CN106905237A - 一种pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针及其合成方法 - Google Patents
一种pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针及其合成方法 Download PDFInfo
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Abstract
本发明涉及肿瘤细胞的定位与检测技术领域，具体是一种pH和乏氧双响应定位肿瘤细胞的萘亚胺类比率荧光探针。本发明的探针以萘酰亚胺为母体引入硝基苄基和吗啉活性基团分别用于检测乏氧和pH，通过实验证明该探针在酸性下检测硝基还原酶的效果要远好于在中性条件下，因此本发明的探针消除了常规的乏氧探针只能检测硝基还原酶的局限性，大大地提高了肿瘤细胞成像的准确性，其在肿瘤的治疗和检测方面提供了一种新的思路，应用前景非常广阔。
Description
技术领域
本发明涉及肿瘤细胞的定位与检测技术领域，具体地说，是一种pH和乏氧双响应定位肿瘤细胞的萘亚胺类比率荧光探针，简单来说，就是一种用于检测氢离子和硝基还原酶的萘亚胺类比率荧光探针。
背景技术
据相关组织报道，2004年全球有约800万人死于癌症，2013年有约900万人死于癌症，预计到2030年死于癌症的人数将超过1300万，显然癌症已经成为威胁人类健康重大疾病。研究人员早在1955年提出了肿瘤中存在乏氧区域的假说，后续大量实验表明了肿瘤细胞的氧浓度比正常细胞低。由于肿瘤乏氧与肿瘤细胞的恶性表型，癌症治疗的抗性，以及癌症病人的死亡率紧密相关，所以对于癌症治疗和诊断并发展有效的乏氧检测方法是刻不容缓的。乏氧是肿瘤微环境的一个重要特征，检测乏氧可以预测并治疗反应。目前对于肿瘤乏氧的检测主要有以下方法：有组织形态分析法、氧电极分析法、DNA断裂分析法、核磁共振分析法、核医学检测方法和乏氧探针成像法。由于乏氧探针成像分析法与前面四中方法相比具有灵敏度度高、方法简单的特点，所以其在乏氧检测方法中是一种具有很大优势。在乏氧细胞内乏氧探针可以被反应还原，生成或者释放荧光物质，达到检测乏氧的目的。
细胞内的pH是细胞很重要的参数，与细胞内受体介导信号传导、酶活性、细胞增殖和凋亡、离子转运等生命过程息息相关。在正常的生理条件下，人体细胞内的H+的浓度为40nmol/L(pH7.4)，仅在很小的范围内有轻微的变化(7.35-7.45)。研究表明，不正常的pH值变动，通常与细胞功能紊乱和一些疾病相关，如肾性中毒、阿尔兹海默症、肺气肿、炎症和癌症等。肿瘤细胞的pH范围约在5.8～7.7，比正常细胞中低0.5单位左右。研究表明肿瘤中酸性环境与离子转运体Na+/H+交换体(NHE)和H+乳酸协同转运蛋白系统等过程有关。因此，肿瘤细胞与正常组织的酸性不同，可作为切入点，用于药物的靶向设计和肿瘤诊断。目前可用于检测pH的方法主要有：微电极法、核磁共振法、吸收光谱法以及荧光光谱法等。其中，荧光技术具有高灵敏性、非损伤性、能原位直接检测等优点，使得该技术在细胞内的微环境的pH检测有着更广阔的应用前景。
综上所述，研究人员为了定位机体中的肿瘤细胞基本上是通过其细胞微环境内的乏氧和pH呈现弱酸性进行的。然而，已报道的荧光探针中大部分的荧光探针只能单独对乏氧环境进行检测或者对单独pH进行检测，通过探针的荧光变化定位肿瘤细胞。这样检测出来的结果对于定位肿瘤细胞的准确性有一定的局限性。
发明内容
本发明的目的在于针对上述问题，设计一种同时响应肿瘤细胞中乏氧环境和弱酸性的小分子探针，是以萘酰亚胺为发光基团，引入吗啉和含硝基的基团，能同时响应肿瘤细胞中乏氧环境和弱酸性。由于灵敏度较高，因此可以用于定位体内的肿瘤细胞。
为了达到上述目的，本发明采取以下技术方案：本发明采用萘酰亚胺为母体，引入吗啉和含有硝基的基团分别作为氢离子和硝基还原酶的活性中心，以便该探针更好地在生物体内的肿瘤细胞成像。
