CN113398285A - 一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法 - Google Patents

一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法 Download PDF

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CN113398285A
CN113398285A CN202110643432.4A CN202110643432A CN113398285A CN 113398285 A CN113398285 A CN 113398285A CN 202110643432 A CN202110643432 A CN 202110643432A CN 113398285 A CN113398285 A CN 113398285A
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CN113398285B (zh
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丁鹤
杨飘萍
贺飞
盖世丽
杨丹
李思怡
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Harbin Engineering University
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Abstract

一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法。本发明属于生物医用材料领域，具体涉及一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法。本发明是为了解决现有肿瘤治疗材料治疗效果较差，单一智能纳米酶研究的稀少的问题。制备方法：一、合成纳米粒子材料；二、纳米材料的修饰。本发明用于具有抗肿瘤效应的双金属纳米酶复合材料的制备。

Description

一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法
技术领域
本发明属于生物医用材料领域，具体涉及一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法。
背景技术
恶性肿瘤被认为是人类肿瘤死亡的主要原因之一，需要高效、安全的多任务治疗纳米平台，作为智能肿瘤治疗的新兴策略，被称为“纳米酶”的催化活性纳米材料引起了人们的极大兴趣。纳米酶作为一种新型的人工材料，得益于纳米技术与生物技术的不断发展和相互融合，可以定制为模拟天然酶的多种催化性质，同时具有可调的催化性能和在恶劣环境下的高稳定性。目前，具有过氧化物酶(Peroxidase,POD)、过氧化氢酶(Catalase,CAT)、超氧化物歧化酶、氧化酶和谷胱甘肽过氧化物酶(Glutathione peroxidase,GPx)活性的纳米酶已被报道。对抗或调节肿瘤微环境(Tumor microenvironment,TME)来实现肿瘤特异性成像和改善癌症治疗，降低对正常组织的损伤以及治疗耐受性。然而，由于纳米酶活性的固有缺陷和TME特殊的物理化学性质的限制，活性氧介导的纳米催化疗法的治疗效果仍然受到严重限制。
与正常组织相比，肿瘤TME表现出独特的特征，包括血管异常、缺氧和微酸环境，以及高水平的谷胱甘肽(Glutathione,GSH)和过氧化氢。TME的极端性和复杂性在一定程度上阻碍了纳米酶的应用，如活性氧介导的纳米催化疗法的治疗效果仍然受到严重限制。通过酶应对TME进行肿瘤治疗，如具有过氧化物酶模拟物的纳米酶能够催化H2O2分解产生羟基自由基，从而诱导肿瘤细胞死亡；具有谷胱甘肽过氧化物酶模拟特性的酶可以通过氧化还原反应降低TME周围GSH的浓度，同时产生O2。因此，精心设计和制备一种具有POD、 CAT和GPx模拟活性的“三位一体”纳米酶，不仅具有纳米催化治疗的功能，而且还具有调节TME环境条件的功能，提供了一种替代策略。
