CN115624980B - 一种金属硒基生物催化材料及其制备方法和用途 - Google Patents
一种金属硒基生物催化材料及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种金属硒基生物催化材料及其制备方法和用途,属于催化材料领域。本发明提供一种金属硒基生物催化材料,所述催化材料为Ru掺杂的CoSe纳米粒子,命名为Ru@CoSe。本发明所得的催化材料具有优异的类CAT酶活性,最大反应速率Vmax为23.05µM s‑1,转化数TON为2.00 s‑1。所得Ru@CoSe在氧化应激环境下可以有效地保护间充质干细胞的增殖与血管生成的潜力;体内实验表明Ru@CoSe对糖尿病炎性创面展现出优异的ROS消除能力;即本发明为催化活性氧清除和炎症伤口的超快愈合提供了一种有效的纳米药物。
Description
技术领域
本发明涉及一种金属硒基生物催化材料及其制备方法和用途,属于催化材料领域。
背景技术
伴随着炎性和难治愈性伤口的糖尿病溃疡是糖尿病的并发症之一,会显著增加糖尿病患者的截肢率和死亡率。高度受限的自我恢复能力以及病变区域的复杂性和易感性(上调的促炎因子、高血糖、缺氧、过表达活性氧(ROS)、血管病变等)给糖尿病溃疡的治疗带来了巨大挑战。传统的临床治疗策略,如高压氧治疗、血糖控制和使用抗生素抗感染等,可以在一定程度上缓解溃疡区域的缺氧与血管病变等。但它们的低治愈率和高复发率使广大患者无法得到充分且有效的治疗。糖尿病溃疡创面的难愈合能力主要归因于伤口处的高活性氧(ROS)水平、氧化应激效应和炎症反应的微环境,干细胞的不良增殖和分化以及许多其他功能细胞的退化。因此,开发具有ROS清除能力的制剂来缓解氧化应激和炎症环境为促进炎性和难治性伤口的愈合提供了新的策略,其中包括抗氧化纳米结构(邻苯二酚基聚合物、碳纳米材料、小分子还原剂等)和类抗氧化酶材料。
近年来,由于类抗氧化酶生物催化剂具有维持氧化还原平衡的高效生物催化活性、低抗原性、给药后的高稳定性和大规模生产等优点,人们对可以模拟天然抗氧化酶(过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GPx)和超氧化物歧化酶(SOD))功能的过渡金属化合物和金属纳米颗粒这类生物催化剂产生了极大的兴趣。尽管近年来在探索活性氧清除材料方面取得了令人兴奋的创新,但发掘具有快速且广谱ROS清除能力的类抗氧化酶催化结构仍然是一个巨大的挑战。目前报道的类抗氧化酶生物催化剂大多基于金属化合物,因为它们具有高生物降解性和良好的生物相容性,如Co3O4、MnO2、CeO2/Mn3O4纳米晶体、和Pt掺杂的CeO2。然而,与天然抗氧化剂相比,目前大多数基于金属化合物的ROS清除材料具有较差的催化效率,因此,通常需要高剂量使用。
H2O2或氧自由基的ROS催化过程常涉及多电子转移反应、复杂中间体的形成以及最终氧物种的脱附的高能量消耗等。天然抗氧化剂可以通过其独特的轴向配位结构和三维空间构型来调节这些复杂的氧化还原反应。然而,目前已经报道的基于金属化合物的抗氧化酶类生物催化剂很难模拟这种复杂的生物化学过程,主要归因于其配位的电负性原子的金属活性中心较差的可逆氧化还原性能。因此,寻找一种合适的策略来克服不平衡的多电子反应,实现具有超快动力学的可逆催化循环是至关重要的。在各类金属化合物中,过渡金属硒化物由于其较高的金属性和可调的带隙、原子环境和电子结构等优点,已成为新型的替代现有金属氧化物进行各种催化反应的催化材料。但纯金属硒化物也伴随着催化活性低和广谱清除能力差等固有缺点。因此,开发一种新的策略来调节金属硒化物中催化原子的配位结构和成键微环境,以获得多方面和高效的ROS清除能力至关重要。目前关于这一领域的研究几乎还未被探索。
发明内容
