CN113265241A - Au/Ni纳米簇制备方法及其在多模式成像和脊髓损伤检测的应用 - Google Patents
Au/Ni纳米簇制备方法及其在多模式成像和脊髓损伤检测的应用 Download PDFInfo
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Abstract
本发明提供了一种Au/Ni纳米簇制备方法及其在多模式成像和脊髓损伤检测的应用，该Au/Ni纳米簇具有纳米尺寸均一、良好分散性、低生物毒性等特点。通过反应条件控制可得到不同波长荧光和X‑射线吸收功能Au/Ni纳米簇。进而获得荧光成像和CT成像等多功能成像特点。可以针对脊髓损伤部位组织充血和坏死病灶部位实现不同的荧光和CT成像效果，可用于医源性脊髓损伤的检测。在生物医学成像和检测方面具有广泛的应用前景。
Description
技术领域
本发明属于多模式成像纳米材料技术领域，具体涉及Au/Ni合金纳米簇的制备及其在多模式成像和脊髓损伤检测的应用。
背景技术
脊髓损伤(SCI)是脊柱手术中最具破坏性的并发症之一，通常会导致麻木、疼痛或瘫痪。由于脊髓瘦小、柔软并且和周围组织没有明显的边界，脊髓损伤总是不可避免。在胶质瘢痕完全形成之前进行干预可最大限度地形成组织并最大限度地减少脊髓损伤，而在损伤后期进行干预则使脊髓再生和功能恢复变得不可能，因而监测损伤部位的病理变化是脊髓损伤分期和治疗决策制定以及预后的关键因素。
计算机断层扫描成像(CT)具有高密度分辨率，能够精准地分辨不同密度组织间的微小差别，在生物影像学领域具有广阔的应用。由于金具有较高原子序数，对于X射线的吸收系数高。因此，具有良好的CT成像效果(Adv.Mater.2016,28,8950-8958)。
荧光成像是一种很有前途的成像方式，可用于改善疾病监测和引导手术。解决传统放射成像在手术过程中图像对比度差和神经组织不可见的局限性。Au/Ni合金具有明亮的红色荧光且具有良好的信噪比，可用于生物组织的术中可视化。复合CT、荧光双模式成像于一体，将具有极大的应用潜能。
发明内容
本发明目的在于提供一种简单易行的方法制备尺寸均一、高分散性、低生物毒性的Au/Ni合金纳米簇，具有荧光和X射线吸收等功能，并实现脊髓微小损伤检测。首先以一种水溶性巯基官能化大分子化合物用作稳定剂，通过一定比例加入两种金属离子，经加热还原得到Au/Ni合金纳米簇，再以沉淀剂离心分离，得到分散性良好、水溶性、可用于荧光成像(图2)及CT成像(图3)的Au/Ni合金纳米簇。
本发明所述的Au/Ni纳米簇制备方法及在多模式成像和脊髓损伤检测应用，具体步骤如下：
1)首先制备用作稳定剂的配体巯基化合物。以DMF作为溶剂，加入比例为0.2～20：1(优选为0.2～10：1，进一步优选为1～5：1)的N-羟基琥珀酰亚胺NHS和1-乙基-(3-二甲基氨基乙基)碳二亚胺盐酸盐EDC，室温搅拌使其充分溶解，加入1～20mmol/L(优选为5～15mmol/L,进一步优选为8～15mmol/L)的带巯基的羧酸化合物(可以为巯基丁二酸、巯基丙酸、巯基乙酸等)的DMF溶液，搅拌30min，使羧基被充分活化。然后缓慢滴加浓度为5～50mmol/L(优选为5～40mmol/L，进一步优选为8～30mmol/L)含氨基的大分子化合物(可以是聚乙烯亚胺，氨基聚乙二醇等)的乙醇溶液，将其置于室温下搅拌6～48h(优选为6～20h，进一步优选为6～12h)，将反应后溶液置于35～55℃(优选为40～50℃，进一步优选为45～50℃)真空环境下进行蒸发浓缩。将大量沉淀剂(可以是丙酮或三氯甲烷)加入浓缩液中，以8900r/min离心15min，将沉淀分散至去离子水中，制成配体巯基化合物水溶液备用。巯基化合物与交联剂用量比例为1～10：1；氨基聚合物分子分子量可选用600～25,000。