鉴于H2O2在肿瘤细胞中的过度表达，金属离子基纳米酶由于存在混合价态的离子而非常适合催化H2O2的分解，然而单一金属离子较低的反应速率又限制了纳米酶的催化性能，通过铁和铜的氧化还原反应来提高纳米酶效率的双金属循环方法。在Fe2+/Fe3+和Cu+/Cu2+的氧化还原能力通过抑制循环Fenton反应表现出催化作用的情况下，纳米粒子更适合于实际的弱酸性TME，并且由于离子和氧空位的混合价态的存在，具有更高的·OH生成效率。 Cu基纳米材料表现出Cu+/Cu2+之间的快速转化率，Cu2+还具有GPx模拟活性，在H2O2的刺激下，与GSH发生氧化还原反应生成Cu+，获得连续生成·OH的闭环。此外，铜基纳米材料具有很强的NIR-II吸收和光-热转换特性，在提高纳米酶的催化活性和实现协同光热疗法(Photothermal therapy,PTT)方面有着广阔的应用前景。
PTT利用光热传导剂的光热效应，可以从光中获取能量并将能量转化为热量，从而提高周围环境的温度并触发癌细胞的死亡。作为一种高效的非侵入性疗法，能够消除各种类型的肿瘤癌症，热疗通常通过局部高温促进细胞死亡和凋亡，这也促进了纳米酶的催化活性和治疗效果。激发材料的光源为双区近红外光，可提供较深的肿瘤包埋。这样在实际治疗中对深部肿瘤有较好的治疗效果。因此，PTT和被热促进的酶催化作用有望实现协同效应治疗。以往对催化治疗的研究大多涉及多个功能纳米颗粒的复合或组装，形成一个纳米平台，实现“一体”的多功能。然而，构建单一的智能工程纳米酶的研究却很少。
发明内容
本发明是为了解决现有肿瘤治疗材料治疗效果较差，单一智能纳米酶研究的稀少的问题，而提供了一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法。
一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法具体是按以下步骤进行的：
一、合成纳米粒子材料：
①将铜源和铁源加入到溶剂中得到混合溶液A；
②、将混合溶液A倒入三口烧瓶中，抽真空，在搅拌速率为200r/min～400r/min的条件磁力搅拌，以3℃/min～10℃/min的升温速率将反应温度从室温升至90℃～120℃，在温度为 90℃～120℃的条件下反应20min～60min，得到混合溶液B；
③、向混合溶液B中通入氮气，以3℃/min～10℃/min的升温速率将反应温度从 90℃～120℃升温至250℃～290℃，在温度为250℃～290℃的条件下反应20min～60min，反应结束后降温至室温，然后静置过滤或离心洗涤，干燥，得到黑色的CuFe2O4粉体；
二、纳米材料的修饰：
①、将CuFe2O4粉体溶解在乙醇中，在搅拌速率为200r/min～400r/min、温度为30℃～60℃的条件下，加入3-氨丙基三乙氧基硅烷，得到混合溶液C，保持搅拌1h～5h，然后抽滤提纯或离心洗涤，干燥，得到CuFe2O4-NH2纳米材料；
②、将CuFe2O4-NH2纳米材料溶解在乙醇中，在搅拌速率为200r/min～400r/min、温度为30℃～60℃的条件下，加入NH2-PEG2000-COOH，得到混合溶液D，离心收集后依次采用水和乙醇洗涤，得到聚乙二醇化的CuFe2O4纳米粒子。
本发明的有益效果：
本发明采用高温热解法法合成聚乙二醇化的CuFe2O4纳米粒子(CFOs)纳米粒子，合成的小尺寸纳米球纳米材料的设计与常规的合成方法相比，具有优异的形貌，其小尺寸有利于细胞摄取。通过表面电性连接氨基，酰胺化反应将PEG接在CuFe2O4表面，在其表面修饰聚乙烯比咯烷酮，提升了复合材料的亲水性能和生物相容性，包含铜铁两种低毒性的金属离子，通过不同的变价反应充分发挥纳米双金属酶的作用。具有高温增强的多酶催化(CAT)活性，结合热消融，在TME下显示出稳定的肿瘤诊断和治疗。
开发了POD和CAT纳米酶的杂交酶，保护了酶的活性，实现了两种酶的相互促进。证明了ROS供应、GSH消耗和光热转换的三合一功能。CDT和PTT联合治疗原发性肿瘤，协同治疗诱导的全身免疫反应抑制肿瘤生长。在酸性和低pH条件下，通过体内双金属离子循环，使TME的POD模拟活性、CAT模拟活性和GSH在弱酸性环境中的耗竭能力增强，从而产生剧毒物质，减轻肿瘤缺氧，减弱TME的还原能力。细胞内产生的H2O2水平，被 (Fe2+/Fe3+和Cu+/Cu2+)催化产生毒性ROS，从而通过引入CDT提高治疗效果。在1064nm 激光照射下，CFOs的光热转换效率可达41.12％，实现了光增强CDT/PTT在体内外的协同抗肿瘤作用。此外，CFOs具有超高的侧向弛豫特性，这表明其在MRI和CT医学成像中有着重要的应用价值。CFOs是一种很有前途的诊疗一体化纳米酶平台，具有很强的TME调节功能，可用于CT、MRI和NIR-II医学影像引导下的肿瘤光增强CDT/PTT治疗。
