CN114437053A - 一种纳米探针与其在检测高尔基体中超氧阴离子的应用 - Google Patents
一种纳米探针与其在检测高尔基体中超氧阴离子的应用 Download PDFInfo
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Abstract
本发明属于新材料技术领域，涉及荧光材料技术，具体涉及一种纳米探针与其在检测高尔基体中超氧阴离子的应用，该纳米探针由荧光探针与牛血清蛋白结合形成，所述荧光探针的化学结构式为
本发明提供的纳米探针表现出优异的靶向定位高尔基体的能力，且能对O2 ·‑进行成像，具有灵敏度高、选择性高等的优点。
Description
技术领域
本发明属于新材料技术领域，涉及荧光材料技术，具体涉及一种纳米探针与其在检测高尔基体中超氧阴离子(O2 ·-)的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
高尔基体是一种细胞器，能够通过NOS等高尔基相关蛋白生成O2 ·-，并在催化底物分子反应时释放O2 ·-。据发明人了解，用于检测细胞高尔基体和小鼠体内O2 ·-水平的荧光探针比较少见。到目前为止，已经报道了两种高尔基靶向基团，包括高尔基体靶向多肽和半胱氨酸。高尔基靶向多肽具有明显的定位能力，但很难合成。半胱氨酸由于脂溶性低，在荧光探针的合成上有局限性。
发明内容
为了解决现有技术的不足，本发明的目的是提供一种纳米探针与其在检测高尔基体中超氧阴离子的应用，该探针表现出优异的靶向定位高尔基体的能力，且能对O2 ·-进行成像，具有灵敏度高、选择性高等的优点。
为了实现上述目的，本发明的技术方案为：
一方面，一种荧光探针，化学结构式如下所示：
另一方面，一种荧光探针的制备方法，包括按照如下反应路线获得，
第三方面，一种纳米探针，包括上述荧光探针与牛血清蛋白。
第四方面，一种上述荧光探针或纳米探针在检测高尔基体中超氧阴离子的应用。
第五方面，一种上述荧光探针或纳米探针在制备检测高尔基体中超氧阴离子药物中的应用。
O2 ·-是调节体内各种生物过程代谢的重要信号分子。例如在神经退行性疾病和癌症中，O2 ·-的稳态已被破坏，因为O2 ·-的产生超过了它们的分解代谢。过表达O2 ·-可损伤蛋白和DNA，引起体内不可逆损伤。因此，O2 ·-可以作为癌症等疾病的标志物，有助于疾病的早期诊断。因而第六方面，一种上述荧光探针或纳米探针在制备检测癌症药物中的应用。
本发明的荧光探针中以磺胺作为靶向基团，用于靶向定位高尔基体，当遇到超氧阴离子时，O2 ·-亲核进攻探针结构中的酯键并水解成为羟基。羟基是供电子基团，由于给电子能力增强使荧光团ICT效应增加，荧光旨在740nm处增加，即可对高尔基体中的O2 ·-进行检测。
为了增加靶向定位高尔基体的能力，用牛血清蛋白(BSA)与荧光探针复合，从而使得纳米探针表现出优异的靶向定位高尔基体的能力。
本发明的有益效果为：
1.本发明提供了一种靶向高尔基体检测O2 ·-的纳米探针，磺胺和BSA共同作为高尔基体的靶向基团，使该探针具有良好靶向定位高尔基体的效果。
2.本发明提供的纳米探针与O2 ·-反应后具有明显的吸收及荧光变化具有良好的光稳定性。该探针的发射位于近红外区，组织的穿透能力较强，利于活体成像。
3.本发明提供的纳米探针具有良好的生物相容性，对细胞和活体毒性较小。
4.本发明提供的纳米探针波长较长具有光声性能，可以用于光声成像。
5.本发明的原料均为廉价易得，有望应用于市场化的生产,成为检测O2 ·-的有利工具。
附图说明
构成本发明的一部分的说明书附图用来提供对本申请的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1是本发明实施例1制备的荧光探针GSO与O2 ·-反应前后的吸收光谱图，其中，横坐标为波长(nm)，纵坐标为紫外吸收强度；
图2是本发明实施例1制备的荧光探针GSO与细胞内常见的活性氧(ROS)、活性氮(RNS)、氨基酸、金属离子等生物活性分子的选择性测定柱状图；
图3是本发明实施例1制备的纳米探针GSOnano与四种商品化的亚细胞器商业染料共孵育后在人肝细胞细胞(HL-7702细胞)中的荧光成像图，a为高尔基体，b为线粒体，c为溶酶体，d为细胞核；
图4是本发明实施例1制备的纳米探针GSOnano在不同条件的刺激下，人肝细胞细胞(HL-7702细胞)中O2 ·-浓度变化的共聚焦成像图，a为GSOnano与高尔基体商业染料共同处理HL-7702细胞，b为GSOnano与线粒体商业染料共同处理HL-7702细胞，c为为GSOnano与溶酶体商业染料共同处理HL-7702 细胞，d为为GSOnano与细胞核商业染料共同处理HL-7702细胞。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本申请的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