针对上述问题,本发明提供一种具有表面非晶化纳米层的金属硒基生物催化材料及其制备方法和用途,所述金属硒基活性催化材料为具有非晶态单原子Ru掺杂CoSe的纳米层的硒化钴基生物催化剂,命名为Ru@CoSe。由于Ru原子的富集电子和更多的未占据轨道,使其在催化ROS清除的反应中充当“电子调节剂”的作用,能有效调节Co位点的电子状态,从而改善活性位点的可逆氧化还原特性,使得所制备的催化材料Ru@CoSe生物催化剂对H2O2、·O2 -、和DPPH·均具有优异的催化清除活性。且Ru@CoSe显示出优异的类CAT酶的反应动力学:最大反应速率(Vmax)为23.05μM s-1,转化数(TON)为2.00s-1,这表明所制备的金属硒基活性催化材料具有超快和优异的催化活性。此外,系统的细胞实验研究表明Ru@CoSe在氧化应激环境下可以有效地保护人骨髓间充质干细胞(hMSCs)的增殖与血管生成的潜力;体内实验表明Ru@CoSe对糖尿病炎性创面展现出优异的ROS消除能力。
本发明的技术方案:
本发明要解决的第一个技术问题是提供一种金属硒基生物催化材料,所述催化材料为Ru掺杂的CoSe纳米粒子,命名为Ru@CoSe。
进一步,所述金属硒基生物催化材料中,CoSe与Ru的摩尔比为:CoSe:Ru=5:1~40:1,例如为5:1、10:1、20:1、30:1、40:1,优选5:1~20:1,最优为10:1。
进一步,所述金属硒基生物催化材料的最大反应速率(Vmax)为23.05μM s-1。
进一步,所述金属硒基生物催化材料的转化数(TON)为2.00s-1。
进一步,所述金属硒基生物催化材料的微观结构为:CoSe晶体的表面上形成含有均匀分布Ru单原子的非晶CoSe层。
本发明要解决的第二个技术问题是提供上述金属硒基生物催化材料的制备方法,所述制备方法为:钴盐、钌盐和硒酸盐通过溶剂配位分子模板法合成。
进一步,所述金属硒基生物催化材料的制备方法如下:将钴盐、钌盐和硒酸盐在去离子水中混匀,再加入溶剂和还原剂,室温下搅拌10~40min,然后将反应体系置于反应釜中于170~190℃反应14~16h,随后通过离心获得黑色产物;最后将所得产物经洗涤干燥制得所述催化材料Ru@CoSe;其中,钴盐与钌盐的摩尔比为5:1~40:1,钴盐与硒酸盐的摩尔比为1:1。
进一步,所述钴盐与去离子水的比例为:1mmol:50~70mL,所述钴盐与溶剂的比例为:1mmol:10~30mL,所述钴盐与还原剂的比例为:1mmol:0.5~2mL。
优选的,所述钴盐为CoCl2·6H2O,所述钌盐为RuCl3·xH2O,所述硒酸盐为Na2SeO3。
进一步,所述溶剂为二亚乙基三胺(DETA)或三乙烯四胺(TETA);所述还原剂为水合肼(N2H4·H2O)或硼氢化钠。
本发明要解决的第三个技术问题是指出上述金属硒基生物催化材料Ru@CoSe在清除活性氧、保护干细胞或促进内皮细胞血管化中的用途。进一步,所述干细胞为间充质干细胞,优选为人骨髓间充质干细胞。
本发明要解决的第四个技术问题是指出上述金属硒基生物催化材料Ru@CoSe在制备治疗神经外伤、心肌梗塞、类风湿性关节炎、骨缺损、糖尿病足、心肌缺血再灌注损伤、卵巢早衰、肺纤维化或溃疡性结肠炎等疾病的药物中的用途。
本发明的有益效果:
本发明开发了一种具有非晶态单原子Ru掺杂CoSe的纳米层的硒化钴基生物催化剂,命名为Ru@CoSe。本发明所得的催化材料具有优异的类CAT酶活性,较好的反应动力学性能:最大反应速率Vmax为23.05μM s-1,转化数TON为2.00s-1。本发明所得Ru@CoSe在氧化应激环境下可以有效地保护间充质干细胞的增殖与血管生成的潜力;体内实验表明Ru@CoSe对糖尿病炎性创面展现出优异的ROS消除能力;即本发明为催化活性氧清除和炎症伤口的超快愈合提供了一种有效的纳米药物,并通过引入无定形催化结构为设计生物催化金属化合物提供了一条新途径。
附图说明
图1为本发明Ru1/10@CoSe的合成示意图以及其结构示意图。
图2为:(a)CoSe,(b)Ru1/5@CoSe,(c)Ru1/10@CoSe,(d)Ru1/20@CoSe,(e)Ru1/30@CoSe和(f)Ru1/40@CoSe的SEM图。
图3为本发明实施例1~5所得Ru1/5@CoSe、Ru1/10@CoSe、Ru1/20@CoSe、Ru1/30@CoSe和Ru1/40@CoSe的XRD图。
图4为本发明实施例1与对比例6的TEM图像:(a)CoSe NPs和(d)Ru1/10@CoSe NPs的TEM图;(b,c)CoSe NPs和(e,f)Ru1/10@CoSe NPs的HRTEM图;Ru1/10@CoSe NPs比纯CoSe NPs有一层额外的非晶态表面积。