附图说明
图1为实施例一制备的CFOs的XRD图；
图2为实施例一制备的CFOs的TEM图；
图3为实施例一制备的CFOs的高分辨透射图；
图4为实施例一制备的CFOs的电子衍射图；
图5为实施例一制备的CFOs的粒径分布统计图；
图6为实施例一反应过程中不同阶段产物的zeta电位对比图，其中1为CuFe2O4粉体， 2为CuFe2O4-NH2纳米材料，3为聚乙二醇化的CuFe2O4纳米粒子；
图7为实施例一制备的CFOs的XPS能谱图；
图8为实施例一制备的CFOs中Cu2p分峰的精细扫描光谱图；
图9为实施例一制备的CFOs中Fe3p分峰的精细扫描光谱图；
图10为实施例一制备的CFOs中O2s分峰的XPS光谱图；
图11为TMB作为染料时CFOs的紫外光吸收光谱图，其中1为TMB，2为TMB+H2O2， 3为TMB+CFOs，4为TMB+H2O2+CFOs，5为TMB+H2O2+CFOs+50℃，6为TMB+H2O2+CFOs+1064nm；
图12为OPD作为染料时CFOs的紫外光吸收光谱图，其中1为OPD，2为OPD+H2O2， 3为OPD+CFOs，4为OPD+H2O2+CFOs，5为OPD+H2O2+CFOs+50℃，6为 OPD+H2O2+CFOs+1064nm；7为OPD+H2O2+CFOs+pH4.5
图13为使用DTNB检测实施例一制备的CFOs对谷胱甘肽的消耗随着时间变化的紫外吸收光谱；
图14为100μg mL-1CFOs+100μL H2O2+TMB随时间变化的紫外吸收光谱；
图15为100μLH2O2+TMB在不同浓度材料浓度条件下的紫外光谱图；
图16为100μg mL-1CFOs+TMB在不同量过氧化氢的条件下的紫外光谱图；
图17为实施例一制备的CFOs对GSH的分解随着时间不同的紫外光谱图；
图18为pH 6.5+H2O2+CFOs与pH 6.5+CFOs不同时间下的产氧对比曲线，其中1为pH6.5+H2O2+CFOs，2为pH 6.5+CFOs；
图19为在不同的pH以及温度下实施例一制备的CFOs的产氧性能对比曲线，其中1为pH 6.0+45℃，2为pH 7.2，3为pH 6.5，4为pH 4.5；
图20为实施例一制备的CFOs采用DMPO捕捉剂获得的ESR对比谱图，其中1为 DMPO+H2O2+CFOs，2为DMPO+H2O2；
图21为实施例一制备的CFOs在不同浓度下的紫外吸收光谱，其中1为100μg mL-1，2为200μg mL-1，3为300μg mL-1，4为400μg mL-1；
图22为实施例一制备的CFOs暴露于1064nm激光下的潜在良好光热转换效果机理图；
图23为实施例一制备的CFOs热红外成像对比图；
图24为不同浓度实施例一制备的CFOs在1.0W cm-2激光照射下的升温曲线图，其中1为空白对照，2为100μg mL-1，3为200μg mL-1，4为300μg mL-1，5为400μg mL-1，6 为500μgmL-1；
图25为不同功率的激光器激发实施例一制备的CFOs获得的升温曲线图，其中1为0.6 W cm-2，2为0.8W cm-2，3为1.0W cm-2，4为1.2W cm-2，5为1.4W cm-2；
图26为实施例一制备的CFOs单循环的升温降温温度变化曲线图；
图27为光热转换效率关系图；
图28为实施例一制备的CFOs进行5个周期的激光开关测量获得的升温降温曲线图
具体实施方式
具体实施方式一：本实施方式的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法具体是按以下步骤进行的：
一、合成纳米粒子材料：
①将铜源和铁源加入到溶剂中得到混合溶液A；
②、将混合溶液A倒入三口烧瓶中，抽真空，在搅拌速率为200r/min～400r/min的条件磁力搅拌，以3℃/min～10℃/min的升温速率将反应温度从室温升至90℃～120℃，在温度为 90℃～120℃的条件下反应20min～60min，得到混合溶液B；
③、向混合溶液B中通入氮气，以3℃/min～10℃/min的升温速率将反应温度从 90℃～120℃升温至250℃～290℃，在温度为250℃～290℃的条件下反应20min～60min，反应结束后降温至室温，然后静置过滤或离心洗涤，干燥，得到黑色的CuFe2O4粉体；
二、纳米材料的修饰：
