CN115160338A - 基于花菁染料的靶向性比率pH荧光探针的制备和应用 - Google Patents
基于花菁染料的靶向性比率pH荧光探针的制备和应用 Download PDFInfo
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Abstract
本发明涉及基于花菁染料的靶向性比率pH荧光探针的制备和应用,该荧光探针的结构式为:
Description
技术领域
本发明属于荧光探针技术领域,具体涉及基于花菁染料的靶向性比率pH荧光探针的制备和应用。
背景技术
细胞内pH在多种生命活动中起着关键作用,包括受体介导的信号转导、细胞生长和凋亡、离子转运和体内平衡、细胞内酶活性会因pH值的变化而降低甚至失活等(R.T.Kennedy,L.Huang,and C.A.Aspinwall,J.Am.Chem.Soc.,1996,118,1795-1796;A.J.Janecki,M.H.Montrose,P.Zimniak,A.Zweibaum,C.M.Tse,S.Khurana,M.Donowitz,JBiol Chem.,1998,273,8790-8798;D.Lagadic-Gossmann,M.Rissel,M.Galisteo,A.Guillouzo,Br J Pharmacol.,1999,128,1673-1682)。随着葡萄糖代谢的增加,癌症中H+的产生和排泄通常会增加(R.Van-Sluis,Z.M.Bhujwalla,N.Raghunand,P.Ballesteros,Magn Reson Med.,1999,41,743-750;J.L.Wike-Hooley,J.Haveman,H.S.Reinhold,Radiother Oncol.,1984,2,343-366)。与生理条件下的正常组织相比,恶性肿瘤的细胞内pH较低(P.A.Schornack,R.J.Gillies,Neoplasia.,2003,5,135–145;M.Stubbs,P.M.McSheehy,J.R.Griffiths,C.L.Bashford,Mol Med Today.,2000,6,15-19),因此,pH被认为是重要的癌症标志物。由于pH在生理环境中的变化小,发展一种高灵敏度检测pH的策略具有重要意义。
目前,已有多种方法可用于pH的测定,如H+渗透微电极法、核磁共振波谱法以及光学显微镜法等(W.Ma,L.Yan,X.He,T.Qing,Y.Lei,Z.Qiao,D.He,K.Huang,K.Wang,Anal.Chem.,2018,90,1889-1896)。但是,这些技术通常需要使用高精度的仪器,并且样品的处理过程比较复杂,从而限制了其在活细胞水平上进行pH分析。相比于这些传统的方法,荧光探针具有响应速度快、信噪比高、非侵入性以及时空分辨率高的优点(K.K.Yu,K.Li,J.T.Hou,J.Yang,Y.M.Xie,X.Q.Yu,Polym.Chem.,2014,5,5804-5812;Q.Yao,S.Lu,F.Lin,T.Zhao,L.Zhao,X.Chen,Sens.Actuators B Chem.,2017,250,484-490),非常适合生物样品中pH的检测。到目前为止,有一些检测pH的荧光探针被报道(F.Galindo,M.I.Burguete,L.Vigara,S.V.Luis,N.Kabir,J.Gavrilovic,Angew Chem Int Edit.,2005,44,6504-6508;Y.Saito,S.Miyamoto,A.Suzuki,K.Matsumoto,T.Ishihara,I.Saito,Bioorg MedChem Lett.,2012,22,2753-2756;W.Liu,R.Sun,J.F.Ge,Y.J.Xu,Y.Xu,J.M.Lu,Anal.Chem.,2013,15,7419-7425;L.L.Wu,Y.Wang,T.D.James,N.Q.Jia,C.Huang,ChemCommun.,2018,54,5518-5521)。但是,这些pH探针存在一些不足:(1)分析波长较短,因此容易被活体内生物子产生的自发荧光信号干扰,且组织穿透能力较弱,从而限制了在生物体内的应用;(2)探针激活后只有一个波长的荧光变化,在复杂的生理环境中难以实现定量分析;(3)不能主动靶向细胞和组织,难以在特定组织聚集,分散在各处的探针会降低检测效率并使背景荧光进一步增强。因此,设计和合成具有长波长和靶向能力的比率pH荧光探针是非常有意义的。