图5为:(a)实施例1所得Ru1/10@CoSe的高角度环形暗场扫描透射电子显微镜(HAADF-STEM)图;(b)Ru1/10@CoSe结晶区域的原子阵列的HAADF-STEM图;(c)Ru1/10@CoSe非晶层的高分辨率HAADF-STEM图;(d)从(c)中的区域1~3中用白色矩形突出显示的区域获得的相应强度分布图。
图6为:(a)Ru1/10@CoSe的STEM光谱成像以显示Co、Se和Ru元素的分布图,(b-d)分别指Co、Ru和Se元素的分布图,K和L指不同元素对应壳层电子的激发。
图7为Ru1/10@CoSe电子结构分析结果图:(a-c)分别为CoSe和Ru1/10@CoSe在(a)Ru3p,(b)Se 3d,和(c)Co 2p区域的高分辨XPS谱图;(d)为CoSe和Ru1/10@CoSe的拉曼光谱图。
图8为CoSe和Ru1/10@CoSe的清除活性氧的性能统计图:(a)CoSe和Ru1/10@CoSe的类酶活性和自由基清除能力的雷达图;(b,c)是CoSe和Ru1/10@CoSe的类CAT酶活性测试图,分别为(b)H2O2消除的能力曲线图和(c)O2的生成能力曲线图;(d)CoSe和Ru1/10@CoSe的最大反应速率Vmax和米氏常数Km值的柱状图;(e)为CoSe和Ru1/10@CoSe的类GPx酶活性的曲线图;(f)为CoSe和Ru1/10@CoSe对·O2 -和DPPH·自由基的清除率的结果图;其中对照组指:没有加入任何催化材料(CoSe和Ru1/10@CoSe)的空白对照组;本发明中,所有提到的对照组均指没有添加生物催化剂材料的空白对照组,其他测试、培育等条件相同;n=3个独立实验,数据表示为平均值±SD。
图9为不同Ru1/10@CoSe浓度的类酶活性以及自由基清除能力图:(a)是不同Ru1/10@CoSe浓度的类CAT酶活性测试图,30min时H2O2的相对清除率结果图;(b)是不同Ru1/10@CoSe浓度对DPPH·自由基的清除率的结果图;n=3个独立实验,数据表示为平均值±SD。
图10为具有不同Co/Ru摩尔比(5:1、10:1、20:1、30:1、40:1)的Rux@CoSe NPs酶模拟性质:(a,b)表示Rux@CoSe NPs的类CAT酶活性,分别为(a)H2O2消除的能力曲线图和(b)30min时H2O2的相对清除率结果图;(c)表示Rux@CoSe NPs的类GPx酶活性图,相对应的NADPH的消耗速率值的统计图;n=3个独立实验,数据表示为平均值±SD。
图11为实施例1和对比例1~4所得催化剂的类CAT酶活性统计结果图。
图12为hMSCs不同浓度的CoSe和Ru1/10@CoSe共孵育后通过CCK-8测定的存活率结果图,n=4个独立实验,数据表示为平均值±SD。
图13为hMSC与CoSe和Ru1/10@CoSe共孵育后的活/死荧光染色图,绿色信号代表活细胞,红色信号代表死细胞;比例尺:100μm。
图14为CoSe和Ru1/10@CoSe在高氧化应激下对干细胞的保护能力的测试:(a)为不同组处理后,使用DCFH-DA探针检测hMSC细胞内ROS水平的荧光图;(b)为相对应的DCFH-DA荧光强度的统计图;(c)F-肌动蛋白和黏着斑Vinculin蛋白染色图来说明高ROS水平下的hMSCs的细胞骨架与粘附情况图。
图15为高ROS水平培养基中与不同样品孵育14天后hMSCs向内皮细胞分化后对特异性蛋白-CD31的荧光染色图;对照组hMSCs在内皮细胞基础培养基-2中培养,不添加H2O2;其余组在含100μM H2O2的内皮基础培养基-2中培养。
图16为高ROS水平培养基中与不同样品孵育14天后hMSCs向内皮细胞分化后对特异性蛋白-CD34的荧光染色图;对照组hMSCs在内皮细胞基础培养基-2中培养,不添加H2O2;其余组在含100μM H2O2的内皮基础培养基-2中培养。
图17为已内皮分化的hMSCs的小管形成能力测定的代表性图像;对照组hMSCs在内皮细胞基础培养基-2中培养,不添加H2O2;其余组在含100μM H2O2的内皮基础培养基-2中培养。