①、将CuFe2O4粉体溶解在乙醇中，在搅拌速率为200r/min～400r/min、温度为30℃～60℃的条件下，加入3-氨丙基三乙氧基硅烷，得到混合溶液C，保持搅拌1h～5h，然后抽滤提纯或离心洗涤，干燥，得到CuFe2O4-NH2纳米材料；
②、将CuFe2O4-NH2纳米材料溶解在乙醇中，在搅拌速率为200r/min～400r/min、温度为30℃～60℃的条件下，加入NH2-PEG2000-COOH，得到混合溶液D，离心收集后依次采用水和乙醇洗涤，得到聚乙二醇化的CuFe2O4纳米粒子。
本实施方式步骤一中高温热解法，合成纳米材料其大小形貌等，方法较为稳定，体积较小，纯度高结晶度高，且有均匀且明显的球状结构。
本实施方式步骤一②中反应前抽真空，可以去除溶液中的水分和氧气。
本实施方式步骤一②及步骤一③按升温速度为3℃/min～10℃/min进行升温有利于减少爆沸现象，反应可以充分进行，同时有利于及时观察与控制。
本实施方式步骤一③中通氮气作为保护气，避免生成杂质或引入外界氧气等杂质，保证反应纯净，避免空气对于反映体系的干扰。
本实施方式搅拌是为了更好的分散试剂，达到反应完全、均匀升温等目的。
本实施方式步骤一中高温热解法，这种方法合成的产物相比溶剂热法合成的颗粒更小，比共沉淀法合成材料的分散性好，因此更适合作用于细胞内部。
本实施方式步骤一③及步骤二②中将产物在乙醇中进行清洗离心，能更有效并稳定地获得干净的产物。
本实施方式步骤二①中通过加入氨基与羟基的聚乙二醇源，利用静电吸附/酰胺化反应连接。
本实施方式公开了一种具有抗肿瘤效应的双金属纳米酶复合材料CuFe2O4@PEG(CFOs)的制备方法，通过双金属的参与，通过设计激发多重治疗方法的协同作用，达到针对肿瘤治疗效果的提升。
本实施方式工艺稳定，方法成熟，反应体系对环境无污染，所提出的工艺路线能成功合成目标复合材料，有着良好的应用前景。高温热解合成的小尺寸CuFe2O4@PEG(CFOs) 纳米球具有优异的形貌，小尺寸有利于细胞摄取。制备的复合材料中，材料亲水性良好且有着低毒性、生物相容性良好的特点，在多种治疗方法的共同作用下，可以提高能量转换效率和治疗效果，且在细胞实验中有着优异的治疗效果。有着良好的应用前景和开拓性的创新引导。
具体实施方式二：本实施方式与具体实施方式一不同的是：步骤一①中所述铜源为乙酰丙酮铜，铁源为乙酰丙酮铁；所述溶剂为三缩四乙二醇。其他步骤及参数与具体实施方式一相同。
具体实施方式三：本实施方式与具体实施方式一或二不同的是：步骤一①中所述铜源和铁源的质量比为1:(0.5～2)，所述铜源和铁源的总质量与溶剂的质量比为1:(50～80)。其他步骤及参数与具体实施方式一或二相同。
具体实施方式四：本实施方式与具体实施方式一至三之一不同的是：步骤一①中所述铜源和铁源的质量比为1:1。其他步骤及参数与具体实施方式一至三之一相同。
具体实施方式五：本实施方式与具体实施方式一至四之一不同的是：步骤一③中所述的离心洗涤是在离心速率为4000r/min～10000r/min的条件下，先用乙醇离心取沉淀，然后用乙酸乙酯离心取沉淀，再用乙醇离心取沉淀。其他步骤及参数与具体实施方式一至四之一相同。
具体实施方式六：本实施方式与具体实施方式一至五之一不同的是：步骤二①中所述的抽滤提纯是通过冰水抽滤，然后再依次利用甲醇、乙酸乙酯、乙二醇进行索式提取。其他步骤及参数与具体实施方式一至五之一相同。
具体实施方式七：本实施方式与具体实施方式一至六之一不同的是：步骤一③与步骤二②中所述的干燥均是在温度为40℃～70℃的真空干燥箱中，干燥12h～24h。其他步骤及参数与具体实施方式一至六之一相同。
具体实施方式八：本实施方式与具体实施方式一至七之一不同的是：步骤二①中所述混合溶液C中CuFe2O4粉体的浓度为0.001g/mL～0.004g/mL，所述混合溶液C中3-氨丙基三乙氧基硅烷与乙醇的体积比为1:125；所述CuFe2O4粉体的质量与3-氨丙基三乙氧基硅烷的体积比为1g:(1～5)mL。其他步骤及参数与具体实施方式一至七之一相同。
具体实施方式九：本实施方式与具体实施方式一至八之一不同的是：步骤二②中所述混合溶液D中NH2-PEG2000-COOH的浓度为0.001g/mL～0.003g/mL；所述CuFe2O4-NH2纳米材料的质量与乙醇的体积为1g:(1000～4000)mL；所述CuFe2O4-NH2纳米材料与 NH2-PEG2000-COOH的质量比为1:(2～5)。其他步骤及参数与具体实施方式一至八之一相同。