正如背景技术所介绍的，现有技术中靶向高尔基体检测O2 ·-的探针极其缺乏，为了解决如上的技术问题，本发明提出了一种纳米探针与其在检测高尔基体中超氧阴离子的应用。
本发明的一种典型实施方式，提供了一种荧光探针，化学结构式如下所示：
本发明的另一种实施方式，提供了一种荧光探针的制备方法，包括按照如下反应路线获得，
该实施方式中，物质1与物质6均为现有已知化合物，可以通过现有技术合成获得。
该实施方式的一些实施例中，物质2是由2,3,3-三甲基苯并吲哚与4-溴-1-丁炔通过季铵化反应获得。2,3,3-三甲基苯并吲哚与4-溴-1-丁炔的摩尔比为 1:0.9～1.1。反应体系的溶剂优选为乙腈，当采用严格除水的乙腈作为溶剂时，反应效果更好。
物质1与物质2的反应温度为室温至75℃，该实施方式的一些实施例中，物质1与物质2的反应温度为室温，反应时间为10～12h。本发明所述的室温是指室内环境的温度，一般为15～30℃。该条件下对无需进行加热，节省能耗。物质1与物质2的摩尔比优选为1:1.9～2.1。反应体系的溶剂优选为乙酸酐。
该实施方式的一些实施例中，物质3与间苯二酚的反应条件为：碱性条件下加热回流。物质3与间苯二酚的摩尔比为1:2.4～2.6。反应体系的溶剂优选为乙腈。
该实施方式的一些实施例中，物质4与三氟甲烷磺酸酐的反应条件为：室温条件下进行反应。反应时间为1～2h。反应体系的溶剂为二氯甲烷。当采用严格除水的二氯甲烷作为溶剂时，反应效果更好。物质4与三氟甲烷磺酸酐的摩尔比为1:0.9～1.1。
该实施方式的一些实施例中，物质5与物质6的反应过程中加入铜离子和抗坏血酸钠。其原理为：抗坏血酸钠的作用是还原剂将Cu2+还原成Cu+，Cu+进一步催化叠氮与炔基的环加成反应。反应条件为室温条件下反应。反应时间为1～5 h。反应体系的溶剂为二甲基亚砜(DMSO)与水的混合物，其中，DMSO与水的体积比有效为1:0.9～1.1。传统的环加成反应时间一般为1h，但本发明实验发现延长反应时间4～5h时，该反应产率明显增加。因此，反应时间改进为4～5 h。
本发明的第三种实施方式，提供了一种纳米探针，包括上述荧光探针与牛血清蛋白。
该实施方式的一些实施例中，荧光探针与牛血清蛋白的质量比为 1:150～350。
该实施方式的一些实施例中，制备方法为：将荧光探针与牛血清蛋白加入至水中混合均匀后透析。
本发明的第四种实施方式，提供了一种上述荧光探针或纳米探针在检测高尔基体中超氧阴离子的应用。
本发明的第五种实施方式，提供了一种上述荧光探针或纳米探针在制备检测高尔基体中超氧阴离子药物中的应用。
本发明的第六种实施方式，提供了一种上述荧光探针或纳米探针在制备检测癌症药物中的应用。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
缩合剂(物质1)的制备过程见Wang,H.,Liu,C.,He,Z.,Li,P.,Zhang,W., Zhang,W.,Tang,Dual-Colored Fluorescence Imaging of Mitochondrial HNO and Golgi-HNOin Mice with DILI,B.Anal.Chem.2021,93,16,6551–6558。
叠氮化的磺胺(物质6)的制备过程见
K.,Bresien,J.,Labbow,R.,Michalik,D.,Schulz,A.,Thomas,M.,Villinger,Borane Adducts of Hydrazoic Acidand Organic Azides:Intermediates for the Formation of Aminoboranes,A.Angew.Chem.Int.Ed.2019,58,6540。
实施例1
荧光探针的合成
取原料2,3,3-三甲基苯并吲哚(4mmol)、4-溴-1-丁炔(4mmol)溶于10 mL乙腈，80℃加热回流48h。在乙醚中析出得到物质2(80％)。
物质2(2mmol)、缩合剂(物质1，1mmol)以及乙酸钠(2.5mmol) 溶于6mL乙酸酐中，70℃下加热回流2h。反应完毕，冷却至室温，在冰乙醚中析出粗产物。随后用用二氯甲烷：甲醇＝10:1作为洗脱剂，柱层析法提纯得到绿固体花菁(物质3，40％)