图18为Ru1/10@CoSe对促进糖尿病炎性创面愈合的治疗作用图:(a)在第0天、第5天、第9天和第11天不同治疗手段下伤口区域的代表性图;(b)不同处理后创面大小的时间演化图;(c)第11天,不同处理组的表皮组织学切片的H&E和Masson染色图。
图19为第11天时,不同处理组的表皮组织学切片的ROS水平:DCFH-DA染色,炎性因子IL-1β和TNF-α,内皮细胞的表达CD31,和细胞增殖情况-Ki67的荧光染色图。
图20为11天后不同处理后的糖尿病兔内脏组织切片的H&E染色图。
具体实施方式
本发明开发了一种具有非晶态单原子Ru掺杂CoSe的纳米层的硒化钴基生物催化剂,命名为Ru@CoSe,用于超快和广谱催化ROS清除。由于Ru原子的富集电子和更多的未占据轨道,使其在催化ROS清除的反应中充当“电子调节剂”的作用,能有效调节Co位点的电子状态,从而改善活性位点的可逆氧化还原特性,使得所制备的催化材料具有优异的类CAT酶活性,较高的最大反应速率Vmax(23.05μM s-1)以及转化数TON(2.00s-1)。同时所制备的Ru@CoSe在氧化应激环境下可以有效地保护间充质干细胞的增殖与血管生成的潜力,并对糖尿病炎性创面展现出优异的ROS消除能力。
本发明实施例、对比例及试验例中,所使用的试剂均为如下来源:六水合氯化钴(II)(CoCl2·6H2O)、二乙烯三胺(DETA)和水合肼(N2H4·H2O)从阿拉丁获得。亚硒酸钠(Na2SeO3)购自Alfa Aesar。氯化钌(III)水合物(RuCl3·xH2O)由安耐吉化学生产。实验中使用的纯水(18.2MΩ·cm)来自Milli-Q学术系统(Millipore Corp.,Billerica,MA,USA)。所有化学品无需进一步纯化,直接使用。
下面结合实施例对本发明的具体实施方式做进一步的描述,并不因此将本发明限制在所述的实例范围之中。
实施例1~5Rux@CoSe的制备:
将1mmol CoCl2·6H2O和0.1mmol RuCl3·xH2O分散到60mL去离子水中;在磁力搅拌下向上述溶液中加入1mmol Na2SeO3搅拌至全溶;然后在磁力搅拌下将20mL DETA和1mLN2H4·H2O缓慢加入上述溶液,待混合均匀便将上述混合溶液转移到带特氟隆衬里的高压釜中,并在180℃下反应15小时;最后通过无水乙醇和蒸馏水离心(10000rpm,6分钟)洗涤获得最终的黑色产物并在60℃的在真空烘箱中干燥制得Ru1/10@CoSe纳米颗粒;本发明Ru1/10@CoSe的合成示意图以及其结构示意图如图1所示。
本发明还通过改变Ru/Co的摩尔比,合成了一系列不同Ru含量掺杂CoSe的纳米粒子(NP),命名为Rux@CoSe。改变CoCl2·6H2O与RuCl3·xH2O的摩尔比,Co/Ru摩尔比分别为5:1(实施例2)、20:1(实施例3)、30:1(实施例4)和40:1(实施例5),所得样品分别记为Ru1/5@CoSe,Ru1/20@CoSe,Ru1/30@CoSe和Ru1/40@CoSe。
对比例1~5:
将实施例1中的RuCl3·xH2O分别替换为MnCl2·xH2O、FeCl3·6H2O、IrCl3·xH2O、OsCl3·xH2O和PtCl4;其他制备过程同实施例1。
对比例6:不加入实施例1中的RuCl3·xH2O,其他制备过程同实施例1。
试验例1 Ru@CoSe的合成表征:
使用Thermo Fisher Scientific(FEI)Apreo S HiVoc获得扫描电子显微镜(SEM)图像,金涂层约1nm。由Tecnai G2 F20 S-TWIN在200kV下操作获得透射电子显微镜(TEM)图像。采用X射线衍射仪(XRD,DX-2700BH,中国昊源仪器公司),在Cu Kα辐射范围为10~80°的2θ条件下分析了催化剂的晶体结构。在K-AlphaTM+X射线光电子能谱仪系统(ThermoScientific)上使用带有128通道探测器的半球180°双聚焦分析仪进行X射线光电子能谱(XPS)检测Ru@CoSe的价态和电子结构。扫描透射电子显微镜(STEM)图像和能量色散X射线能谱(EDX)元素映射是在cs校正的STEM(FEI Titan Cubed Themis G2300)上获得的。