具体实施方式十：本实施方式与具体实施方式一至九之一不同的是：步骤二②中制备的聚乙二醇化的CuFe2O4纳米粒子用作针对靶向肿瘤微环境的纳米制剂，在可控的近红外二区光照射下，通过光热增强多酶活性引发的纳米催化治疗。其他步骤及参数与具体实施方式一至九之一相同。
本实施方式应用于生物医学方面治疗肿瘤，将材料注射到生物体内，良好生物相容性的药物通过肿瘤的EPR效应聚集和堆积在肿瘤附近的微环境内。超小型双金属循环纳米酶 CuFe2O4@PEG(CFOs)可用作针对TME的纳米制剂，在可控的近红外二区光(NIR-II) 的照射下，通过光热增强多酶活性(POD、CAT和GPx)引发的纳米催化治疗。存在的双金属离子使CFOs的多酶活性在pH和GSH双重激活下产生剧毒·OH，降低TME的还原性，减轻肿瘤缺氧。在激光照射下，光子热疗协同酶催化效果提高了CFOs的催化活性。提供了良好的肿瘤治疗效果。
根据本实施方式方法可以得到CuFe2O4@PEG(CFOs)纳米复合材料，提供了新的设计思路和工艺流程，合理设计TME反应和ROS介导的纳米催化治疗策略为基础的“三位一体”纳米酶增强抗癌材料。通过良好的治疗效率以及生物体友好性能等方面体现出全新的科研思路和应用前景。
通过以下实施例验证本发明的有益效果：
实施例一：一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法具体是按以下步骤进行的：
一、合成纳米粒子材料：
①将铜源和铁源加入到溶剂中得到混合溶液A；
所述铜源为乙酰丙酮铜，铁源为乙酰丙酮铁；所述溶剂为三缩四乙二醇；所述铜源和铁源的质量比为1:1，所述铜源和铁源的总质量与溶剂的质量比为1:50；
②、将混合溶液A倒入三口烧瓶中，抽真空，在搅拌速率为300r/min的条件磁力搅拌，以5℃/min的升温速率将反应温度从室温升至110℃，在温度为110℃的条件下反应30min，得到混合溶液B；
③、向混合溶液B中通入氮气，以5℃/min的升温速率将反应温度从110℃升温至285℃，在温度为285℃的条件下反应60min，反应结束后降温至室温，然后离心洗涤，干燥，得到黑色的CuFe2O4粉体；离心洗涤是在离心速率为8000r/min的条件下，先用乙醇离心取沉淀，然后用乙酸乙酯离心取沉淀，再用乙醇离心取沉淀；
二、纳米材料的修饰：
①、将CuFe2O4粉体溶解在乙醇中，在搅拌速率为300r/min、温度为45℃的条件下，加入3-氨丙基三乙氧基硅烷，得到混合溶液C，保持搅拌3h，然后抽滤提纯或离心洗涤，干燥，得到CuFe2O4-NH2纳米材料；所述混合溶液C中CuFe2O4粉体的浓度为0.001g/mL，所述混合溶液C中3-氨丙基三乙氧基硅烷与乙醇的体积分别为2mL和250mL；所述CuFe2O4粉体的质量为1g，3-氨丙基三乙氧基硅烷的体积为5mL；
②、将CuFe2O4-NH2纳米材料溶解在乙醇中，在搅拌速率为300r/min、温度为45℃的条件下，加入NH2-PEG2000-COOH，得到混合溶液D，离心收集后依次采用水和乙醇洗涤，得到聚乙二醇化的CuFe2O4纳米粒子，记为CFOs；所述混合溶液D中NH2-PEG2000-COOH 的浓度为0.001g/mL；所述CuFe2O4-NH2纳米材料的质量为1g，乙醇的体积为2000mL；所述CuFe2O4-NH2纳米材料质量为1g，NH2-PEG2000-COOH的质量为2g。
实施例二：一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法具体是按以下步骤进行的：
一、合成纳米粒子材料：
①将铜源和铁源加入到溶剂中得到混合溶液A；
所述铜源为乙酰丙酮铜，铁源为乙酰丙酮铁；所述溶剂为三缩四乙二醇；所述铜源和铁源的质量比为1:1，所述铜源和铁源的总质量与溶剂的质量比为1:70；
②、将混合溶液A倒入三口烧瓶中，抽真空，在搅拌速率为300r/min的条件磁力搅拌，以5℃/min的升温速率将反应温度从室温升至110℃，在温度为110℃的条件下反应30min，得到混合溶液B；
③、向混合溶液B中通入氮气，以5℃/min的升温速率将反应温度从110℃升温至290℃，在温度为290℃的条件下反应60min，反应结束后降温至室温，然后离心洗涤，干燥，得到黑色的CuFe2O4粉体；离心洗涤是在离心速率为8000r/min的条件下，先用乙醇离心取沉淀，然后用乙酸乙酯离心取沉淀，再用乙醇离心取沉淀；
二、纳米材料的修饰：
