CN110960696A - 具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法 - Google Patents
具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法，涉及纳米酶的化学合成领域，更具体地涉及中空氧化钴@金铂纳米球的制备方法。具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法包括以下步骤：利用牺牲模板法制备中空氧化钴@金铂纳米球。所得的中空氧化钴@金铂纳米球具有氧化酶、过氧化物酶和过氧化氢酶作用，在癌症治疗中可以响应肿瘤特异性微环境，并且氧化钴在肿瘤酸性和过氧化氢过表达的条件下可以溶解成钴离子，金铂也瓦解成更小的尺寸从而具有更好的催化活性，同时可以被排除生物体外。
Description
技术领域
本发明涉及化学药物领域，具体涉及具有生物酶活性的中空氧化钴@金铂纳米球制备与用途。
背景技术
具有模拟酶活性的人工酶是当前研究的热点。与天然酶相比，人造酶具有不同的组成，但显示出相似的类酶催化活性。人造酶具有明显的优势，例如制备简便、成本低廉和稳定性高。更重要的是，人造酶是催化医学的潜在候选者，它可以原位催化肿瘤微环境一些特异性物质。例如，作为人造葡萄糖氧化酶的金纳米颗粒已被广泛用于将肿瘤内葡萄糖氧化为H2 O2用于抗肿瘤治疗。具有氧化酶和过氧化物酶（POD）活性的氮掺杂碳纳米材料会产生活性氧（ROS）从而使肿瘤消退。金和铂纳米材料由于其优异的物理和化学性质，在癌症诊断和成像治疗中得到了广泛的应用，但其优异纳米酶性质在肿瘤治疗中的应用没有被完全发掘。
中空氧化钴@金铂双金属纳米球。融合了金铂合金和氧化钴材料的双重性质。同时具有多种类酶活性。其过氧化氢酶样活性可以催化癌细胞中过表达的过氧化氢产生氧气，从而促进其氧化酶活性利于氧化癌细胞中的一些还原物质。例如氧化葡萄糖和谷胱甘肽降低其氧化应激能力，增强活性氧的氧化治疗效果。并且氧化葡萄糖产生的过氧化氢被催化成氧气达到氧气自供给的效果。重要的是，其过氧化物酶活性也可以催化过氧化氢产生羟基自由基来抑制肿瘤生长。这种多功能的类酶纳米材料可以为癌症治疗新策略提供参考。
发明内容
由于目前治疗肿瘤的光热、光动力、声动力等方法都需要外部刺激和穿透深度不够等缺点，本发明旨在制备出一种具有多功能类酶效果的中空氧化钴@金铂纳米材料，在肿瘤微环境发生特异性生物化学反应，达到抑制肿瘤生长的效果。
本发明的技术方案具体如下：
具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法，其特征在于：包含以下步骤：
（1）将水加入到三口烧瓶中，再加入柠檬酸钠、氯化钴得到混合溶液，并磁力搅拌均匀；
（2）向步骤（1）得到的混合溶液中通入氩气除去氧气；
（3）向步骤（2）得到的混合溶液中加入硼氢化钠溶液，继续通入氩气搅拌20min；
（4）向步骤（3）得到的混合溶液中加入氯金酸溶液和氯铂酸溶液，停止通入氩气，在空气中搅拌反应30min；得到的墨蓝色溶液用去离子水洗涤三次，离心分离得到中空氧化钴@金铂纳米球。
进一步，所述步骤（1）中混合溶液中的柠檬酸钠浓度为0.1 mmol/L~0.8mmol/L，氯化钴浓度为0.4 mmol/L~0.6mmol/L。
进一步，其特征在于：所述步骤（3）中的硼氢化钠溶液浓度为1 mol/L。
进一步，其特征在于：所述步骤（4）中的氯金酸溶液和氯铂酸溶液的浓度均为25mmol/L，氯金酸和氯铂酸的摩尔比为1:1~5:1。
本发明主要优点有：
针对目前纳米药物存在的问题，本发明创造性地提出一种不需要外部刺激，同时具有多功能的纳米酶材料来治疗肿瘤。本项目创新性地设计制备了金铂合金的一个复合纳米材料具有良好的类酶催化效果。同时，该材料具有光声和CT成像效果，在成像引导的癌症治疗领域有良好的应用前景。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚，本发明提供如下附图：
图1为本发明实施例1中具有类生物酶活性的中空氧化钴@金铂纳米球的电镜图。
图2为本发明实施例1中具有类生物酶活性的中空氧化钴@金铂纳米球的DLS及X射线光电子能谱图。
图3为本发明实施例1中具有类生物酶活性的中空氧化钴@金铂纳米球作为类似氧化酶、过氧化氢酶和过氧化物酶作用的评估。