本发明实施例1~5所得Rux@CoSe(x=1/5、1/10、1/20、1/30、1/40)的SEM结果如图2a-f所示,由图可知本发明所得的Rux@CoSe呈纳米级颗粒状。粉末X射线衍射谱图(PXRD)表示Rux@CoSe显示出与CoSe相似的晶体结构(PDF#97-005-3959),揭示了Ru的引入不会改变CoSe的晶体相或形成晶体分离的双相结构,且特征峰的强度随着Ru含量的增加而逐渐减小(图3),表明Ru含量的增加使得材料的无定型化增加。
本发明实施例1所得Ru1/10@CoSe(本发明后续性能测试主要是对Ru1/10@CoSe进行的测试,除非另有规定,下文中的Ru@CoSe均指Ru1/10@CoSe)的TEM图像、高分辨率TEM(HRTEM)图像和高角度环形暗场扫描透射电子显微镜(HAADF-STEM)图像如图4、5所示。首先TEM图像(图4a,d)验证对比了Ru1/10@CoSe NPs的颗粒的形态,HRTEM图像(图4b,e)显示清晰的CoSe的(101)晶面的晶格条纹,未观察到Ru相关相的痕迹,这与PXRD图谱一致。此外,图4c,f显示,与CoSe NPs相比,Ru1/10@CoSe NPs的表层多了一层额外的无定形区域。其次,通过HAADF-STEM图像描述了Ru1/10@CoSe NPs的原子分辨率结构。如图5a所示,Ru1/10@CoSe NPs的结晶区域被非晶态纳米层(黑色)包围,与HRTEM图像结果一致。Ru1/10@CoSe的纳米晶体区域的原子分辨率STEM图像(图5b)显示出规则和明亮的CoSe原子阵列,其非晶层的子分辨率STEM图像(图5c)观察到无序排列的Co、Se原子并带有一些较亮的原子,可以区分为表面上的Ru原子;HADDF图像的线轮廓(图5d)显示了原子柱强度的变化,表明Ru原子以单原子的形式在非晶层中随机分布。原子水平的选定区域能量色散X射线光谱(EDX)元素映射(图6a)进一步证实了非晶CoSe层中均匀分布的Ru原子,图6b-d分别指Co、Ru和Se元素的分布图,K和L指不同元素对应壳层电子的激发。可见,本发明中Ru的引入导致CoSe表面的非晶化,并且在CoSe晶体的表面上形成包含Ru单原子的非晶CoSe层。
采用X射线光电子能谱(XPS)来进一步了解Ru1/10@CoSe生物催化剂的化学和电子结构。如图7a中Ru1/10@CoSe的Ru 3p3/2的结合能位于461.74eV,可证实带部分正电荷的Ru原子可能以Ru-Se键的形式存在。图7b,c中Ru1/10@CoSe的Co 2p和Se 3d谱图显示,与裸CoSe相比,Ru1/10@CoSe的Se 3d和Co 2p峰都表现出向高结合能方向偏移,这主要归因于Ru原子的掺杂导致的整体电子密度增加。Ru1/10@CoSe的高分辨率Co 2p光谱显示,与CoSe相比,Ru1/10@CoSe表面硒化峰的强度有所降低,Co处于更高的氧化态(图7c)。此外,拉曼光谱证实Ru原子和CoSe基底之间的电子转移(图7d)。
试验例2类酶活性和ROS清除活性的评估:
(1)自由基清除测试:
1.1DPPH·清除试验:
通过测量519nm处的吸收波长来评估本发明所得生物催化剂对1,1-二苯基-2-苦基肼自由基(DPPH·)的清除能力。将总共50μg/mL的DPPH·乙醇溶液和一定浓度的生物催化剂(50μg/mL)混合并定容至2mL;然后将混合溶液静止反应10min后测试λmax=519nm处的吸光度;此外,还测试了不同催化剂浓度(25、50、75、100和125μg/mL)对DPPH·清除性能的影响。
1.2·O2 -清除试验:
将1mg KO2溶解于1mL二甲基亚砜溶液(DMSO,含3mg/mL 18-冠-6-醚)中,以生成并稳定·O2 -;然后,将Ru1/10@CoSe以50μg/mL的最终浓度分散到上述KO2/DMSO溶液中;反应5分钟后,残余·O2 -将被硝基蓝四唑(NBT)-DMSO溶液(10μL,10mg/mL)捕获;测量680nm处溶液的吸光度,然后与·O2 -的原始浓度进行比较得到·O2 -的清除能力。
(2)类CAT酶测试:
2.1H2O2清除:
将总计10mM H2O2和50μg/mL的Ru1/10@CoSe在PBS(pH=7.4)中混合至2mL;然后,将50μL上述溶液与硫酸钛溶液(100μL,13.9mM)混合,每隔10分钟记录一次405nm处的吸光度值,直至反应60分钟;在反应至30分钟时,测试溶液在405nm处的吸光度以评估生物催化剂的H2O2清除能力。
