CN112022841B - 一种铁/紫草素纳米复合物、其超分子自组装的制备方法及该纳米复合物的应用 - Google Patents
一种铁/紫草素纳米复合物、其超分子自组装的制备方法及该纳米复合物的应用 Download PDFInfo
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Abstract
一种铁/紫草素纳米复合物、其超分子自组装的制备方法及该纳米复合物的应用,属于功能材料技术领域。复合物由紫草素单体和三价铁离子组成;紫草素单体与三价铁离子配位,紫草素单体中的羟基、羰基与三价铁离子配位形成复合物,然后通过π‑π堆积和疏水相互作用组装形成具有谷胱甘肽响应的纳米复合物。其是于室温搅拌下在水中依次加入三价铁盐水溶液和紫草素单体的有机溶剂溶液;持续室温搅拌后,通过离心提纯、水洗后得到。本发明反应条件温和,复合物粒径均一可控,可以显著增加紫草素在水中的溶解度,提高生物利用度;可以在肿瘤细胞环境下响应性拆解,释放出铁与紫草素,有效的应用于生物医学领域中,从而用于制备治疗癌症的药物。
Description
技术领域
本发明属于功能材料技术领域,具体涉及一种铁/紫草素纳米复合物、其超分子自组装的制备方法及该纳米复合物的应用。该制备方法可有效增加紫草素在水中的溶解度,该纳米复合物在癌症治疗方面能够较好地发挥化学动力学治疗、化疗的作用,可以用于制备治疗癌症的药物。
背景技术
紫草素是从紫草根中提取的主要生物活性成分,是一类多酚化合物。在癌症治疗方面,得到了人们的广泛关注。许多研究表明,紫草素可以通过抑制癌细胞增殖,诱导细胞凋亡、抑制癌细胞迁移和侵袭发挥抗癌作用;还可以通过多种分子机制激活抗肿瘤免疫力。然而,紫草素的水溶性很差,生物利用率不高,且具有与许多其他小分子药物相似的初期代谢广泛、肿瘤累积差、对肿瘤选择性不高等缺点,使其治疗效果有一定的局限性。针对以上问题,研究者们将紫草素负载于纳米材料(如脂质体纳米粒子等)中,应用于癌症治疗。纳米药物在增强通透与滞留效果(EPR)的基础上,具有增加疏水性药物溶解度等诸多优点,然而负载紫草素的纳米材料在运输到肿瘤区域过程中,药物的损耗与释放问题有待解决;再则,设计纳米材料,使其能够在病灶部位触发药物释放也是一大挑战;此外,这些纳米药物的治疗性能也并不令人满意,促使研究者们将更多的治疗方式纳入纳米制剂,以提高其抗癌效果。因此,设计一种能够增加紫草素在水中的溶解度,减少药物的损耗且能够充分发挥抗癌作用的纳米药物是很有必要的。
利用金属配位作用,设计制备纳米药物,可有效增加纳米药物体系的稳定性,特别是结合π-π堆积和疏水相互作用等协同组装得到的纳米药物,既可提高纳米药物的稳定性,又可赋予其多重响应性。
近年来,新型生物响应纳米材料的设计引起了人们的极大兴趣,其中,具有肿瘤区域谷胱甘肽响应的纳米材料得到了广泛的关注。肿瘤细胞内的谷胱甘肽浓度为2~10mM,胞外环境的谷胱甘肽浓度约为2~20μM,且肿瘤细胞内的谷胱甘肽比正常细胞高很多倍,因此,谷胱甘肽被认为是一种理想的和普遍存在的内部刺激,可以利用谷胱甘肽响应快速破坏细胞内纳米载体的稳定性,实现细胞内药物的高效释放。
发明内容
本发明的目的是提供一种铁/紫草素纳米复合物,以增加紫草素在水中的溶解度,增加生物利用度,同时通过刺激响应释放、引入多种癌症治疗方式来增加癌症治疗效果。本发明另一目的是提供一种制备铁/紫草素纳米复合物的超分子自组装方法。本发明的再一目的是提供上述铁/紫草素纳米复合物在制备治疗癌症药物中的应用。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供了一种铁/紫草素纳米复合物,其由紫草素单体和三价铁离子组成;紫草素单体与三价铁离子配位,紫草素单体中的羟基、羰基与三价铁离子配位形成复合物,然后通过π-π堆积和疏水相互作用组装形成纳米复合物,所述纳米复合物具有谷胱甘肽响应。