图4为本发明实施例1中具有类生物酶活性的中空氧化钴@金铂纳米球对4T1癌细胞的体外毒性图。
图5为本发明实施例1中具有生物酶活性的中空氧化钴@金铂纳米球对乳腺癌小鼠模型的体内治疗效果图。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1 制备具有类生物酶活性的中空氧化钴@金铂纳米球。
具有生物酶活性的中空氧化钴@金铂纳米球的制备方法：首先取100ml二次水，然后加入柠檬酸钠和氯化钴，搅拌混合后柠檬酸钠浓度为0.4mmol/L，氯化钴浓度为0.4mmol/L。通入氩气搅拌20min，除去溶液中的氧。加入新鲜制备的1 mol/L硼氢化钠溶液400μL。继续通入氩气搅拌反应20min。加入25mmol/L氯金酸和氯铂酸（摩尔比=4:1），每次加100μL 间隔1min。加6次。停止通入氩气在空气中反应30min。用去离子水离心洗涤三次，得到中空氧化钴@金铂纳米球。将所得产物分散在二次水中置于4 ℃冰箱备用。
中空氧化钴@金铂纳米球的电镜照片见图1，图1a- c可以观察到纳米球的大小、中空结构以及各部位的晶面间距，并且通过图1d的Mapping图可以看到金铂纳米材料成功的在氧化钴上形成，以上表明成功合成中空氧化钴@金铂纳米球。通过图2a-b的DLS图，显示中空氧化钴@金铂纳米球水合粒径约为61.7 nm。图2c为三种元素比例。通过图2d-f的X射线光电子能谱图，可以观察到金、铂、钴三种元素，进一步表明成功制备中空氧化钴@金铂纳米球。图3是对中空氧化钴@金铂纳米球的模拟氧化酶、过氧化氢酶和过氧化物酶评估结果。图3a是各种模拟生物酶活性的示意图。所得结果表明中空氧化钴@金铂纳米球可以氧化葡萄糖（3c、3d），可以起到类似氧化酶的作用；所得中空氧化钴@金铂纳米球可以催化双氧水产生氧气（3e），可以起到类似过氧化氢酶的作用；还可以催化双氧水产生活性氧（3h、3j），可以起到类似过氧化物酶的作用。图4是所得中空氧化钴@金铂纳米球对4T1癌细胞的体外毒性，通过暗场成像等结果可以看出该中空氧化钴@金铂纳米球可以成功进入细胞（4a），可以对细胞产生脂质氧化损伤（4e）、线粒体膜电位变化（4d）和DNA损伤（4f），并且这些伤害都来自于该材料催化癌细胞内的一些生物化学反应产生活性氧（4c）。图5是所得纳米颗粒对BALB/c小鼠4T1肿瘤模型的体内治疗效果图。小鼠体重在治疗期间较为稳定（5a），从图中可以看出通过不同的处理，肿瘤质量和体积差异较大（5b，5c），说明该方法合成的中空氧化钴@金铂纳米球对BALB/c小鼠4T1肿瘤模型体现出了明显的治疗效果。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其做出各种各样的改变，而不偏离本发明权利要求书所限定的范围。
Claims (4)
1.具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法，其特征在于：包含以下步骤：
（1）将水加入到三口烧瓶中，再加入柠檬酸钠、氯化钴得到混合溶液，并磁力搅拌均匀；
（2）向步骤（1）得到的混合溶液中通入氩气除去氧气；
（3）向步骤（2）得到的混合溶液中加入硼氢化钠溶液，继续通入氩气搅拌20min；
（4）向步骤（3）得到的混合溶液中加入氯金酸溶液和氯铂酸溶液，停止通入氩气，在空气中搅拌反应30min；得到的墨蓝色溶液用去离子水洗涤三次，离心分离得到中空氧化钴@金铂纳米球。
2. 根据权利要求1所述的具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法，其特征在于：所述步骤（1）中混合溶液中的柠檬酸钠浓度为0.1 mmol/L~0.8mmol/L，氯化钴浓度为0.4 mmol/L~0.6mmol/L。
3.根据权利要求1所述的具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法，其特征在于：所述步骤（3）中的硼氢化钠溶液浓度为1mol/L。
4. 根据权利要求1所述的具有类生物酶活性的中空氧化钴@金铂纳米球的制备方法，其特征在于：所述步骤（4）中的氯金酸和氯铂酸的浓度均为25 mmol/L，氯金酸和氯铂酸的摩尔比为1:1~5:1。
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