2.2O2生成测定:
将总计100mM H2O2和10μg/mL的Ru1/10@CoSe在PBS(pH=7.4)中混合至20mL,然后使用溶解氧计(INESA,JPSJ-605F)每隔5秒测量O2浓度,直至300s。为了分析O2生成的生物催化动力学,将10μg/mL的生物催化剂和不同浓度的H2O2(分别为100、200、300、400、500和600mM)在PBS中混合以获得20mL,然后每隔5秒测量O2浓度,直至100s。根据相应的H2O2浓度绘制反应速率,然后用Michaelis–Menten曲线拟合;此外,使用线性双倒数图(Lineweaver–Burk图)确定最大反应速度(Vmax)和米氏常数(Km)。最后,计算周转数(TON,每单位活性催化中心的最大转化底物数)。
(3)类GPx酶测试:
向775μL PBS(pH=7.4)中添加100μL GR(17U/mL)、62μL GSH(10mg/mL)、33μLNADPH(10g/mL)、50μg/mL生物催化剂和25μL H2O2(0.01M)。通过监测代表NADPH浓度的340nm处吸光度的变化来评估催化剂的类GPx酶的活性。反应动力学分析过程通过在动力学模式下(5分钟,60次)由UV-vis分光光度计监测的340nm处的吸光度变化来反映。
本发明实施例1和对比例6所得生物催化剂的酶活性和自由基清除能力结果如图8a-f所示;由图可知:CoSe的H2O2清除效率为16.6%(反应30分钟),而Ru原子的引入使H2O2去除率提高了5.03倍,达到83.6%(图8b)。同时,氧气生成测试也验证了Ru1/10@CoSe生物催化剂可以有效分解H2O2底物以产生大量O2(图8c)。随后计算了米氏常数(Km)、最大反应速度(Vmax)和转化数(TON,每单位活性催化原子转化底物的最大数量)的值。如图8d所示,与CoSe相比,Ru1/10@CoSe显示更大的Vmax(23.05μM s-1)和更高的TON(2.00s-1),表明Ru1/10@CoSe呈现了更有效的H2O2催化动力学。随后,本发明系统地将Ru1/10@CoSe与最新报道的活性氧清除材料,包括RuTe NRs、Co3O4 NPs、Cu5.4O、Pd八面体、Au24Cu1等的Vmax和TON值进行了比较(表1),结果表明Ru1/10@CoSe在这些已建立的生物催化剂中表现出最佳的类CAT酶活性;此外Ru1/10@CoSe对H2O2的清除和氧气的产生呈现出剂量依赖性(图9a)。
除了CAT,GSH依赖性GPx对维持细胞内稳态也至关重要,在GSH的参与下,细胞的内稳态可以将H2O2分解为H2O。这种催化过程可以通过谷胱甘肽还原酶(GR)偶联分析和NADPH浓度的降低来监测。如图8e所示,Ru1/10@CoSe显示出略微优异的类GPx酶活性,表明Ru的引入略微改善了CoSe基底的类GPx酶活性。
SOD酶还通过催化清除·O2 -在anti-ROS系统中发挥重要作用。本发明采用硝基四唑蓝氯化物法研究了所制备的催化剂对·O2 -自由基的清除能力。有趣的是,CoSe和Ru1/10@CoSe都表现出显著的·O2 -清除效率(5分钟内清除率达到~80%),表明非晶态Ru@CoSe纳米层没有影响其类SOD酶催化活性(图8f)。DPPH·是评价生物催化剂对RNS清除能力的常用试剂。如图8f和9b所示,Ru1/10@CoSe对DPPH·自由基的清除具有剂量依赖性,且清除效率明显高于CoSe。综上所述,本发明揭示了Ru@CoSe生物催化剂比原始CoSe表现出了更强的类CAT酶催化活性,且原子Ru的引入也提高了类GPx酶活性和RNS的清除率。
本发明实施例1~5和对比例6所得生物催化材料的酶模拟特性测试结果如图10所示,图10(a,b)表示Rux@CoSe NPs的类CAT酶活性;图10(c)表示Rux@CoSe NPs的类GPx酶活性图;表明Ru1/10@CoSe NP表现出最佳性能。本发明实施例1和对比例1~6所得生物催化剂材料的酶模拟特性测试结果如图11所示,图中Ru代表本发明实施例1,其他各金属代表对比例1~5。