所述铁/紫草素纳米复合物的直径为10~200nm,浓度可高达100mg/mL甚至更高,远远高于紫草素单体在水中的溶解度(一般认为,紫草素单体不溶于水)。
第二方面,本发明提供一种铁/紫草素纳米复合物的制备方法,其步骤如下:
室温搅拌下在水中加入三价铁盐水溶液,然后加入紫草素单体的有机溶剂溶液;持续室温搅拌后,通过离心提纯后即可制备得到铁/紫草素纳米复合物溶液,干燥可得铁/紫草素纳米复合物固体粉末。
其中,有机溶剂与水互溶,可以是甲醇、乙醇、异丙醇、乙腈、甘油、丙酮、二甲基亚砜、四氢呋喃、二甲基甲酰胺等;三价铁盐可以是三氯化铁、硝酸铁、硫酸铁等;三价铁盐与紫草素单体的摩尔比例为0.1~12:1;紫草素单体的有机溶剂溶液中,紫草素单体的浓度为1~10mg/mL;三价铁盐水溶液中,三价铁盐水溶液的浓度为50~800mg/mL;室温搅拌时间为30分钟~24小时。与现有技术相比,本发明具有如下有益效果:
(1)本发明制备的铁/紫草素纳米复合物,具有良好的生物相容性、生物稳定性。
(2)本发明制备的铁/紫草素纳米复合物可以显著增加紫草素在水中的溶解度,提高生物利用度,且纳米复合物中紫草素为骨架成分,不涉及紫草素药物的负载与消耗问题。
(3)本发明制备的铁/紫草素纳米复合物具有谷胱甘肽响应,该纳米复合物可以在肿瘤细胞环境下拆解,释放出铁与紫草素。铁与细胞内的过氧化氢可以发生芬顿反应,生成羟基自由基,实现化学动力学治疗;释放的紫草素可以发挥化疗的作用。纳米复合物还可以通过进一步的表面修饰,更加有效的应用于纳米医学领域中,从而用于制备治疗癌症的药物。
(4)本发明制备的铁/紫草素纳米复合物,可以在合成过程中,掺入其他的金属离子,制备多金属/紫草素纳米复合物。
(5)本发明实验条件温和,室温即可;操作简单,无需复杂的合成和制备过程;产物尺寸均一可调,实验重复性好,因此能够大批量制备,适合工业化生产。
附图说明
图1:实施例1制备的铁/紫草素纳米复合物的透射电镜照片,尺寸为30nm。
图2:实施例2制备的铁/紫草素纳米复合物的透射电镜照片,尺寸为50nm。
图3:实施例3制备的铁/紫草素纳米复合物的透射电镜照片,尺寸为70nm。
图4:实施例4制备的铁/紫草素纳米复合物的透射电镜照片,尺寸为90nm。
图5:实施例5制备的铁/紫草素纳米复合物的透射电镜照片,尺寸为60nm。
图6:实施例6制备的铁/紫草素纳米复合物的透射电镜照片,尺寸为50nm。
图7:实施例2制备的铁/紫草素纳米复合物(FSNPs)及紫草素单体(Shikonin)、三价铁盐(Fe)的紫外可见吸收光谱图。在紫外可见光谱图中可以看到,与紫草素单体(Shikonin)对比,新生成的铁/紫草素纳米复合物(FSNPs)出现602nm处的新宽包峰,这一现象是由于有机配体紫草素与中心铁离子之间的配位键引起的电荷转移跃迁所致,证明了铁/紫草素纳米复合物的形成。
图8:实施例7制备的铁/紫草素纳米复合物对2mM谷胱甘肽溶液的响应测试曲线。图8(A)是纳米复合物在2mM谷胱甘肽溶液中不同时间对应的紫外可见吸收光谱图;图8(B)是纳米复合物在2mM谷胱甘肽溶液中固定吸收峰位为602nm的吸收值(纳米复合物的峰位)随时间变化曲线。从图8(A)、图8(B)中可以发现,铁/紫草素纳米复合物在602nm处的吸收值逐渐降低,表明了配位峰逐渐减弱,纳米药物的拆解。图8(C)是纳米复合物在2mM谷胱甘肽溶液中1小时后的透射电镜图。可以看出铁/紫草素纳米复合物结构破裂,形态改变,进一步表征了纳米药物的拆解。
