CN113209309A - 一种可分散碳纳米角/金颗粒纳米复合物及其制备和应用 - Google Patents
一种可分散碳纳米角/金颗粒纳米复合物及其制备和应用 Download PDFInfo
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Abstract
本发明属于碳基复合材料技术领域，具体涉及一种可分散碳纳米角/金颗粒纳米复合物及其制备和应用，所述可分散碳纳米角/金颗粒纳米复合物的制备方法，以碳纳米角为基底，通过共价连接聚缩水甘油并在碳纳米角的表面修饰金纳米颗粒。本发明通过PG共价连接CNH，解决了碳纳米角在生物医学方面的分散性问题，极大的促进了CNH的多方面应用；表面修饰金颗粒后制备了可分散的CNH‑PG‑Au纳米复合物，该纳米载体集成了药物递送和生物成像的功能，装载化疗药物并结合Au纳米颗粒的放疗增敏作用，展现出了放化疗的协同效应在肿瘤治疗中的优秀效果；由光声成像获取了肿瘤的影像学信息，因此DOX@CNH‑PG‑Au可以在生物成像的引导下实现更为精准的放化疗联合治疗。
Description
技术领域
本发明属于碳基复合材料技术领域，具体涉及一种可分散碳纳米角/金颗粒纳米复合物及其制备和应用。
背景技术
癌症是世界范围内的一个主要的医学难题，也是当今导致人类死亡的第二大原因，每年确诊和死于各类癌症的人数呈爆炸式的增长。手术、化疗和放疗是目前临床上治疗癌症的常用方法，然而，癌症治疗是一个十分复杂的系统性工程，单一的治疗手段在如今癌症变化复杂的环境下变得捉襟见肘。因此，临床上通常将多种治疗方法联合起来以期获得更好的治疗效果。
纳米技术在生物医学方面经过二十多年的快速发展引起了极大的关注。由于纳米颗粒众多优良的特点，它们在药物递送、生物成像和癌症治疗研究领域中变得普遍。这些纳米颗粒经过合理的设计和制备可以作为一种纳米载体，并能够集成药物递送和生物成像等多种功能。
碳纳米角(Carbonnanohorns，CNHs)是一种碳的同素异形体，它由碳原子的单壁纳米锥组成，当成千上万的纳米锥聚集在一起，形成直径为80-100nm的大丽花状球形聚集体。碳纳米角常用的制备方法是激光烧蚀石墨合成的，因此合成的碳纳米角纯度高，无有毒金属物，所以在生物相容性上比其他碳纳米材料要好。另外，碳纳米角具有许多优秀的理化性质，比如大比表面积，可作为一种良好的纳米药物载体；光热转换，在近红外区具有很强的吸收特性以及具有优秀的光热效应。
聚缩水甘油(Polyglycerol，PG)是一种柔韧的亲水脂肪族聚醚多元醇，由于其生物相容性高、低免疫原性和低毒性，被认为是一种很有前途的药物递送物质。
金作为一种高原子序数(高Z)的金属，将其制成纳米颗粒可以用在多方面的领域中。其中，金纳米颗粒具有高X射线吸收率、合成多样性以及独特的化学和光学性质，作为一种放疗增敏剂被广泛使用，且生物相容性好，无毒无害。
在一些报道中，单壁碳纳米角修饰的碳电极表面电沉积金纳米粒子，制备出了一种新型的联氨传感器，该传感器用来检测肼，对肼的检测具有良好的电催化作用，但该传感器使用有毒的联氨参与反应，在安全性方面有较大的限制。研究人员合成了一种新型的金纳米粒子-单壁碳纳米角的杂化材料，用于构建电流生物传感平台，但该平台制备的步骤较多，具有一定难度。另外，有报道通过胺连接剂将碳纳米角连接到电极表面，然后将核酸抗体修饰的金海胆双探针连接到纳米角上，制备出了金纳米海胆和纳米角杂交体的双探针，有助于识别和诊断阿尔茨海默病，但该探针分散性较差，限制了其生物应用。
发明内容
本发明旨在解决上述问题，提供了一种可分散碳纳米角/金颗粒纳米复合物，结合碳纳米角和金纳米颗粒的优良特性，同时聚缩水甘油PG使该纳米复合物能稳定分散在各种溶剂中，作为一种新型的药物载体和成像探针在生物医学方面具有巨大的潜力。
按照本发明的技术方案，所述可分散碳纳米角/金颗粒纳米复合物的制备方法，以碳纳米角为基底，通过共价连接聚缩水甘油并在碳纳米角的表面修饰金纳米颗粒。
进一步的，包括以下步骤，
S1：将碳纳米角CNH粉末和聚缩水甘油PG混合，分散后搅拌加热得到分散液A；