2)制备巯基大分子稳定的Au/Ni合金纳米簇，首先将先前制备的浓度为0.25～25mmol/L(优选为0.5～15mmol/L,进一步优选为0.5～10mmol/L)的配体巯基化合物加入浓度为0.25～25mmol/L(优选为0.5～15mmol/L,进一步优选为0.5～10mmol/L)的Au3+化合物(可以是四氯金酸、水合四溴金酸等)和Ni2+化合物(可以是碳酸镍、硝酸镍、硫酸镍、氯化镍等)混合溶液中，二者摩尔比例为0.05～10：1。加入0.01～1mL/mL(优选为0.01～0.5mL/mL，进一步优选为0.01～0.1mL/mL)还原剂(可以是水合肼或硼氢化钠)。将混合溶液置于60～100℃下反应2～24h(优选为2～12h，进一步优选为3～6h)。产物以异丙醇进行沉淀并离心分离，沉淀分散在5mL去离子水中。将所得产物渗析6～48h，
即得到Au/Ni合金纳米簇。
本发明所制备的Au/Ni纳米簇具有如下特点：所制备的Au/Ni纳米簇具有纳米尺寸均一、良好分散性、低生物毒性等特点。通过反应条件控制两种金属(金和镍)原料的比例，可得到不同波长荧光和X-射线吸收功能Au/Ni纳米簇。进而获得荧光成像和CT成像等多功能成像特点。可以针对脊髓损伤部位组织充血和坏死病灶部位实现不同的荧光和CT成像效果，可用于医源性脊髓损伤的检测。而且，此种合成条件温和，方法简单，重复性好，适合大量生产，具有广泛的应用前景。
附图说明
图1：实施例3所制备的Ni2+掺杂量为10％的Au/Ni纳米簇的TEM图；
图2：实施例2所制备Ni2+掺杂量为20％的Au/Ni纳米簇的荧光激发及发射曲线及其在自然光下和可见光下的照片；表明纳米簇水溶性良好，具有明亮的荧光发射功能。
图3：实施例1所制备的不同Ni2+掺杂量时的Au/Ni纳米簇对应的CT信号强度，所制备的Au/Ni合金在Ni2+掺杂量为10％时具有很强的CT信号，可用于CT成像检测。
图4：实施例3所制备Ni2+掺杂量为10％的Au/Ni纳米簇用于脊髓损伤部位的荧光检测。对比白光图片和荧光图片可以发现，由于脊髓损伤部位组织充血和坏死，损伤处不能吸收纳米簇，荧光明显降低。Au/Ni纳米簇可用于医源性脊髓损伤的检测。
具体实施方式
实施例1
在60mL DMF溶剂中，加入比例为1:1的NHS和EDC，室温搅拌使其充分溶解，制成浓度均为0.03mmol/L的DMF溶液。加入2mL浓度为10mmol/L巯基丁二酸的DMF溶液，室温搅拌30分钟，然后缓慢滴加入2mL浓度为12mmol/L氨基聚乙二醇(Mw＝10,000)的乙醇溶液，室温搅拌反应24小时。然后将混合溶液在真空45℃条件下进行蒸发浓缩，将大量丙酮加入浓缩液中，以8900r/min离心15min。将沉淀分散至3mL水中，制成配体巯基化合物水溶液备用。
在5mL浓度为5mmol/L的配体巯基化合物水溶液中加入总体积为250μL，浓度为50mmol/L的HAuCl4水溶液、50mmol/LNiSO4的水溶液和200μL NaBH4，其中Ni2+的掺杂量依次为0％，10％，20％，40％，60％，80％。将混合溶液置于90℃水浴中搅拌反应4小时。产物以异丙醇进行沉淀并离心分离，沉淀分散在5mL去离子水中。将所得溶液渗析24小时，即为终产物Au/Ni合金纳米簇。
实施例2
在80mL DMF溶剂中，加入比例为1:1的NHS和EDC，室温搅拌使其充分溶解，制成浓度均为0.0375mmol/L的DMF溶液。加入2mL浓度为15mmol/L巯基丙酸的DMF溶液，室温搅拌30分钟，然后缓慢加入2mL浓度为30mmol/L氨基聚乙二醇(Mw＝10,000)的乙醇溶液，室温搅拌反应8小时。然后将混合溶液在真空50℃条件下进行蒸发浓缩，将大量三氯甲烷加入浓缩液中，以8900r/min离心15min。将沉淀分散至3mL水中，制成配体巯基化合物水溶液备用。
在5mL浓度为5mmol/L的配体巯基化合物水溶液中加入150μL浓度为50mmol/L的水合四溴金酸水溶液、100μL浓度为50mmol/L的NiCl2的水溶液和300μLN2H4·H2O。将溶液置于80℃水浴中搅拌反应6小时。产物以异丙醇进行沉淀并离心分离，沉淀分散在5mL去离子水中。将所得溶液渗析24小时，即为终产物Au/Ni合金纳米簇。
实施例3