花菁染料是目前荧光探针领域中应用比较广泛的一类染料,它具有摩尔吸光系数大、光稳定性高等优势,最重要的是,具有近红外发射性能。近红外发射能够穿透更深的组织,不易受到生物自体荧光的干扰,对生物成像更有利。生物素是一种很好的靶向肿瘤细胞的结构,据报道,各种癌细胞,如宫颈癌、乳腺癌、肺癌和卵巢癌,都过度表达生物素受体(N.U.Deshpande,M.Jayakannan,Biomacromolecules.,2018,19,3572-3585;K.Li,L.Qiu,Q.Liu,G.Lv,X.Zhao,S.Wang,J.Lin,J.Photochem.Photobiol.,2017,174,243-250;Y.Singh,K.K.Durga-Rao-Viswanadham,A.Kumar-Jajoriya,J.G.Meher,K.Raval,S.Jaiswal,J.Dewangan,H.K.Bora,S.K.Rath,J.Lal,Mol.Pharmaceutics.,2017,14,2749-2765),在探针中引入生物素结构是实现肿瘤特异性分布的一种有效策略,探针在细胞和组织的特异性分布有望提升细胞中pH检测的灵敏度和信噪比。但是,现在还没有能同时靶向细胞和比率检测pH的荧光探针。因此,设计和合成一种基于花菁染料的靶向性比率pH荧光探针,作为检测细胞中pH的有效工具,是非常必要的。
发明内容
根据所提出的要求,本发明人对此进行了深入研究,在付出了大量创造性劳动后,提供了一种基于花菁染料的靶向性比率pH荧光探针
本发明的技术方案是,一种基于花菁染料的靶向性比率pH荧光探针,其结构式如下:
一种基于花菁染料的靶向性比率pH荧光探针的制备方法。步骤如下:
在15~25℃下,将1当量的Cy-Biotin-Cl用10~20mL无水DMF溶解后加入50mL的圆底烧瓶中,接着,将3~5当量的三水合乙酸钠加入上述体系;氮气保护下,升温至80~100℃,搅拌5~7h;反应完成后,冷却至室温;粗产物用盐水和二氯甲烷萃取,取有机相在减压条件下除去溶剂,用体积比为30:1~10:1的CH2Cl2/CH3OH洗脱剂进行柱层析纯化,得到红色固体化合物Cy-Biotin-O,即为所述的荧光探针。
本发明的有益效果是,一种基于花菁染料的靶向性比率pH荧光探针的良好的光谱响应性能。首先,研究该探针的荧光光谱性质。荧光探针本身在645nm有荧光发射,758nm没有荧光;将pH调至酸性后,645nm的荧光明显减弱,在758nm处出现了明显的近红外荧光发射。并且随着酸性的增强,探针645nm处的荧光逐渐减弱,758nm处的近红外荧光强度不断增强。接着,研究探针的紫外吸收光谱。探针本身在540nm附近有吸收带,pH调至酸性后,540nm的吸收明显减小,在716nm附近出现新的吸收峰。然后,研究探针的选择性。考察了探针与无机离子(Mg2+,Ca2+,K+,Na+,Fe3+),活性氧(ClO-,H2O2,·OH),活性氮(NO2 -,NO3 -),活性硫(H2S,SO3 2-),常见氨基酸(Phe,Lys,Leu,Val,Trp,Ile,Met,Thr)以及生物硫醇(Cys,Hcy,GSH)的荧光响应情况。结果发现,只有酸性环境能引起荧光光谱的改变,其他检测物对探针的荧光光谱没有明显的影响。以上结果表明,此荧光探针可以灵敏地检测溶液的酸性而不受其他检测物的影响。
基于花菁染料的靶向性比率pH荧光探针的应用。在肝癌细胞中加入Cy-Biotin-O和不同pH值的尼日利亚霉素,检测两个通道的荧光。发现在pH=7.4时,通道1(580~680nm)有强荧光,通道2(700~775nm)没有荧光产生;随着pH的降低,通道1的荧光逐渐减弱,通道2的荧光逐渐增强。这些结果说明探针Cy-Biotin-O能够比率检测细胞内的pH,为监控人体内pH相关病变提供了一种可靠的手段。
附图说明
图1为荧光探针的合成路线。
图2为荧光探针在不同pH下的荧光光谱图。
横坐标为波长,纵坐标为荧光强度。(A)550~750nm荧光光谱图,激发波长为540nm;(B)720~900nm荧光光谱图,激发波长为716nm。荧光探针的浓度为10μM,pH值分别为4.12,4.30,4.50,4.72,4.93,5.09,5.31,5.44,5.59,5.82,6.02,6.24,6.44,6.67,6.84,7.03,7.24,7.37,7.50。
