h~15h;
步骤(ii)中所述的洗涤为依次采用无水乙醇和水进行洗涤。
4.根据权利要求1中所述的用于结直肠癌靶向治疗的介孔钌纳米粒子的制备方法,其特征在于:
步骤(1)中所述的高氯酸溶液中的高氯酸与三氯化钌的摩尔比为0.7~1:1;
步骤(1)中所述的非离子表面活性剂和三氯化钌的质量比为10:5~6;
步骤(2)中所述的氨基修饰的胶体二氧化硅纳米粒子与所述三氯化钌的质量比为3:29.4~30;
步骤(3)中所述的硼氢化钠溶液中的硼氢化钠与所述三氯化钌的摩尔比为5:1。
5.根据权利要求1中所述的用于结直肠癌靶向治疗的介孔钌纳米粒子的制备方法,其特征在于:
步骤(1)中所述的非离子表面活性剂为普兰尼克F127;
步骤(1)中所述的高氯酸溶液的浓度为0.5mmol/L~0.2mol/L;
步骤(3)中所述的硼氢化钠溶液的浓度为0.1mol/L;
步骤(3)中所述的反应的条件为:在35~37℃、50~70Hz条件下超声反应4h;
步骤(4)中所述的氢氟酸溶液的浓度为质量百分比20~40%;
步骤(4)中所述的分散的时间为12h~15h;
步骤(4)中所述的干燥的条件为:室温下干燥2天以上。
6.权利要求1~5任一项所述的用于结直肠癌靶向治疗的介孔钌纳米粒子制备光热材料或制备抗癌药物中的应用。
7.一种功能化纳米复合物,其特征在于:包括权利要求6所述的用于结直肠癌靶向治疗的介孔钌纳米粒子、钌配合物和双特异性抗体。
8.权利要求7所述的功能化纳米复合物的制备方法,其特征在于:包括如下步骤:
(A)将权利要求6所述的用于结直肠癌靶向治疗的介孔钌纳米粒子加入到钌配合物溶液中,混合均匀,洗涤,离心,得到负载钌配合物的纳米粒子;
(B)将步骤(A)中得到的负载钌配合物的纳米粒子重悬于去离子水中,然后加入双官能化聚乙二醇,避光搅拌反应,待反应结束后洗涤、离心,得到PEG修饰后的负载钌配合物的纳米粒子;
(C)将步骤(B)中得到的PEG修饰后的负载钌配合物的纳米粒子重悬于去离子水中,并调节pH至6.0,然后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基磺基琥珀酰亚胺钠盐进行反应,待反应结束后调节pH至7.0,再加入双特异性抗体,在避光条件下继续反应,最后加入猝灭试剂终止反应,洗涤、离心,得到功能化纳米复合物;
步骤(A)中所述的用于结直肠癌靶向治疗的介孔钌纳米粒子与钌配合物的质量比为2:1;
步骤(A)中所述的钌配合物为钌配合物[Ru(bpy)2(tip)]2+;
步骤(B)中所述的双官能化聚乙二醇的用量为按每毫克所述用于结直肠癌靶向治疗的介孔钌纳米粒子配比1μM双官能化聚乙二醇计算;
步骤(C)中所述的PEG修饰后的负载钌配合物的纳米粒子与双特异性抗体的质量比4~5:1;
步骤(C)中所述的双特异性抗体为SS-Fc。
9.根据权利要求8所述的功能化纳米复合物的制备方法,其特征在于:
步骤(A)中所述的混合均匀通过如下方式实现:先在50Hz的条件下超声处理1h,然后在避光条件下、400rpm/min搅拌24h;
步骤(B)中所述的双官能化聚乙二醇的分子量为4000~6000;
步骤(B)中所述的搅拌的条件为:400rpm/min搅拌2~3h;
步骤(C)中所述的反应时间为10~20min;
步骤(C)中所述的继续反应的条件为:400rpm/min搅拌反应2~3h;
步骤(C)中所述的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的添加量为按其在反应体系中的终浓度为2mM计算;
步骤(C)中所述的N-羟基磺基琥珀酰亚胺钠盐的添加量为按其在反应体系中的终浓度为5mM计算;
步骤(C)中所述的猝灭试剂为甘氨酸;所述甘氨酸的用量为按其在最终反应体系中的终浓度为40mM计算。
10.权利要求7所述的功能化纳米复合物在制备光热材料或制备抗结直肠癌症药物中的应用。
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