花菁(物质3，1mmol)、间苯二酚(2.5mmol)、碳酸钾(2.5mmol) 溶于10mL乙腈，50℃加热回流2h。反应完毕，冷却至室温，旋转蒸发除去溶剂。随后用二氯甲烷：甲醇＝10：1作为洗脱剂，通过柱层析法提纯得到蓝色固体部花菁(物质4，50％)。
部花菁(物质4，0.5mmol)、三氟甲烷磺酸酐(0.5mmol)、吡啶(50μL) 溶于5mL二氯甲烷中。室温(20-25℃)反应2h。减压蒸发除去溶剂，使用柱层析法提纯得到蓝紫色固体(二氯甲烷：甲醇＝10:1，产率30％)。
物质5(0.5mmol)、叠氮化的磺胺(物质6，0.5mmol)、五水硫酸铜浓度为(0.1mmol)以及抗坏血酸钠的浓度为(0.005mmol)溶于DMSO：H2O (1；1，2mL)，室温(20-25℃)反应4h。经柱层析提纯得到GSO(30％)。
得到的GSO与牛血清蛋白(BSA)共沉淀得到纳米探针GSOnano。将0.2mg 的GSO、0.05g BSA溶于4mL水中搅拌1h后用透析袋透析12h，最终得到 GSOnano。
GSO核磁及质谱表征：
1H NMR(400MHz,MeOD)δ＝8.71(d,J＝15.2Hz,1H),8.36–8.31(m,1H), 8.20(d,J＝8.4Hz,1H),8.05(dd,J＝18.2,8.5Hz,2H),7.73(s,5H),7.11(d,J＝1.8Hz,3H),6.83–6.76(m,2H),4.86(q,J＝7.3Hz,2H),2.90(t,J＝5.8Hz,4H), 2.10–1.78(m,8H),1.62(t,J＝7.2Hz,6H).13C NMR(101MHz,MeOD) δ＝182.11,157.57,152.81,150.03,144.34,144.00,143.96,138.88,138.18,137.45, 133.48,131.17,129.91,128.93,128.81,128.07,127.61,126.62,122.63,122.14, 119.63,117.64,114.21,111.60,109.37,106.49,53.48,53.40,48.47,48.26,48.12, 48.05,47.90,47.83,47.62,47.41,47.19,46.98,45.61,29.36,28.84,26.20,23.87, 23.51,22.34,19.74,13.06.HRMS(ESI)m/z:[M+]calculatedfor C40H35F3N5O6S2 +, 802.1981found 802.1943。
效果实验：
通常，可以将染料分子溶解在生理盐水、缓冲液或由乙腈、二甲亚砜等水溶性有机溶剂，然后加入适当缓冲液及其他有机试剂进行测试。分别研究了探针GSO在pH＝7.4的磷酸缓冲水溶液的光物理性质。随后，将包裹的纳米探针 GSOnano用于活细胞成像实验。细胞染色的方法是将细胞与含有纳米探针的培养液共孵育，孵育一定的时间后用磷酸缓冲水溶液洗涤两次，进行荧光成像实验。
探针GSO与O2 ·-反应的紫外吸收及选择性实验：
对照组：GSO(2μM)、PBS缓冲溶液(25mM)、pH＝7.4；实验组： GSO(2μM)、PBS缓冲溶液(25mM)、pH＝7.4、O2 ·-(50μM)。将对照组和实验组都在37℃下孵育10min，测量紫外吸收光谱的变化，其光谱图显示于图1。横坐标为波长(nm)，纵坐标为紫外吸收强度。如图1所示，GSO 与O2 ·-反应后其吸收波长明显红移。图2为各种生物活性分子对GSO干扰情况，检测的生物活性分子包括生物硫醇(同型半胱氨酸半、谷胱甘肽、半胱氨酸)、盐(CaCl2、KCl、MgCl2、NaCl、FeCl3、ZnCl2)、活性氧、活性氮(NO、ClO-、 H2O2、ONOO·、1O2)和O2 ·-。如图2所示，只有当O2 ·-存在时，GSO的荧光显著的增强且响应倍数高达30倍，而在与其他生物分子共抚育后，荧光基本保持不变。以上结果表明，GSO可以作为优良的生物传感器在复杂生物环境中，高选择性地检测超氧阴离子。并且GSO用BSA包裹好铺，纳米探针GSOnano也可以用于特异性检测细胞及活体中的O2 ·-。
GSOnano的高尔基体靶向性实验：
人肝细胞(HL-7702细胞)是由高糖的DMEM培养液培养的，0.2μg mL-1的纳米探针以及0.5μM亚细胞器的商业化染料(包括高尔基体、线粒体、溶酶体、细胞核)与细胞共孵育40min后，使用激光共聚焦显微镜进行共定位成像实验。共定位细胞成像实验如图3所示，探针表现出优异的高尔基体定位效果。
探针对活细胞共聚焦荧光成像实验：