表1本发明实施例1所得催化剂与现有技术报道的其他生物催化剂的比较
试验例3生物实验测试:
从Cyagen Biosciences(HUXMA-01001,Cyagen,中国)购买的人骨髓源性间充质干细胞(hMSCs),并在37℃、5%CO2条件下的人骨髓间充质细胞生长培养基(HUXM-90011,中国)中传代培养。随后将第四代至第六代的细胞以5000个细胞/孔的密度接种到48孔板上,培养过夜后进行处理。
首先,在模拟ROS环境(100μM H2O2)中检测了本发明所制备的生物催化剂(Ru1/10@CoSe和CoSe)对间充质干细胞(hMSCs)的生物相容性。如图12,Ru1/10@CoSe在工作浓度(1~10μg mL-1)下没有明显的细胞毒性,后续实验以5μg m L-1作为最佳浓度。同时,活/死染色显示,在浓度为5μg mL-1的生物催化剂组中几乎没有观察到死细胞(图13)。随后,使用2,7-二氯荧光素二乙酸酯(DCFH-DA)探针来定量检测生物催化剂对hMSCs细胞内ROS的清除效率。如图14a,b所示,在组I(100μM H2O2)中观察到明显的ROS信号(绿色细胞成形物体),而在用生物催化剂处理后,检测到的ROS信号显著降低,特别是对于Ru1/10@CoSe组,表明Ru1/10@CoSe可以有效清除细胞内的ROS。上述结果表明Ru1/10@CoSe在5μg mL-1的浓度下具有有效的ROS清除能力,可用于调节高ROS水平下的干细胞的生存、增殖与分化等。
由于ROS不仅会导致细胞凋亡,还会影响细胞骨架的排列和粘附蛋白的表达,从而抑制细胞运动、增殖和分化。因此,在验证Ru1/10@CoSe具有保护hMSCs免受ROS攻击的能力后,进一步评估了其对hMSCs扩散和粘附的影响。如图14c所示,经H2O2处理的hMSCs的扩散较差,形态异常,骨骼组织和突起物很少。相比之下Ru1/10@CoSe培养的hMSCs呈现扩张和扁平的形态,细胞骨架组织良好。此外,为了评估扩散区域的变化,本发明还研究了影响细胞迁移和扩散的黏着斑结构,这是连接肌动蛋白细胞骨架和细胞外基质的关键元素。如图14c中的Vinculin染色所示,H2O2处理的hMSCs的黏着斑表达较少,且主要分布在细胞核周围,说明在高ROS环境下,hMSCs与底物的粘附性较差。但与Ru1/10@CoSe共孵育后,hMSCs的黏着斑表达明显增加且空间分布均匀,表明hMSCs与底物的粘附性增强。这些结果表明Ru1/10@CoSe可以有效减少hMSCs的损伤,从而实现细胞骨架重构和更好的细胞粘附。
试验例4促进血管内皮细胞(EC)的分化潜能:
本发明还验证了hMSCs在高ROS环境下对血管内皮细胞(EC)的分化潜力。在内皮细胞分化过程中,CD31和CD34被认为是内皮细胞的特异性标记物。如图15和图16所示,在纯hMSC和H2O2处理的hMSCs中,CD31和CD34信号都非常有限,这表明高ROS环境损害了hMSCs向ECs的分化能力。然而,对于生物催化剂孵育的hMSCs,在整个井中观察到增强的红色信号,尤其是Ru1/10@CoSe显示了与对照组相似的结果(图15、16)。此外,为了探索hMSCs在不同处理后的血管生成能力,本发明进行了小管实验来体外模拟血管生成。原则上,hMSCs的内皮分化程度越高,形成的管状网络越多。如图17所示,Ru1/10@CoSe组在促进小管形成方面表现出比H2O2组和CoSe组更高的效率,其特点是更明显的管状结构、更高的分支数和更长的毛细管长度。上述结果表明Ru1/10@CoSe可以通过减轻氧化应激对细胞的功能损伤来维持hMSCs的血管生成能力。
试验例5体内治疗糖尿病炎性创面愈合的评价:
本发明建立了高血糖兔耳溃疡模型,以评估糖尿病足溃疡的血管生成、抗炎和伤口愈合。图18a、b总结了伤口愈合过程的照片和伤口的愈合率。其中,Ru1/10@CoSe组的创面愈合率高于其他组,在第11天几乎完全愈合,而CoSe或磷酸盐缓冲盐水(PBS)组的创面仍暴露在外,并被痂覆盖。随后,用苏木精-伊红(H&E)和Masson染色观察创面处理后第11天的组织学状况。如图18c所示,受损皮肤组织中胶原蛋白显著减少,导致创面愈合不良,组织重塑受损,疤痕大小和表皮厚度指数增大。第11天,CoSe组或PBS组仅出现少量胶原纤维,胶原纤维松散无序。相比之下,Ru1/10@CoSe组表现出较低的表皮厚度指数和更多的胶原沉积,皮肤组织中的胶原纤维更密集、更厚、排列更好,与正常皮肤和真皮层相似。