S2：将分散液A纯化，得到CNH-PG；
S3：将所得CNH-PG与HAuCl4·4H2O溶液混合，加热至沸腾，加入水溶性还原剂，沸腾后继续加热，得到分散液B；
S4：去除分散液B中过量的水溶性还原剂；
S5：将去除水溶性还原剂的分散液B纯化，得到所述可分散碳纳米角/金颗粒纳米复合物CNH-PG-Au。
进一步的，所述步骤S1加热的温度为140℃。
进一步的，所述步骤S2和S5中纯化的具体操作为离心，去除上清液，再加超纯水分散沉淀物，重复3-4次。
进一步的，所述步骤S2中CNH-PG与HAuCl4·4H2O的质量比为1：1。
进一步的，所述步骤S2中水溶性还原剂为柠檬酸三钠或硼氢化钠。
进一步的，所述步骤S4的具体操作为将分散液B转入到截留透析袋中用纯水透析。
本发明还提供了上述任一制备方法制得的可分散碳纳米角/金颗粒纳米复合物。
本发明的另一方面提供了上述可分散碳纳米角/金颗粒纳米复合物在药物递送和生物成像上的应用。
进一步的，所述药物递送的药物为阿霉素DOX。
本发明的技术方案相比现有技术具有以下优点：
安全性高(图11)，制备和应用操作简单；
通过PG共价连接CNH，解决了碳纳米角在生物医学方面的分散性问题，极大的促进了CNH的多方面应用；
表面修饰金颗粒后制备了可分散的CNH-PG-Au纳米复合物，该纳米载体集成了药物递送和生物成像的功能，装载化疗药物并结合Au纳米颗粒的放疗增敏作用，展现出了放化疗的协同效应在肿瘤治疗中的优秀效果；
由光声成像获取了肿瘤的影像学信息，因此DOX@CNH-PG-Au可以在生物成像的引导下实现更为精准的放化疗联合治疗。
附图说明
图1为DOX@CNH-PG-Au的合成路线图。
图2为DOX@CNH-PG-Au为肿瘤光声成像和联合放化疗中的示意图。
图3为CNH基纳米材料的透射电镜图。
图4为粉末X射线衍射仪表征Au载上CNH-PG。
图5为X射线光电子能谱仪表征Au载上CNH-PG。
图6为热重分析验证Au载上CNH-PG。
图7为CNH基纳米材料的水合粒径的稳定性变化图。
图8为CNH基纳米材料的Zeta电位的稳定性变化图。
图9为肿瘤在不同时间点的成像图。
图10为肿瘤区域的强度值。
图11显示为细胞毒性图，(a)表明CNH-PG和CNH-PG-Au作为纳米载体的无毒性；(b)展示了DOX、DOX@CNH-PG和DOX@CNH-PG-Au在不同浓度梯度下对4T1细胞的毒性；(c)和(d)显示为在不同剂量的X射线照射下，不同浓度的DOX@CNH-PG和DOX@CNH-PG-Au对4T1细胞的毒性。
图12为流式细胞术测定了X射线存在下，DOX@CNH-PG-Au组杀伤肿瘤细胞的示意图。
图13为各组小鼠肿瘤治疗后的体积图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实施例1
可分散碳纳米角/金颗粒纳米复合物的制备，如图1所示，包括以下步骤，
S1：将碳纳米角CNH粉末和聚缩水甘油PG混合，室温水浴超声20-40min使其充分分散后，在140℃的油浴锅中磁力搅拌加热18-22h，得到分散液A；
S2：以10000-14000r/min的速度离心分散液A，0.8-1.2h/次，每次都去掉含游离PG的上清液，再加超纯水超声分散沉淀物，重复3-4次，得到CNH-PG。
S3：将所得CNH-PG与HAuCl4·4H2O溶液混合，其中CNH-PG与HAuCl4·4H2O的质量比为1：1，在油浴锅中加热至沸腾，快速加入柠檬酸三钠(Na3Ct)水溶液，柠檬酸三钠与CNH-PG的质量比为10-20：1，沸腾后再煮20-40min，得到分散液B；
S4：将分散液B转入到截留分子量为8000～14000da的透析袋中用纯水透析2-3天，除掉过量的柠檬酸三钠；
S5：以10000-14000r/min的速度离心，15-20min/次，重复离心/分散来进一步纯化，得到CNH-PG-Au。
实施例2
在实施例1的基础上将柠檬酸三钠替换为硼氢化钠，硼氢化钠与CNH-PG的质量比为1:2-5。
实施例3
可分散碳纳米角/金颗粒纳米复合物作为纳米载体装载药物的应用