人肝细胞(HL-7702细胞)用各种刺激剂预处理(包括1μg mL-1 2-Meyhoxyestradiol(2-ME)刺激以及10μMTiron刺激)，然后分别加入0.2μg mL-1纳米探针GSO在37℃中孵育40min，用PBS洗涤两次，进行共聚焦荧光成像，如图4所示。经2-ME刺激有细胞中O2 ·-的浓度明显增加，探针GSOnano的荧光增加2.3倍。加入Tiron处理后细胞中O2 ·-的浓度减少，探针GSOnano的荧光降低0.4倍。图4中探针的激发光为633nm，收集700-800nm处的荧光。
实施例2
花菁的合成
物质2(2mmol)、缩合剂(物质1，1mmol)以及乙酸钠(2.5mmol) 溶于6mL乙酸酐中，室温(20-25℃)反应12h。乙醚中析出粗产物。随后用二氯甲烷：甲醇＝10:1作为洗脱剂，柱层析法提纯得到绿色固体花菁(物质3， 20％)。
实施例3
荧光探针GSO的合成
物质5(0.5mmol)、叠氮化的磺胺(物质6，0.5mmol)、五水硫酸铜浓度为(0.1mmol)以及抗坏血酸钠的浓度为(0.005mmol)溶于DMSO：H2O (1；1，2mL)，室温(20℃)反应1h。经柱层析提纯得到GSO(23％)。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种荧光探针，其特征是，化学结构式如下所示：
2.一种荧光探针的制备方法，其特征是，包括按照如下反应路线获得，
3.如权利要求2所述的荧光探针的制备方法，其特征是，物质2是由2,3,3-三甲基苯并吲哚与4-溴-1-丁炔通过季铵化反应获得；优选地，2,3,3-三甲基苯并吲哚与4-溴-1-丁炔的摩尔比为1:0.9～1.1；优选地，反应体系的溶剂优选为乙腈。
4.如权利要求2所述的荧光探针的制备方法，其特征是，物质1与物质2的反应温度为室温，反应时间为10～12h；优选地，物质1与物质2的摩尔比优选为1:1.9～2.1；优选地，反应体系的溶剂优选为乙酸酐。
5.如权利要求2所述的荧光探针的制备方法，其特征是，物质3与间苯二酚的反应条件为：碱性条件下加热回流；优选地，物质3与间苯二酚的摩尔比为1:2.4～2.6；优选地，反应体系的溶剂优选为乙腈。
6.如权利要求2所述的荧光探针的制备方法，其特征是，物质4与三氟甲烷磺酸酐的反应条件为：室温条件下进行反应；优选地，反应时间为1～2h；优选地，反应体系的溶剂为二氯甲烷；
或，物质5与物质6的反应过程中加入铜离子和抗坏血酸钠；优选地，反应时间为2～5h；优选地，反应体系的溶剂为二甲基亚砜与水的混合物，进一步优选地，DMSO与水的体积比有效为1:0.9～1.1。
7.一种纳米探针，其特征是，包括权利要求1所述的荧光探针与牛血清蛋白。
8.一种权利要求1所述的荧光探针或权利要求7所述的纳米探针在检测高尔基体中超氧阴离子的应用。
9.一种权利要求1所述的荧光探针或权利要求7所述的纳米探针在制备检测高尔基体中超氧阴离子药物中的应用。
10.一种权利要求1所述的荧光探针或权利要求7所述的纳米探针在制备检测癌症药物中的应用。
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| CN105985379A (zh) * | 2015-02-11 | 2016-10-05 | 中国科学院化学研究所 | 一种线粒体靶向超氧阴离子探针及其制备方法 |
| CN111875560A (zh) * | 2020-07-09 | 2020-11-03 | 山东师范大学 | 一种比率型双光子荧光探针及其制备方法和应用 |
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| CN105154071A (zh) * | 2015-10-16 | 2015-12-16 | 山东师范大学 | 一种荧光探针及其制备方法与应用 |
| CN111875560A (zh) * | 2020-07-09 | 2020-11-03 | 山东师范大学 | 一种比率型双光子荧光探针及其制备方法和应用 |
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| CN115710299A (zh) * | 2022-10-31 | 2023-02-24 | 北京工业大学 | 肝靶向的早期药物性肝炎和自身免疫性肝炎的荧光/光声双模态探针 |
| CN115710299B (zh) * | 2022-10-31 | 2024-05-24 | 北京工业大学 | 肝靶向的早期药物性肝炎和自身免疫性肝炎的荧光/光声双模态探针 |
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