在100mL DMF溶剂中，加入比例为1:1的NHS和EDC，室温搅拌使其充分溶解，制成浓度均为0.024mmol/L的DMF溶液。加入2mL浓度为12mmol/L巯基丁二酸的DMF溶液，室温搅拌30分钟，然后缓慢滴加3mL浓度为8mmol/L聚乙烯亚胺(Mw＝25,000)的乙醇溶液，室温搅拌反应12小时。然后将混合溶液在真空50℃条件下进行蒸发浓缩，将大量丙酮加入浓缩液中，以8900r/min离心15min。将沉淀分散至3mL水中，制成配体巯基化合物水溶液备用。
在5mL浓度为5mmol/L的配体巯基化合物水溶液中加入225μL浓度为50mmol/L的HAuCl4水溶液、25μL浓度为50mmol/L的NiCO3的水溶液和300μL NaBH4。将溶液置于90℃水浴中搅拌反应8小时。产物以异丙醇进行沉淀并离心分离，沉淀分散在5mL去离子水中。将所得溶液渗析48小时，即为终产物Au/Ni合金纳米簇。
Claims (8)
1.一种Au/Ni纳米簇制备方法，其特征在于：具体步骤如下：
1)以DMF作为溶剂，加入比例为0.2～20：1(优选为0.2～10：1，进一步优选为1～5：1)的N-羟基琥珀酰亚胺NHS和1-乙基-(3-二甲基氨基乙基)碳二亚胺盐酸盐EDC，室温搅拌使其充分溶解，加入1～20mmol/L(优选为5～15mmol/L,进一步优选为8～15mmol/L)的带巯基的羧酸化合物的DMF溶液，搅拌30min，使羧基被充分活化；然后缓慢滴加浓度为5～50mmol/L(优选为5～40mmol/L，进一步优选为8～30mmol/L)含氨基的大分子化合物的乙醇溶液，将其置于室温下搅拌6～48h(优选为6～20h，进一步优选为6～12h)，将反应后溶液置于35～55℃(优选为40～50℃，进一步优选为45～50℃)真空环境下进行蒸发浓缩；将大量沉淀剂加入浓缩液中，以8900r/min离心15min，将沉淀分散至去离子水中，制成配体巯基化合物水溶液备用；
2)首先将先前制备的浓度为0.25～25mmol/L(优选为0.5～15mmol/L,进一步优选为0.5～10mmol/L)的配体巯基化合物加入浓度为0.25～25mmol/L(优选为0.5～15mmol/L,进一步优选为0.5～10mmol/L)的Au3+化合物和Ni2+化合物混合溶液中，二者摩尔比例为0.05～10：1；加入0.01～1mL/mL(优选为0.01～0.5mL/mL，进一步优选为0.01～0.1mL/mL)还原剂；将混合溶液置于60～100℃下反应2～24h(优选为2～12h，进一步优选为3～6h)；产物以异丙醇进行沉淀并离心分离，沉淀分散在5mL去离子水中；将所得产物渗析6～48h，即得到Au/Ni合金纳米簇。
2.根据权利要求1所述的一种Au/Ni纳米簇制备方法，其特征在于：步骤(1)中所述的带巯基的羧酸化合物是巯基丁二酸或巯基丙酸或巯基乙酸。
3.根据权利要求1所述的一种Au/Ni纳米簇制备方法，其特征在于：步骤(1)所述的含氨基的大分子化合物是聚乙烯亚胺或氨基聚乙二醇；含氨基的大分子化合物分子量可选用600～25,000。
4.根据权利要求1所述的一种Au/Ni纳米簇制备方法，其特征在于：步骤(1)所述的沉淀剂是丙酮或三氯甲烷。
5.根据权利要求1所述的一种Au/Ni纳米簇制备方法，其特征在于：步骤(2)所述的Au3+化合物是四氯金酸或水合四溴金酸；Ni2+化合物是碳酸镍或硝酸镍或硫酸镍或氯化镍。
6.根据权利要求1所述的一种Au/Ni纳米簇制备方法，其特征在于：步骤(2)所述的还原剂是水合肼或硼氢化钠。
7.根据权利要求1～6任意一种Au/Ni纳米簇制备方法所制备的Au/Ni纳米簇，其特征在于：Au/Ni纳米簇具有同时进行荧光成像和CT成像等多功能生物成像特点。
8.根据权利要求1～6任意一种Au/Ni纳米簇制备方法所制备的Au/Ni纳米簇，其特征在于：Au/Ni纳米簇针对脊髓损伤部位组织充血和坏死病灶部位实现不同的荧光和CT成像效果，可用于医源性脊髓损伤的检测。
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