图9:实施例8制备的铁/紫草素纳米复合物不同条件下对亚甲基蓝降解情况的紫外可见吸收光谱图,表明纳米药物中的三价铁与谷胱甘肽发生氧化还原反应后,结构拆解,将二价铁释放出来,进而发生芬顿反应,生成羟基自由基,降解亚甲基蓝。
图10:实施例9制备的铁/紫草素纳米复合物的cck8细胞毒性测试图。该图可以看到,癌细胞的细胞存活率呈现纳米药物浓度依赖性,随着纳米药物浓度的增加,癌细胞的细胞存活率逐渐降低,表明该纳米药物对癌细胞具有很好的杀伤能力。
具体实施方式
下面结合实施例对本发明做进一步的阐述,而不是要以此对本发明进行限制。
实施例1
将六水合三氯化铁溶解在水中,配制浓度为100mg/mL的三氯化铁水溶液;将紫草素单体溶解在乙醇中,配制浓度为5mg/mL的紫草素乙醇溶液。室温搅拌下在40.75mL水中依次加入1mL氯化铁水溶液、5mL紫草素乙醇溶液。室温搅拌1小时之后,以15000转/分钟的转速,离心15分钟,共离心3遍,得到平均尺寸30nm的铁/紫草素纳米复合物溶液,最终可以将铁/紫草素纳米复合物溶解至水中得到浓度为100mg/mL的纳米复合物溶液。
实施例2
将六水合三氯化铁溶解在水中,配制浓度为100mg/mL的三氯化铁水溶液,将紫草素单体溶解在乙醇中,配制浓度为5mg/mL的紫草素乙醇溶液。室温搅拌下在41.25mL水中依次加入500μL氯化铁水溶液、5mL紫草素乙醇溶液。室温搅拌1小时之后,以15000转/分钟的转速,离心15分钟,共离心3遍,得到平均尺寸50nm的铁/紫草素纳米复合物溶液。
实施例3
将六水合三氯化铁溶解在水中,配制浓度为100mg/mL的三氯化铁水溶液,将紫草素单体溶解在乙醇中,配制浓度为5mg/mL的紫草素乙醇溶液。室温搅拌下在41.65mL水中依次加入100μL氯化铁水溶液、5mL紫草素乙醇溶液。室温搅拌1小时之后,以15000转/分钟的转速,离心15分钟,共离心3遍,得到平均尺寸70nm的铁/紫草素纳米复合物溶液。
实施例4
将六水合三氯化铁溶解在水中,配制浓度为100mg/mL的三氯化铁水溶液,将紫草素单体溶解在乙醇中,配制浓度为5mg/mL的紫草素乙醇溶液。室温搅拌下在41.70mL水中依次加入50μL氯化铁水溶液、5mL紫草素乙醇溶液。室温搅拌1小时之后,以15000转/分钟的转速,离心15分钟,共离心3遍,得到平均尺寸90nm的铁/紫草素纳米复合物溶液。
实施例1~4阐述的是:改变三价铁盐的投入量,可以调节铁/紫草素纳米复合物的尺寸。随着三价铁投入量的增加,纳米粒子的尺寸减小。
实施例5
将六水合三氯化铁溶解在水中,配制浓度为100mg/mL的三氯化铁水溶液,将紫草素单体溶解在二甲基甲酰胺中,配制浓度为5mg/mL的紫草素二甲基甲酰胺溶液。室温搅拌下在40.75mL水中依次加入1mL氯化铁水溶液、5mL紫草素二甲基甲酰胺溶液。室温搅拌1小时之后,以15000转/分钟的转速,离心15分钟,共离心3遍,得到平均尺寸60nm的铁/紫草素纳米复合物溶液。
实施例6
将九水合硝酸铁溶解在水中,配制浓度为400mg/mL的硝酸铁水溶液,将紫草素单体溶解在乙醇中,配制浓度为5mg/mL的紫草素乙醇溶液。室温搅拌下在40.75mL水中依次加入1mL硝酸铁水溶液、5mL紫草素乙醇溶液。室温搅拌1小时之后,以15000转/分钟的转速,离心15分钟,共离心3遍,得到平均尺寸50nm的铁/紫草素纳米复合物溶液。
实施例7
将实施例2制备的铁/紫草素纳米复合物分散于2mM的谷胱甘肽溶液中,记录初始、1min、3min、5min、10min、20min、30min、60min时纳米复合物在对应的紫外可见吸收光谱图。60min后取样拍摄透射电镜照片。