①、将CuFe2O4粉体溶解在乙醇中，在搅拌速率为300r/min、温度为45℃的条件下，加入3-氨丙基三乙氧基硅烷，得到混合溶液C，保持搅拌3h，然后抽滤提纯或离心洗涤，干燥，得到CuFe2O4-NH2纳米材料；所述混合溶液C中CuFe2O4粉体的浓度为0.001g/mL，所述混合溶液C中3-氨丙基三乙氧基硅烷与乙醇的体积分别为2mL和250mL；所述CuFe2O4粉体的质量为1g，3-氨丙基三乙氧基硅烷的体积为5mL；
②、将CuFe2O4-NH2纳米材料溶解在乙醇中，在搅拌速率为300r/min、温度为45℃的条件下，加入NH2-PEG2000-COOH，得到混合溶液D，离心收集后依次采用水和乙醇洗涤，得到聚乙二醇化的CuFe2O4纳米粒子，记为CFOs；所述混合溶液D中NH2-PEG2000-COOH 的浓度为0.001g/mL；所述CuFe2O4-NH2纳米材料的质量为1g，乙醇的体积为2000mL；所述CuFe2O4-NH2纳米材料质量为1g，NH2-PEG2000-COOH的质量为2g。
图1为实施例一制备的CFOs的XRD图；样品的衍射峰在2θ值31.3°,36.9°,38.6°,44.9°,55.7°,59.4°,和65.3°分别对应于(220)、(311)、(222)、(400)、(422)、 (511)和(440)晶面，它们证实了具有尖晶石结构的CuFe2O4纳米晶体(JCPDS卡号： 77-0010)的形成。获得了高结晶度、纯相的纳米粒子。
图2为实施例一制备的CFOs的TEM图；表明CFOs纳米颗粒具有定义良好的三维纳米结构，且均匀尺寸(8±1nm)；
图3为实施例一制备的CFOs的高分辨透射图；HRTEM可见晶格条纹间距为0.254nm，主要对应于(311)晶面；
图4为实施例一制备的CFOs的电子衍射图；图案中的主要衍射环与CuFe2O4的(220)、 (311)、(400)、(511)和(220)面匹配；
图5为实施例一制备的CFOs的粒径分布统计图；通过图可知纳米粒子的平均直径为 7nm～9nm。
图6为实施例一反应过程中不同阶段产物的zeta电位对比图，其中1为CuFe2O4粉体， 2为CuFe2O4-NH2纳米材料，3为聚乙二醇化的CuFe2O4纳米粒子；通过zeta电位测量的表面电性，材料的初始负电位为-2.83mV，羧基连接后获得较高的正电位，达到+5.90mV，证明该工艺中的修饰改性成功；
图7为实施例一制备的CFOs的XPS能谱图；证实了CFOs样品中Cu、Fe、O的存在；
图8为实施例一制备的CFOs中Cu2p分峰的精细扫描光谱图；由图中可以看出分为两个峰，分别分配给Cu2p3/2(932.82ev)和Cu2p1/2(952.77ev)，证明样品中形成了稳定的Cu2+纳米结构；
图9为实施例一制备的CFOs中Fe3p分峰的精细扫描光谱图；由图中可以看出显示出一个双峰，分别对应于Fe3p1/2(711.23ev)和Fe3p3/2(724.78ev)，证明样品中形成了稳定的Fe3+纳米结构
图10为实施例一制备的CFOs中O2s分峰的XPS光谱图；由图中可以看出分为两个峰，分别为530.51和532.77eV。较高的结合能归因于CuFe2O4相的晶格氧，而较低的结合能则与基体间隙位置的氧空位有关；
图11为TMB作为染料时CFOs的紫外光吸收光谱图，其中1为TMB，2为TMB+H2O2， 3为TMB+CFOs，4为TMB+H2O2+CFOs，5为TMB+H2O2+CFOs+50℃，6为 TMB+H2O2+CFOs+1064nm；本组实验中TMB氧化产物在652nm处有特征吸，分组为： TMB+H2O2+CFOs+1064nm；TMB+H2O2+CFOs+50℃；TMB+H2O2+CFOs；TMB+CFOs； TMB+H2O2。空白组中，TMB或OPD单独与CFOs或H2O2混合时，可忽略的吸光度表明没有发生氧化。而在TMB和H2O2混合溶液中加入CFOs后，其最大吸光度随时间而增加，呈现出明显的颜色，证实了具有OPD活性的CFOs可以催化H2O2生成ROS。 TMB+H2O2+CFOs+50℃是采用50℃水浴加热进行对比验证，其活性氧生成能力增强。 TMB+H2O2+CFOs+1064nm是在1064nm激光照射10min，使混合溶液达到50℃左右时显色吸收显著增加。这些结果表明，1064nm激光照射产生的高温效应确实促进了活性氧的产生，即温度升高促进了CFOs纳米酶的活性；
图12为OPD作为染料时CFOs的紫外光吸收光谱图，其中1为OPD，2为OPD+H2O2， 3为OPD+CFOs，4为OPD+H2O2+CFOs，5为OPD+H2O2+CFOs+50℃，6为 OPD+H2O2+CFOs+1064nm；7为OPD+H2O2+CFOs+pH4.5。OPD氧化产物在417nm处有特征吸收；进一步鉴定了酶活性。