图3为荧光探针对不同pH荧光线性响应图。
横坐标为pH值,纵坐标为758nm和645nm荧光强度比值的对数。
图4为荧光探针在不同pH下的紫外可见吸收光谱图。
荧光探针的浓度为10μM,pH值为4.12,4.30,4.50,4.72,4.93,5.09,5.31,5.44,5.59,5.82,6.02,6.24,6.44,6.67,6.84,7.03,7.24,7.37,7.50。
图5为荧光探针的选择性图。
荧光探针的浓度为10μM,pH为4.12和7.37。1:Blank;2:Mg2+;3:Ca2+;4:K+;5:Na+;6:Fe3+;7:ClO-;8:H2O2;9:·OH;10:NO2 -;11:NO3 -;12:H2S;13:SO3 2-;14:Phe;15:Lys;16:Leu;17:Val;18:Trp;19:Ile;20:Met;21:Thr;22:Cys;23:Hcy;24:GSH,各种分析物浓度为200μM。
图6为荧光探针在不同pH下响应时间的测定。
荧光探针的浓度为10μM,pH值为5.44,6.02,6.44,7.24。
图7为细胞毒性试验。
横坐标为荧光探针的浓度,纵坐标为细胞的存活率。
图8荧光探针在不同pH下的细胞成像图。
细胞在不同pH下用荧光探针Cy-Biotin-O进行成像。(A)通道1,不同pH下580-680nm范围的荧光成像,激发波长为560nm;通道2,不同pH下700-775nm范围的荧光成像,激发波长为640nm;(B)通道2和通道1荧光强度的比值与细胞pH的关系。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明,但不限于此。
实施例1:
荧光探针的合成
合成路线如图1。pH荧光探针(Cy-Biotin-O)的合成:在20℃下,将Cy-Biotin-Cl(211mg,0.25mmol)用15mL无水DMF溶解后加入50mL的圆底烧瓶中,接着,将三水合乙酸钠(136mg,1mmol)加入上述体系,氮气保护下,升温至90℃,搅拌6h;反应完成后,冷却至室温;粗产物用盐水和二氯甲烷萃取,取有机相在减压条件下除去溶剂,用体积比为20:1的CH2Cl2/CH3OH洗脱剂进行柱层析纯化,得到红色固体化合物Cy-Biotin-O,即为荧光探针。1HNMR(400MHz,DMSO-d6)δ7.97–7.90(m,2H),7.32(d,J=7.3Hz,2H),7.19(t,J=7.7Hz,2H),6.90(t,J=7.1Hz,4H),6.44(s,1H),6.37(s,1H),5.56–5.38(m,2H),4.28(d,J=6.4Hz,1H),4.11(s,1H),3.87–3.70(m,4H),3.22–3.00(m,4H),2.80(dd,J=12.4,5.1Hz,1H),2.58–2.53(m,4H),2.08(t,J=7.5Hz,2H),1.74(s,4H),1.55(s,12H),1.31(d,J=8.6Hz,4H),1.15(t,J=7.0Hz,5H).13C NMR(100MHz,DMSO-d6)δ184.5,172.0,162.7,161.4,161.2,143.7,143.3,138.9,138.8,132.0,131.8,127.8,127.8,125.9,125.7,121.8,120.4,107.2,107.0,92.1,91.8,61.0,59.2,55.4,54.9,45.9,36.2,35.3,28.2,28.1,26.2,25.4,25.3,22.2,10.9.HRMS(ESI-MS)for C45H58N5O3S:m/z found,[M+H]+748.4253(calcd,748.4260)。
实施例2:
荧光探针溶液配制
探针溶液的制备:称取一定量探针溶解在二甲基亚砜(DMSO)中,配成4×10-4M的探针溶液。十二烷基硫酸钠储备溶液的制备:将一定量的十二烷基硫酸钠超声溶解在二次蒸馏水中,配成0.2M的十二烷基硫酸钠储备溶液。将0.25mL的探针溶液、0.25mL的十二烷基硫酸钠储备溶液加入10mL容量瓶,用不同pH值的PBS缓冲溶液定容。得到含有1.0×10-5M荧光探针、5.0×10-3M十二烷基硫酸钠的不同pH待测溶液。
实施例3:
荧光探针在不同pH下荧光光谱的测定
