CN117599017A - 一种氧化钆/钯纳米团簇及其制备方法 - Google Patents
一种氧化钆/钯纳米团簇及其制备方法 Download PDFInfo
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- 229940075613 gadolinium oxide Drugs 0.000 title claims abstract description 42
- 229910001938 gadolinium oxide Inorganic materials 0.000 title claims abstract description 42
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 title claims abstract description 42
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Abstract
本发明公开了一种氧化钆/钯纳米团簇及其制备方法，所述氧化钆/钯纳米团簇以生长在聚丙烯酸网络结构中的氧化钆团簇为核心，在聚丙烯酸网络结构表面镶嵌着纳米钯。利用纳米钯的类过氧化氢酶和类过氧化物酶活性，催化内源性H2O2产生氧气和细胞毒性的羟基自由基，通过化学动力学抑制肿瘤生长；同时利用钆剂的磁共振T1弛豫能力，实现磁共振造影和化学动力学治疗的一体化。
Description
技术领域
本发明涉及纳米材料技术领域，具体涉及一种氧化钆/钯纳米团簇及其制备方法。
背景技术
肿瘤目前发病率越来越高，发病年龄亦趋向于年轻化，因此，早期诊断并及时阻断肿瘤进程，限制肿瘤的进一步发展，已成为一个重要的研究课题。肿瘤组织常常伴随血管的新生和异常血管结构。因此，针对肿瘤独特的组织微环境，设计可被动靶向肿瘤的诊疗一体化纳米材料，及时逆转疾病进程，同时可视化治疗进程，目前已成为最有潜力的处理策略。
肿瘤组织中存在过量的过氧化氢(H2O2)，因此利用纳米材料的纳米酶特性，将内源性丰富的H2O2转化为氧气和细胞毒性的羟基自由基(·OH)，有助于高效清除肿瘤细胞。一方面生成的氧气可缓解肿瘤缺氧微环境，抑制缺氧耐药的信号通路；另一方面利用·OH杀伤肿瘤细胞，通过化学动力学疗法(CDT)抑制肿瘤增殖。
然而，纳米材料的有限的溶解性及稳定性极大影响了治疗效果，使纳米材料难以精确观察和高效治疗肿瘤组织，限制了纳米酶的进一步应用。通过被动靶向的方式递送MRI对比剂，可视化纳米材料的治疗进展，
因此，开发针对肿瘤组织的诊疗一体化纳米材料，实现肿瘤的高效抑制，同时可视化纳米材料的治疗效果，是本领域技术人员亟需解决的问题。
专利CN106620729B公开了一种双介孔核壳结构的无机-无机纳米杂化材料及其制备方法与应用，所得的材料具有核壳结构，核为介孔无机纳米粒子，外壳为介孔二氧化硅壳层，且该介孔二氧化硅壳层表面经过无机金属杂化修饰。介孔无机纳米粒子为介孔铂纳米粒子、介孔钯纳米粒子、及介孔金纳米粒子中的一种，所述介孔二氧化硅壳层表面经过钆、铁、及锰中一种杂化修饰。其具有尺寸均一、生物相容性好等优点，且光稳定性高、光热转化率高、磁共振成像分辨率高，可实现磁共振造影与光热治疗一体化。但该专利使用介孔二氧化硅外壳，首先需要大量的步骤合成载体，通过刻蚀等技术合成介孔二氧化硅，步骤较为繁琐，操作更复杂。随后利用介孔二氧化硅多空隙特点，物理负载钆剂，其负载率并不稳定，无法实现钆剂的稳定负载，未来转化较为困难。同时该纳米杂化材料主要利用光热的方式治疗恶性肿瘤，过高的温度易损伤正常组织。
发明内容
针对上述现有技术，本发明的目的是提供一种氧化钆/钯纳米团簇，基于聚丙烯酸作为交联剂，通过一步溶剂热反应直接制备出一种氧化钆/钯纳米团簇，规避了介孔二氧化硅孔道随机化载药。同时，本发明基于纳米钯强大的CAT样和POD样活性，以肿瘤组织特有的内源性H2O2为反应底物，最大程度减轻正常组织细胞的死亡，具备更好的生物安全性。使用纳米材料负载的钆剂，可进一步实现肿瘤治疗过程中的可视化。
为实现上述目的，本发明采用如下技术方案：
本方面第二方面提供一种氧化钆/钯纳米团簇，所述氧化钆/钯纳米团簇以生长在聚丙烯酸网络结构中的氧化钆团簇为核心，在聚丙烯酸网络结构表面镶嵌着纳米钯。