实施例8
MB+FSNPs+GSH+H2O2组:将铁/紫草素纳米复合物(FSNPs)分散于2mL、2mM的谷胱甘肽(GSH)溶液中1h(铁/紫草素纳米复合物的终浓度为50μg/mL),离心后加入45μL 1mg/mL的亚甲基蓝(MB)溶液和20μL、10mM的过氧化氢(H2O2)溶液,放置15min后,记录紫外可见吸收光谱图。
MB+FSNPs+GSH组:将铁/紫草素纳米复合物(FSNPs)分散于2mL、2mM的谷胱甘肽(GSH)溶液中1h(铁/紫草素纳米复合物的终浓度为50μg/mL),离心后加入45μL、1mg/mL的亚甲基蓝(MB)溶液放置15min后,记录紫外可见吸收光谱图。
MB+FSNPs+H2O2组:向2mL的铁/紫草素纳米复合物(FSNPs)水溶液(铁/紫草素纳米复合物的终浓度为50μg/mL)中加入45μL、1mg/mL的亚甲基蓝(MB)溶液和20μL、10mM的过氧化氢(H2O2)溶液,放置15min后,记录紫外可见吸收光谱图。
MB+GSH+H2O2组:向2mL、2mM的谷胱甘肽(GSH)溶液中加入45μL、1mg/mL的亚甲基蓝(MB)溶液和20μL、10mM的过氧化氢(H2O2)溶液,放置15min后,记录紫外可见吸收光谱图。
MB+H2O2组:向2mL的水溶液中加入45μL、1mg/mL的亚甲基蓝(MB)溶液和20μL、10mM的过氧化氢(H2O2)溶液,放置15min后,记录紫外可见吸收光谱图。
MB+H2O组:向2mL的水溶液中加入45μL、1mg/mL的亚甲基蓝(MB)溶液,放置15min后,记录紫外可见吸收光谱图。
实施例8说明,MB+FSNPs+GSH+H2O2组与其他组相比,亚甲基蓝溶液由蓝色变为无色,紫外可见光光谱图的吸收峰消失,表明铁/紫草素纳米复合物在谷胱甘肽溶液中拆解后,能够将亚铁离子释放出来与过氧化氢发生芬顿反应,生成羟基自由基,降解亚甲基蓝。
实施例9
将4T1细胞(购于碧云天生物技术有限公司)以初始密度为每孔1×104个细胞接种在96孔培养板中,温育24小时;再将细胞与浓度分别为2μg/mL、5μg/mL、10μg/mL、12.5μg/mL、15μg/mL、20μg/mL、25μg/mL、30μg/mL的铁/紫草素纳米复合物共培养24小时;然后每孔加入10μL cck8(Cell Counting Kit-8,购于bimake.cn),1小时后用酶标仪测试。
实施例9结果表明随着铁/紫草素纳米复合物浓度增加,4T1小鼠乳腺癌细胞的存活率逐渐降低,当浓度达到30μg/mL时,细胞存活率仅为20%,表明纳米复合物具有较好的杀伤癌细胞的能力。
Claims (2)
1.一种铁/紫草素纳米复合物的制备方法,其特征在于:室温搅拌下在水中加入三价铁盐水溶液,然后加入紫草素单体的有机溶剂溶液,有机溶剂与水互溶;持续室温搅拌后,通过离心提纯后即制备得到铁/紫草素纳米复合物溶液,干燥后得到铁/紫草素纳米复合物固体粉末;
所述铁/紫草素纳米复合物溶液能分散在水溶液中;
三价铁盐与紫草素单体的摩尔比例为0.1~12:1,紫草素单体的有机溶剂溶液中,紫草素单体的浓度为1~10mg/mL;三价铁盐水溶液中,三价铁盐的浓度为50~800mg/mL;
所述有机溶剂为乙醇、二甲基甲酰胺;
所述三价铁盐为三氯化铁、硝酸铁或硫酸铁;
所述室温搅拌时间为30分钟~24小时。
2.权利要求1所述的制备方法制备的铁/紫草素纳米复合物在制备治疗乳腺癌的药物中的应用。
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