图13为使用DTNB检测实施例一制备的CFOs对谷胱甘肽的消耗随着时间变化的紫外吸收光谱；时间检测范围是0min～14min；随着时间的变化紫外吸收峰逐渐降低，谷胱甘肽被持续消耗；
图14为100μg mL-1CFOs+100μLH2O2+TMB随时间变化的紫外吸收光谱，显示了随时间，材料对过氧化氢持续分解产生活性氧的能力；
图15为100μLH2O2+TMB在不同浓度材料浓度条件下的紫外光谱图；可见随着底物浓度的增加，材料的反应速率也在增加；
图16为100μg mL-1CFOs+TMB在不同量过氧化氢的条件下的紫外光谱图；催化过程的效率也与底物H2O2的浓度密切相关，即随着H2O2浓度的增加，指示剂的特征吸光度也均匀增加；
图17为实施例一制备的CFOs对GSH的分解随着时间不同的紫外光谱图；由紫外光谱表征获得的结果；具有CAT活性的纳米酶能催化H2O2分解为H2O，同时释放O2，具有很高的缓解TME缺氧的潜力。纳米酶的GPx活性可促进GSH的消耗，从而清除产生的ROS，影响治疗效果。测定CFOs的CAT活性，DTNB与GSH的巯基发生反应，在412nm处出现紫外吸收峰，测定了黄色的5,5'-二硫代二(2-硝基苯甲酸)产物。结果表明，在CFOs的催化作用下，GSH在6h内被有效消耗；
图18为pH 6.5+H2O2+CFOs与pH 6.5+CFOs不同时间下的产氧对比曲线，其中1为pH6.5+H2O2+CFOs，2为pH 6.5+CFOs；通过溶氧仪测试，获得的不同时间下的产生氧气的结果，分组为pH 6.5+H2O2+CFOs与pH 6.5+CFOs；结果显示随着时间的延长，CFOs参与后的产氧量显著增加，说明材料能有效缓解缺氧环境；
图19为在不同的pH以及温度下实施例一制备的CFOs的产氧性能对比曲线，其中1为pH 6.0+45℃，2为pH 7.2，3为pH 6.5，4为pH 4.5；可以证明在光热增强POD活性的基础上，也在一定程度上证明了加热对CAT和GPx活性的增强作用；
图20为实施例一制备的CFOs采用DMPO捕捉剂获得的ESR对比谱图，其中1为 DMPO+H2O2+CFOs，2为DMPO+H2O2；通过ESR测试图，分组为DMPO+H2O2+CFOs与 DMPO+H2O2；近一步研究了ROS的具体类型。使用DMPO作为捕集剂检测到·OH的1:2:2:1 特征峰；
图21为实施例一制备的CFOs在不同浓度下的紫外吸收光谱，其中1为100μg mL-1，2为200μg mL-1，3为300μg mL-1，4为400μg mL-1；检测不同浓度材料的紫外吸收光谱曲线，可以显示CFOs作为光热转换剂的潜力；
图22为实施例一制备的CFOs暴露于1064nm激光下的潜在良好光热转换效果机理图；
图23为实施例一制备的CFOs热红外成像对比图，由不同浓度(100、200、300、400和500μg mL-1)在1.0W cm下辐照获得的热红外图像可知，样品的温度随光照射时间的延长而升高；
图24为不同浓度实施例一制备的CFOs在1.0W cm-2激光照射下的升温曲线图，其中1为空白对照，2为100μg mL-1，3为200μg mL-1，4为300μg mL-1，5为400μg mL-1，6 为500μgmL-1；分组为不同浓度的CFOs水溶液(100、200、300、400和500μg mL-1)在 1.0W cm-2激光照射下获得的相应的温升曲线。10min后，CFOs浓度越大，溶液温度升高越快。当其浓度为500μg mL-1时，温度升高了30℃、具有良好的光热转换能力；
图25为不同功率的激光器激发实施例一制备的CFOs获得的升温曲线图，其中1为0.6 W cm-2，2为0.8W cm-2，3为1.0W cm-2，4为1.2W cm-2，5为1.4W cm-2；(0.6、0.8、1.0、1.2、1.4W cm-2)结果表明，温度的提高不仅与CFOs的浓度有关，而且与激光器的功率密度有关；
图26为实施例一制备的CFOs单循环的升温降温温度变化曲线图；激光照射10分钟后关闭激光器，溶液自然冷却至初始温度；
图27为光热转换效率关系图。根据-lnθ的线性时间数据可以得到τ＝283.63秒。根据方程可知，该材料具有较高的转换效率，光热转换效率为41.12％；
图28为实施例一制备的CFOs进行5个周期的激光开关测量获得的升温降温曲线图。检测了CFOs的光稳定性，循环期间没有明显的温度升高或衰减说明材料的光热稳定性良好。