本发明第二方面提供上述氧化钆/钯纳米团簇的制备方法，包括以下步骤：
将乙酰丙酮钯与乙酰丙酮钆加入到一缩二乙二醇中搅拌形成混合溶液，向混合溶液中加入聚丙烯酸和三乙醇胺搅拌，进行溶剂热反应得到第一产物；随后离心得到氧化钆/钯纳米团簇。
作为优选，所述乙酰丙酮钯、乙酰丙酮钆、一缩二乙二醇、聚丙烯酸、三乙醇胺加入量的比为(10-15)mg：(10-15)mg：(15-25)mL：(0.1-0.3)g：(0.5-1.5)mL。
作为优选，搅拌温度为75-85℃，搅拌时间为1-2h，搅拌转速为50-150rpm；反应温度为150-250℃，反应时间为20-25h。
本发明研究设计了一种能够被动靶向肿瘤组织的氧化钆/钯诊疗一体化纳米团簇，纳米钯具有强大的CAT样和POD样活性，一方面改善了肿瘤组织的缺氧微环境，另一方面杀伤肿瘤细胞，逆转肿瘤生长进程，赋予了该纳米团簇良好的肿瘤治疗效果。同时利用该纳米材料负载的钆剂，实现优异的磁共振成像效果，提升Gd3+的磁共振T1成像效果，有望实现肿瘤治疗过程可视化和随访监测。
本发明使用一步溶剂热法制备氧化钆/钯纳米团簇，利用聚丙烯酸作为交联剂，将钆和钯直接聚合，操作安全、经济、简便；并且相对于介孔二氧化硅，可最大程度控制钆和钯的负载率，具有流程稳定性，为未来临床转化提供合成基础。同时该纳米材料利用肿瘤组织内高含量的H2O2作为反应底物，可实现肿瘤组织的特异性杀伤，而不损伤正常组织(正常组织内H2O2含量极低)。
本发明的氧化钆/钯纳米团簇有望实现肿瘤组织的早期干预和可视化治疗进程，为肿瘤的监测和干预提供了新的工具。相较于传统的钆剂成像造影剂，氧化钆/钯纳米团簇具有更高的弛豫性能。
本发明的有益效果：
本发明中设计使用用于肿瘤细胞的氧化钆/钯诊疗一体化纳米团簇，相较于传统的钆剂成像造影剂，氧化钆/钯纳米团簇具有更高的弛豫性能，有望可视化肿瘤组织治疗进程和随访监测。另外，该纳米团簇中钯元素具有CAT样和POD样活性。本发明可以作为一种可拓展的功能强大的全新纳米团簇，工艺更加简单，方法更加简练，原材料成本低，易于大规模生产。
附图说明
图1：本发明的氧化钆/钯纳米团簇结构示意图；
图2：本发明实施例1制备的氧化钆/钯纳米团簇的透射电镜图；其中红色箭头所示为钯，白色箭头所示为氧化钆；
图3：本发明实施例1制备的氧化钆/钯纳米团簇各元素的Mapping图像；
图4：氧化钆/钯纳米团簇各元素的XPS光谱图；
图5：氧化钆/钯纳米团簇的XRD谱图；
图6：氧化钆/钯纳米团簇的平均粒径；
图7：不同浓度氧化钆/钯纳米团簇的r1弛豫率；
图8：不同浓度氧化钆/钯纳米团簇对乳腺癌4T1的细胞毒性检测；
图9：TMB检测不同浓度氧化钆/钯纳米团簇与H2O2共孵育后的·OH产生情况；
图10：H2O2含量试剂盒检测不同浓度的氧化钆/钯纳米团簇与H2O2共孵育后的H2O2消耗情况。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案，以下将结合具体的实施例详细说明本申请的技术方案。
本发明实施例中所用的试验材料均为本领域常规的试验材料，均可通过商业渠道购买得到。本发明以下实施例中所用乙酰丙酮钆、乙酰丙酮钯、聚丙烯酸、三乙醇胺购自于上海阿拉丁生化科技股份有限公司，聚丙烯酸购自于天津市大茂化学试剂厂，钆贝葡胺造影剂购自于上海麦克林生化科技股份有限公司。
实施例1
合成氧化钆/钯纳米团簇GdPd(GP)：
将12.5mg乙酰丙酮钯与12.5mg乙酰丙酮钆加入到20mL一缩二乙二醇中，在80℃下搅拌(转速100rpm)40min。然后向上述溶液中加入0.2g聚丙烯酸(PAA)，在80℃下搅拌20min；然后加入1mL三乙醇胺，继续80℃搅拌(转速100rpm)30min。上述反应结束后溶液转移到100mL的特氟龙高压反应釜中，在200℃加热24小时。反应结束后，将氧化钆/钯纳米团簇离心，并分别用去离子水和无水乙醇清洗三遍，放置4℃冰箱保存。
实验例
1.结构表征：
图2为实施例1中步骤(1)制备的氧化钆/钯纳米团簇(GP)的透视电镜图，图中红色箭头所示为钯小球，白色箭头所示为氧化钆；图2中显示出氧化钆/钯纳米团簇形状呈球形，大小均匀，颗粒分散，能显现出明显的球形镶嵌结构，该球形镶嵌结构表现为钯单质小球随机散布氧化钆大球的表面。
图3所示为GP纳米团簇的Mapping图像，图3清楚地显示钯单质小球成功接种在氧化钆大球的表面。