图2为荧光探针在不同pH下的荧光光谱,荧光探针的浓度为10μM,pH值分别为4.12,4.30,4.50,4.72,4.93,5.09,5.31,5.44,5.59,5.82,6.02,6.24,6.44,6.67,6.84,7.03,7.24,7.37,7.50。荧光激发波长为540nm时,发射波长范围为550~750nm;荧光激发波长为716nm时,发射波长范围为720~900nm。激发和发射狭缝宽度均为5nm,所用的荧光测定仪器为日立F4600荧光分光光度计。从图中可以看出,荧光探针在pH=7.50条件下荧光发射位于645nm,758nm几乎没有荧光;在pH值为7.50~4.12时,随着酸性的增强,在758nm处出现了明显的近红外发射峰,645nm的荧光发射逐渐减弱。这是由于H+诱导Cy-Biotin-O质子化以获得具有大π共轭系统的Cy-Biotin-OH,从而产生近红外荧光。并且,随着酸性的增强,探针分子758nm的近红外荧光强度不断增强,645nm的荧光逐渐减弱。图3为探针在不同pH下的线性响应图。758nm和645nm荧光强度比值的对数跟pH呈现线性关系。这说明该探针可以很好地检测酸性环境的pH。
实施例4:
荧光探针在不同pH下的紫外可见吸收光谱的测定
图4为荧光探针在不同pH下的紫外可见吸收光谱图,荧光探针的浓度为10μM,pH值分别为4.12,4.3,4.5,4.72,4.93,5.09,5.31,5.44,5.59,5.82,6.02,6.24,6.44,6.67,6.84,7.03,7.24,7.37,7.50。紫外可见吸收光谱测定用的仪器为安捷伦Cary60紫外可见分光光度计。从图中可以看出,探针本身在540nm附近有吸收带,pH调至酸性后,540nm的吸收明显减小,在716nm附近出现新的吸收峰。
实施例5:
荧光探针对pH测定的选择性
图5为荧光探针pH测定的选择性图。考察在pH为4.1和7.4条件下,10μM的荧光探针溶液中加入生物体内常见的无机离子(Mg2+,Ca2+,K+,Na+,Fe3+),活性氧(ClO-,H2O2,·OH),活性氮(NO2 -,NO3 -),活性硫(H2S,SO3 2-),常见氨基酸(Phe,Lys,Leu,Val,Trp,Ile,Met,Thr)以及生物硫醇(Cys,Hcy,GSH)(200μM)的荧光响应情况。从图中可以看出,只有酸性能引起荧光光谱的改变,其他检测物对探针的荧光光谱没有明显的影响。这些结果表明,荧光探针对pH有很好的选择性。
实施例6:
荧光探针在不同pH下响应时间的测定
我们研究了荧光探针对pH的响应时间,其结果如图6。从图中可以看出,该探针对pH的响应时间为30s,这能够满足在实际样品中进行实时监测的要求。
实施例7:
荧光探针在活细胞中的应用
首先,我们做了细胞毒性试验,如图7所示。当加入0~30μM荧光探针,肝癌细胞的成活率均在90%以上。这可以说明,该荧光探针毒性较小,可应用于检测活细胞内的pH。然后,我们研究荧光探针在活细胞中的应用,选择肝癌细胞进行共聚焦显微成像,结果如图8所示。使用不同pH的尼日利亚霉素调节细胞pH并用荧光探针Cy-Biotin-O进行染色。通道1收集了580~680nm范围的荧光;通道2收集了700~775nm范围的荧光。pH为7.4时,细胞在通道1有强荧光,通道2几乎没有荧光;随着pH的降低,通道1的荧光逐渐减弱,通道2荧光逐渐增强(图8A)。图8B为通道2和通道1荧光强度比值与细胞pH的关系图。这些结果说明探针Cy-Biotin-O能够灵敏地检测细胞内的pH,这为监控人体内pH相关病变提供了一种可靠的手段。
Claims (3)
2.根据权利要求1所述的一种基于花菁染料的靶向性比率pH荧光探针的制备方法,其特征在于,反应步骤如下:
在15~25℃下,将1当量的Cy-Biotin-Cl用10~20mL无水DMF溶解后加入50mL的圆底烧瓶中,接着,将3~5当量的三水合乙酸钠加入上述体系;氮气保护下,升温至80~100℃,搅拌5~7h;反应完成后,冷却至室温;粗产物用盐水和二氯甲烷萃取,取有机相在减压条件下除去溶剂,用体积比为30:1~10:1的CH2Cl2/CH3OH洗脱剂进行柱层析纯化,得到红色固体化合物Cy-Biotin-O,即为所述的荧光探针。
3.根据权利要求1所述的一种基于花菁染料的靶向性比率pH荧光探针的应用,其特征在于,所述荧光探针应用于细胞内pH的检测。
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