随后,本发明采用DCFH-DA、白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、CD31和Ki67染色来检测Ru1/10@CoSe对伤口创面氧化应激和炎症的缓解情况,以及伤口区域的细胞增殖和血管生成情况。如图19所示,未愈合伤口区域显示大量ROS(绿色)和炎症因子(红色)信号;Ru1/10@CoSe组几乎没有ROS和炎症因子,表明Ru1/10@CoSe在炎症性糖尿病创面具有有效的清除ROS的能力。同时,Ru1/10@CoSe组比PBS组和CoSe组CD31和Ki67表达更高,新生血管长度更长,这表明Ru1/10@CoSe在愈合期间可以促进细胞增殖,从而加速肉芽组织的形成,促进胶原沉积。此外本发明还通过对主要器官(心、肝、脾、肺、肾)的H&E染色来评估了所制备的生物催化剂(Ru1/10@CoSe和CoSe)的生物安全性。如图20所示,主要器官和组织均未出现明显损伤和异常,说明本发明所制备的生物催化剂具有较低的细胞毒性。以上动物实验结果表明,Ru1/10@CoSe可以作为一种有效、安全的纳米药物来对抗氧化应激,实现糖尿病炎症性伤口的超快速愈合。
综上,通过上述研究结果证实,本发明合成的具有非晶态Ru@CoSe纳米层的硒化钴基生物催化剂是一种理想的高效的超快、广谱催化ROS清除的抗氧化酶类纳米平台。非晶态生物催化纳米层的引入有助于最大限度地提高内在活性、活化惰性表面和提高原子利用效率。本发明所制备的Ru@CoSe生物催化剂具有优异的类CAT酶反应动力学,并通过体外和体内实验证实,Ru@CoSe可显著下调细胞内的ROS浓度,缓解缺氧,从而提高hMSCs的生存与增殖的能力,维持其血管生成潜能,最终促进组织再生,实现炎性糖尿病溃疡创面的超快愈合。
Claims (8)
1.一种金属硒基生物催化材料,其特征在于,所述催化材料为Ru掺杂的CoSe纳米粒子,命名为Ru@CoSe;所述金属硒基生物催化材料的微观结构为:CoSe晶体的表面上形成含有均匀分布Ru单原子的非晶CoSe层。
2.根据权利要求1所述的一种金属硒基生物催化材料,其特征在于,所述金属硒基生物催化材料中,CoSe与Ru的摩尔比为:CoSe:Ru=5:1~40:1。
3.根据权利要求2所述的一种金属硒基生物催化材料,其特征在于,所述CoSe与Ru的摩尔比为5:1、10:1、20:1、30:1或40:1。
4.权利要求1~3任一项所述的一种金属硒基生物催化材料的制备方法,其特征在于,所述制备方法为:钴盐、钌盐和硒酸盐通过溶剂配位分子模板法合成,将钴盐、钌盐和硒酸盐在去离子水中混匀,再加入溶剂和还原剂,室温下搅拌10~40min,然后将反应体系置于反应釜中于170~190℃反应14~16h,随后通过离心获得黑色产物;最后将所得产物经洗涤干燥制得所述催化材料Ru@CoSe;其中,钴盐与钌盐的摩尔比为5:1~40:1,钴盐与硒酸盐的摩尔比为1:1。
5.根据权利要求4所述的一种金属硒基生物催化材料的制备方法,其特征在于,所述钴盐为CoCl2·6H2O,所述钌盐为RuCl3·xH2O,所述硒酸盐为Na2SeO3。
6.根据权利要求4所述的一种金属硒基生物催化材料的制备方法,其特征在于,所述钴盐与去离子水的比例为:1mmol:50~70mL,所述钴盐与溶剂的比例为:1mmol:10~30mL,所述钴盐与还原剂的比例为:1mmol:0.5~2mL;或:
所述溶剂为二亚乙基三胺或三乙烯四胺,所述还原剂为水合肼或硼氢化钠。
7.权利要求1~3任一项所述的金属硒基生物催化材料在制备清除活性氧、保护干细胞或促进内皮细胞血管化的材料中的用途;或:
权利要求1~3任一项所述的金属硒基生物催化材料在制备治疗神经外伤、心肌梗塞、类风湿性关节炎、骨缺损、糖尿病足、心肌缺血再灌注损伤、卵巢早衰、肺纤维化或溃疡性结肠炎疾病的药物中的用途。
8.根据权利要求7所述的用途,其特征在于,所述干细胞为间充质干细胞。
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