本发明的第一方面，提供一种pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针，其结构通式I如下所示：
其中，R1，R2，R3为C1～C20的烷基或者氢；
R4为吗啉类、乙二胺、N-甲基乙二胺、N,N-二甲基乙二胺、哌嗪，吡啶等可以检测氢离子的基团且所连的碳链长度n≥1；
R5为对硝基苯甲醇、5-硝基呋喃、5-硝基噻吩、硝基咪唑及这些化合物的衍生物。
所述的烷基包括直链或带有支链的链状烷基。
优选的，所述的R1为C1～C4的烷基。最优选的，所述的R1为C4的烷基。
优选的，所述的R2和R3为氢。
优选的，所述的R4所接的碳链长度为2(即n＝1时)，R4为吗啉。
优选的，所述的R5为对硝基苯甲氧基。
优选的，所述的R1为C4的烷基，R2和R3为氢，R4所接的碳链长度为2(即n＝1时)，R4为吗啉，R5为对硝基苯甲醇，此时所述的荧光探针为化合物3，其化学结构式为：
将通式Ⅰ的荧光探针置于一定的pH和乏氧条件下，通式Ⅰ与硝基还原酶和氢离子反应生成通式Ⅱ，结构的变化导致紫外吸收以及荧光信号的变化，因此所述的荧光探针可以检测硝基还原酶和pH。
通式Ⅰ的荧光探针在一定pH的0.01M PBS缓冲溶液中加入硝基还原酶和NADH，37℃下，反应一定时间，会生成通式Ⅱ所代表的化合物，其颜色会变黄。
通式Ⅱ结构如下所示：
反应过程如下所示：
本发明的第二方面，提供上述通式Ⅰ的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针在检测氢离子和硝基还原酶中的应用。
本发明的第三方面，提供上述通式Ⅰ的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针在制备用于肿瘤细胞的定位与检测的试剂盒中的应用。所述的荧光探针能很好地响应pH和硝基还原酶，因此可以定位生物体内的肿瘤细胞，其在癌症的治疗和检测方面，有着非常广阔地前景。
本发明优点在于：
本发明所述的小分子荧光探针以萘酰亚胺为母体引入硝基苄基和吗啉活性基团分别用于检测乏氧和pH。通过实验证明所述的探针在酸性下检测硝基还原酶的效果要远好于在中性条件下(即正常的生理条件下)。因此该探针消除了常规的乏氧探针只能检测硝基还原酶的局限性，大大地提高了肿瘤细胞成像的准确性。所述的小分子探针能很好地响应pH和硝基还原酶，因此可以定位生物体内的肿瘤细胞，其在癌症的治疗和检测方面提供了一种新的思路，有着非常广阔地前景。
附图说明
图1.化合物2和化合物3紫外-可见吸收光谱。
图2.化合物2的pH滴定的荧光强度变化，其中左图为荧光光谱，右图为滴定曲线。
图3.pH 7.0下化合物3与硝基还原酶反应的荧光强度变化，其中左图为荧光光谱，右图为荧光变化时间曲线。
图4.pH 6.0下化合物3与硝基还原酶反应的荧光强度变化，其中左图为荧光光谱，右图为荧光变化时间曲线。
图5.pH 5.0下化合物3与硝基还原酶反应的荧光强度变化，其中左图为荧光光谱，右图为荧光变化时间曲线。
图6.化合物3在pH 5.0、6.0和7.0下与硝基还原酶反应的荧光变化时间曲线对比图。
图7.化合物2的核磁共振氢谱图。
图8.化合物3的核磁共振氢谱图。
图9.化合物3的核磁共振碳谱图。
图10.化合物3的质谱。
具体实施方式
下面结合实施例对本发明提供的具体实施方式作详细说明。
实施例1(探针的合成)
反应路线如下所示：
1.1合成化合物1：
将5.54g的A和40mL的正丁胺放入250mL的烧瓶中加入100mL无水乙醇，120℃，冷凝回流3h。冷却至室温，抽滤得8.0g白色固体。
1.2合成化合物2：
将2.0g化合物1和3.2mL的N-(2-氨基乙基)吗啉加入到100mL的烧瓶中并加入0.01mg的五水硫酸铜和40mL乙氧基乙醇。氮气保护下，120℃回流8h，旋干，用柱层析方法提纯(DCM：甲醇＝10:1)得化1.3g黄色固体。
化合物2的核磁共振氢谱见图7。