Claims (10)

1.一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于具有抗肿瘤效应的双金属纳米酶复合材料的制备方法具体是按以下步骤进行的：
一、合成纳米粒子材料：
①将铜源和铁源加入到溶剂中得到混合溶液A；
②、将混合溶液A倒入三口烧瓶中，抽真空，在搅拌速率为200r/min～400r/min的条件磁力搅拌，以3℃/min～10℃/min的升温速率将反应温度从室温升至90℃～120℃，在温度为90℃～120℃的条件下反应20min～60min，得到混合溶液B；
③、向混合溶液B中通入氮气，以3℃/min～10℃/min的升温速率将反应温度从90℃～120℃升温至250℃～290℃，在温度为250℃～290℃的条件下反应20min～60min，反应结束后降温至室温，然后静置过滤或离心洗涤，干燥，得到黑色的CuFe2O4粉体；
二、纳米材料的修饰：
①、将CuFe2O4粉体溶解在乙醇中，在搅拌速率为200r/min～400r/min、温度为30℃～60℃的条件下，加入3-氨丙基三乙氧基硅烷，得到混合溶液C，保持搅拌1h～5h，然后抽滤提纯或离心洗涤，干燥，得到CuFe2O4-NH2纳米材料；
②、将CuFe2O4-NH2纳米材料溶解在乙醇中，在搅拌速率为200r/min～400r/min、温度为30℃～60℃的条件下，加入NH2-PEG2000-COOH，得到混合溶液D，离心收集后依次采用水和乙醇洗涤，得到聚乙二醇化的CuFe2O4纳米粒子。
2.根据权利要求1所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤一①中所述铜源为乙酰丙酮铜，铁源为乙酰丙酮铁；所述溶剂为三缩四乙二醇。
3.根据权利要求2所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤一①中所述铜源和铁源的质量比为1:(0.5～2)，所述铜源和铁源的总质量与溶剂的质量比为1:(50～80)。
4.根据权利要求3所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤一①中所述铜源和铁源的质量比为1:1。
5.根据权利要求1所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤一③中所述的离心洗涤是在离心速率为4000r/min～10000r/min的条件下，先用乙醇离心取沉淀，然后用乙酸乙酯离心取沉淀，再用乙醇离心取沉淀。
6.根据权利要求1所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤二①中所述的抽滤提纯是通过冰水抽滤，然后再依次利用甲醇、乙酸乙酯、乙二醇进行索式提取。
7.根据权利要求1所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤一③与步骤二②中所述的干燥均是在温度为40℃～70℃的真空干燥箱中，干燥12h～24h。
8.根据权利要求1所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤二①中所述混合溶液C中CuFe2O4粉体的浓度为0.001g/mL～0.004g/mL，所述混合溶液C中3-氨丙基三乙氧基硅烷与乙醇的体积比为1:125；所述CuFe2O4粉体的质量与3-氨丙基三乙氧基硅烷的体积比为1g:(1～5)mL。
9.根据权利要求1所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤二②中所述混合溶液D中NH2-PEG2000-COOH的浓度为0.001g/mL～0.003g/mL；所述CuFe2O4-NH2纳米材料的质量与乙醇的体积为1g:(1000～4000)mL；所述CuFe2O4-NH2纳米材料与NH2-PEG2000-COOH的质量比为1:(2～5)。
10.根据权利要求1所述的一种具有抗肿瘤效应的双金属纳米酶复合材料的制备方法，其特征在于步骤二②中制备的聚乙二醇化的CuFe2O4纳米粒子用作针对靶向肿瘤微环境的纳米制剂，在可控的近红外二区光照射下，通过光热增强多酶活性引发的纳米催化治疗。
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