图4所示为GP纳米团簇各元素的X射线光电子能谱(XPS)分析结果图。图4表明，钯元素在334.8eV(3d 5/2)和340.4eV(3d 3/2)处出现两个峰，钆元素在钆4d区域的147.6eV(4d 7/2)和142.2eV(4d5/2)处出现两个峰，这与金属钆和钯的结合能较好对应。
图5所示为GP纳米团簇的XRD分析结果图。图5的衍射峰显示Pd(111)、(200)、(220)能较好地对应Gd2O3的衍射峰，进一步证明钆和钯成功掺杂在一起。
图6所示为GP纳米团簇的粒径测定结果图。图6显示实施案例1合成的纳米团簇的粒径大约是100nm，粒径大小均匀一致。
2.测定在3.0T MRI下的GP纳米团簇弛豫率。
由于钆是磁共振成像主要元素，因此对实施例1中步骤(1)制备的氧化钆/钯纳米团簇(GP)进行弛豫率测试。首先制备不同浓度梯度的GP纳米团簇凝胶样本，随后使用3.0T磁共振扫描仪获得凝胶图像。根据T1-mapping图像计算T1弛豫率r1值(1/Ts-1)；实验结果如图7所示，图7A为GP凝胶在3.0T MRI的T1加权图像以及弛豫率曲线，显示该纳米团簇的弛豫率为7.543，图7B为临床常见的钆贝葡胺造影剂，弛豫率为3.150，实施例1制备的氧化钆/钯纳米团簇相比于钆贝葡胺造影剂有更好的T1弛豫性能。
3.MTT检测GP纳米团簇对4T1细胞的增殖抑制情况。
将4T1细胞接种到96孔细胞培养板中(8000个细胞/孔)，分别以不同浓度(0、5、10、20、40、80和160μg/mL)的GP纳米团簇材料共孵育24h。随后吸弃废液，孔中加入MTT后继续孵育3小时。最后除去多余的MTT，每孔并加入150μL二甲基亚砜。检测490nm处的吸光度，并计算细胞的增殖抑制情况。图8为不同浓度GP纳米团簇对4T1的细胞毒性测定结果。在5μg/mL时(以钯浓度计算)，细胞活性为95.9％，而在160μg/mL下，细胞活性降至46.8％。
4.检测GP纳米团簇的类过氧化物酶活性。
将不同浓度(10、20和40μg/mL)的GP纳米团簇溶液加入到3，3，5，5-四甲基联苯胺(TMB)和4mM H2O2的混合溶液中(2mL)。常温孵育10min后，测量652nm处的吸光度值。图9为TMB检测不同浓度GP纳米团簇与H2O2共孵育后的·OH产生情况结果图，随着GP浓度的增加，自由基反应产生的蓝色色素增多，吸收光谱的最大峰增高，说明·OH的产生随着GP纳米团簇浓度的增加而增加，GP具有良好的POD样活性。
将H2O2和GP纳米团簇溶液混合成不同浓度的1mL溶液(0、40、80和160μg/mL)，静置10min。然后14000rpm离心5min，取上清置冰上待测。将过氧化氢含量检测试剂盒试剂，按说明书要求顺序添加到待测试剂，最后弃上清，留沉淀。蒸馏水调零，记录测定管沉淀物质在415nm处的吸光度。图10为利用H2O2含量试剂盒检测不同浓度的GP纳米团簇对H2O2的消耗能力。结果表明随着GP纳米团簇浓度的增加，H2O2消耗量增大，吸收曲线逐渐降低，说明GP纳米团簇具有良好的CAT样活性。
以上所述仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。
Claims (4)
1.一种氧化钆/钯纳米团簇，其特征在于，所述氧化钆/钯纳米团簇/聚乙二醇/葡萄糖氧化酶/十肽以生长在聚丙烯酸网络结构中的氧化钆团簇为核心，在聚丙烯酸网络结构表面镶嵌着纳米钯。
2.权利要求1所述的氧化钆/钯纳米团簇的制备方法，其特征在于，包括以下步骤：
将乙酰丙酮钯与乙酰丙酮钆加入到一缩二乙二醇中搅拌形成混合溶液，向混合溶液中加入聚丙烯酸和三乙醇胺搅拌，进行溶剂热反应得到第一产物；随后离心得到氧化钆/钯纳米团簇。
3.根据权利要求1所述的氧化钆/钯纳米团簇的制备方法，其特征在于，所述乙酰丙酮钯、乙酰丙酮钆、一缩二乙二醇、聚丙烯酸、三乙醇胺加入量的比为(10-15)mg：(10-15)mg：(15-25)mL：(0.1-0.3)g：(0.5-1.5)mL。
4.根据权利要求1所述的氧化钆/钯纳米团簇的制备方法，其特征在于，搅拌温度为75-85℃，搅拌时间为1-2h，搅拌转速为50-150rpm；反应温度为150-250℃，反应时间为20-25h。
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