1.3合成化合物3：
将130mgNaH溶于2mLTHF中，氩气保护冷却至0℃，将50mg化合物2溶于3mLTHF中并逐滴加入到反应液中反应3h。将氯甲酸对硝基苄酯溶于2mLTHF中并逐滴加入到反应液中反应2h。40℃下反应12h。加入10mL去离子水，萃取，用柱层析方法提纯(EA：DCM＝13:1)。得到10mg淡黄色固体。化合物3的核磁共振氢谱见图8。化合物3的核磁共振碳谱见图9。化合物3的质谱见图10。
实施例2(化合物2与化合物3的紫外-可见吸收光谱)
配置浓度为1mM化合物2和化合物3的DMSO溶液。取3mL0.01M PBS缓冲溶液加入30μLDMSO溶液做空白对照。同样取相同的PBS溶液3mL分别加入配置好的化合物2和化合物3溶液，分别测试得到图1化合物2和化合物3的紫外吸收曲线。由图1可知，化合物2和化合物3的等吸收点为389nm。
实施例3(化合物2的pH滴定)
从图1中获取化合物2的激发波长分别为449nm。取3mL 0.01M PBS(pH7.4)缓冲溶液加入分别加入30μL1mM化合物2和化合物3的溶液用0.1M HCl和NaOH溶液滴定。分别收集化合物2在pH 3.0、4.0、5.0、6.0、7.0、8.0、9.0、10.0下的荧光强度。化合物2测得结果见图2。由图2可知，化合物2的滴定跃迁为4.0～7.0。
实施例4(化合物3在pH 7.0下与硝基还原酶反应的荧光变化)
设置仪器的激发波长为389nm，取3mL 0.01M PBS(pH 7.0)缓冲溶液加入30μL化合物3的溶液，30μL的NTR溶液，20μL NADH溶液。使溶液中含有化合物3 10μM、NTR 10μg/mL、NADH 500μM和1％DMSO。将反应液置于37℃条件下0-6min每30s测其荧光强度。测得结果见图3。由图3可知，化合物3可以和硝基还原酶反应故能用于检测细胞中的乏氧条件。
实施例5(化合物3在pH 6.0下与硝基还原酶反应的荧光变化)
设置仪器的激发波长为389nm，取3mL 0.01M PBS(pH 6.0)缓冲溶液加入30μL化合物3的溶液，30μL的NTR溶液，20μL NADH溶液。使溶液中含有化合物3 10μM、NTR 10μg/mL、NADH 500μM和1％DMSO。将反应液置于37℃条件下0-6min每30s测其荧光强度。测得结果见图4。由图4可知，化合物3可以在pH 6.0的条件下和硝基还原酶反应。
实施例6(化合物3在pH 5.0下与硝基还原酶反应的荧光变化)
设置仪器的激发波长为389nm，取3mL 0.01M PBS(pH 6.0)缓冲溶液加入30μL化合物3的溶液，30μL的NTR溶液，20μL NADH溶液。使溶液中化合物3的浓度为10μM、NTR 10μg/mL、NADH 500μM和1％DMSO。将反应液置于37℃条件下0-6min每30s测其荧光强度。测得结果见图5。由图5可知，化合物3可以在pH 6.0的条件下和硝基还原酶反应。
实施例7(化合物3在pH 5.0、6.0和7.0下与硝基还原酶反应的荧光变化对比)
将化合物3在pH 5.0、6.0和7.0下与硝基还原酶反应的荧光变化时间曲线对比图。见图6。由图6可知，化合物3在不同的pH条件下比率荧光强度变化的不同且随着酸性的增强，该化合物的比率荧光强度变化在增大。故该化合物可以用于定位肿瘤细胞。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可做出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (8)
1.一种pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针，其特征在于，其结构通式I如下所示：
其中，R1，R2，R3为C1～C20的烷基或者氢；
R4为吗啉、乙二胺、N-甲基乙二胺、N,N-二甲基乙二胺、哌嗪、或吡啶且n≥1；