如图1所示，将DOX和实施例1所得CNH-PG-Au按质量比2：1混合，加入稀氢氧化钠溶液将pH值调节至8-9之间，室温下避光搅拌18-22小时；将混合溶液以3000r/min的速度超滤，5-10min/次，每次都去掉含游离DOX的上清液，然后加纯水分散，重复2-3次该纯化步骤，得到DOX@CNH-PG-Au。将纳米载体CNH-PG-Au替换成CNH-PG，用相同的方法得到了DOX@CNH-PG。
实施例1和2中的CNH基纳米材料：CNH-PG、CNH-PG-Au、DOX@CNH-PG和DOX@CNH-PG-Au的透射电镜图如图3所示；各种表征方法图如图4-6所示；水合粒径的稳定性如图7所示，表明了CNH基纳米材料在为期30天的监测中粒径没有明显的变化；Zeta电位的稳定性如图8所示，表明在30天之内各纳米颗粒的电位也没有明显改变，证实了CNH基纳米颗粒的稳定性。
实施例4
可分散碳纳米角/金颗粒纳米复合物作为成像探针实现光声成像
得益于碳纳米角在近红外区的强吸收特性，这就为碳纳米角作为一种很有前景的光声成像(PAI)造影剂提供了理论基础。
如图2所示，将实施例2所得DOX@CNH-PG-Au静脉注射到荷瘤小鼠体内，因为CNH在近红外区的强吸收特性，利用光声成像这种先进的生物医学成像方式，提供了良好的空间分辨率，其图片能清晰地显示DOX@CNH-PG-Au稳定积聚在肿瘤中。如图9、10所示，通过光声成像系统对荷瘤小鼠注射前后进行扫描，重建原始数据得到成像图，能够清晰的显示肿瘤。
实施例5
可分散碳纳米角/金颗粒纳米复合物递送药物后在体内外的放化疗协同作用
如图12所示，通过流式细胞术可知，X射线+DOX@CNH-PG-Au组细胞凋亡最多，杀伤细胞效果更好，验证了放化疗协同作用具有更强的杀伤肿瘤作用。如图13所示，体内治疗实验表明X射线+DOX@CNH-PG-Au组杀伤肿瘤细胞的效果最好，能有效抑制肿瘤生长，这跟体外凋亡实验的结果一致，也证实了放化疗的协同作用在抗肿瘤方面的高效作用。
显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种可分散碳纳米角/金颗粒纳米复合物的制备方法，其特征在于，以碳纳米角为基底，通过共价连接聚缩水甘油并在碳纳米角的表面修饰金纳米颗粒。
2.如权利要求1所述的可分散碳纳米角/金颗粒纳米复合物的制备方法，其特征在于，包括以下步骤，
S1：将碳纳米角CNH粉末和聚缩水甘油PG混合，分散后搅拌加热得到分散液A；
S2：将分散液A纯化，得到CNH-PG；
S3：将所得CNH-PG与HAuCl4·4H2O溶液混合，加热至沸腾，加入水溶性还原剂，沸腾后继续加热，得到分散液B；
S4：去除分散液B中过量的水溶性还原剂；
S5：将去除水溶性还原剂的分散液B纯化，得到所述可分散碳纳米角/金颗粒纳米复合物CNH-PG-Au。
3.如权利要求2所述的可分散碳纳米角/金颗粒纳米复合物的制备方法，其特征在于，所述步骤S1加热的温度为140℃。
4.如权利要求2所述的可分散碳纳米角/金颗粒纳米复合物的制备方法，其特征在于，所述步骤S2和S5中纯化的具体操作为离心，去除上清液，再加超纯水分散沉淀物，重复3-4次。
5.如权利要求2所述的可分散碳纳米角/金颗粒纳米复合物的制备方法，其特征在于，所述步骤S2中CNH-PG与HAuCl4·4H2O的质量比为1：1。
6.如权利要求2所述的可分散碳纳米角/金颗粒纳米复合物的制备方法，其特征在于，所述步骤S2中水溶性还原剂为柠檬酸三钠或硼氢化钠。
7.如权利要求2所述的可分散碳纳米角/金颗粒纳米复合物的制备方法，其特征在于，所述步骤S4的具体操作为将分散液B转入到截留透析袋中用纯水透析。
8.如权利要求1-7任一所述制备方法制得的可分散碳纳米角/金颗粒纳米复合物。
9.如权利要求8所述的可分散碳纳米角/金颗粒纳米复合物在药物递送和生物成像上的应用。
10.如权利要求9所述的可分散碳纳米角/金颗粒纳米复合物在药物递送和生物成像上的应用，其特征在于，所述药物递送的药物为阿霉素。
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