R5为对硝基苯甲醇、5-硝基呋喃、5-硝基噻吩、硝基咪唑及其衍生物。
2.根据权利要求1所述的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针，其特征在于，R1为C1～C4的烷基。
3.根据权利要求1所述的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针，其特征在于，R2和R3为氢。
4.根据权利要求1所述的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针，其特征在于，n＝1时，R4为吗啉。
5.根据权利要求1所述的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针，其特征在于，R5为对硝基苯甲氧基。
6.根据权利要求1所述的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针，其特征在于，所述的荧光探针为化合物3，其化学结构式为：
7.一种如权利要求1-6任一所述的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针在检测氢离子和硝基还原酶中的应用。
8.一种如权利要求1-6任一所述的pH和乏氧双响应定位肿瘤细胞的萘酰亚胺类比率荧光探针在制备用于肿瘤细胞的定位与检测的试剂盒中的应用。
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| CN107446571A (zh) * | 2017-08-01 | 2017-12-08 | 济南大学 | 一种内质网靶向的双光子硝基还原酶荧光探针及其合成方法和应用 |
| CN108559085A (zh) * | 2018-03-02 | 2018-09-21 | 南京邮电大学 | 一种双发射共轭聚合物乏氧探针的制备及应用 |
| CN108559085B (zh) * | 2018-03-02 | 2021-09-03 | 南京邮电大学 | 一种双发射共轭聚合物乏氧探针的制备及应用 |
| CN112745303A (zh) * | 2019-10-30 | 2021-05-04 | 南京大学 | 一种乏氧荧光探针及其应用 |
| CN112745303B (zh) * | 2019-10-30 | 2022-04-22 | 南京大学 | 一种乏氧荧光探针及其应用 |
| CN110878085A (zh) * | 2019-12-13 | 2020-03-13 | 山东省科学院生物研究所 | 一种快速高选择性次溴酸荧光探针、制备方法与应用 |
| WO2021120653A1 (zh) * | 2019-12-16 | 2021-06-24 | 大连理工大学 | 辅因子—底物探针平台用于肿瘤缺氧相关酶的快速定量检测 |
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| CN113984729A (zh) * | 2021-10-29 | 2022-01-28 | 中国科学院自动化研究所 | 乏氧响应型比率探针合成方法及其应用 |
| CN114456116A (zh) * | 2022-02-23 | 2022-05-10 | 南京师范大学 | 一种以萘酰亚胺为骨架的小分子抗癌剂及其制备方法和应用 |
| CN114456116B (zh) * | 2022-02-23 | 2024-01-23 | 南京师范大学 | 一种以萘酰亚胺为骨架的小分子抗癌剂及其制备方法和应用 |
| CN114702447A (zh) * | 2022-04-26 | 2022-07-05 | 苏州大学 | 一种萘酰亚胺衍生物及其制备方法与应用 |
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