CN110407736A - 具有强双光子吸收的近红外化合物的制备及应用 - Google Patents
具有强双光子吸收的近红外化合物的制备及应用 Download PDFInfo
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Abstract
本发明公开了具有强双光子吸收的近红外聚集诱导发光材料的设计合成及其细胞器成像与光动力治疗应用。通过合理的分子结构设计,我们获得了四个具有大双光子吸收截面以及高亮度的近红外聚集诱导发光材料。这些材料具有较大的斯托克斯位移、良好的生物相容性以及优异的光稳定性。其中三个中性材料可以特异性成像脂滴,另外一个阳离子型材料可以特异性成像线粒体。鉴于它们优异的双光子性质,这四种材料可以用于细胞和活体组织的双光子荧光成像。这四种材料在光照下可以有效的产生单线态氧,使它们可以用于双光子激发的细胞器靶向光动力治疗。本发明合成得到的材料,表现出聚集诱导发光的性质,有效克服了传统的荧光染料的缺陷。
Description
技术领域
本发明涉及生物成像与细胞器靶向光动力治疗领域,具体涉及多种强双光子吸收的近红外化合物及其制备方法和生物应用。
背景技术
荧光成像具有操作简单、结果直观、灵敏度高等优点。与可见光相比,近红外光(波长>700nm)具有穿透深度大、生物自发荧光干扰小、对生物体造成的光损伤小等优势,因此开发同时具有近红外激发和发射的荧光染料成为荧光成像领域的研究热点。传统的近红外荧光染料通常具有较大的刚性平面结构,在高浓度或聚集态下易发生π-π堆积而导致荧光淬灭(aggregation-caused quenching,ACQ),除此之外,传统染料常常具有较小的斯托克斯位移、荧光效率低、光稳定性差等缺点。
近年来,聚集诱导荧光(aggregation-induced emission,AIE)材料的发展可以有效地解决上述诸多的疑难问题,然而,已开发的近红外AIE材料的种类仍有限,能用于双光子细胞器荧光成像和治疗的近红外AIE材料的报道更是屈指可数。鉴于此,设计开发具有高亮度近红外发射和强双光子吸收的多功能AIEgens对于生物医学影像及诊疗具有重要实用意义。
发明内容
为了解决上述问题,本发明提供了多种具有强双光子吸收、高亮度近红外发射的聚集诱导荧光材料用于特异性细胞器(脂滴或线粒体)成像以及细胞器靶向的光动力治疗,为生物医学影像及诊疗提供一系列新型探针和光敏剂。
本发明解决其技术问题所采用的技术方案是提供一系列具有强双光子吸收的近红外聚集诱导荧光材料,具有下式所示的结构:
其中,R为各种电子受体,R1和R2为H或为烷基、烷氧基、芳基或其他功能性官能团中的一种。
进一步地,电子受体具体包括如下结构式中的一种:
进一步地,所述R1,R2和R3选自以下结构中的一种:
本发明还提供一种强双光子吸收的近红外聚集诱导荧光材料的制备方法,所述强双光子吸收的近红外聚集诱导荧光材料的制备方法包括以下步骤:
步骤S1、由化合物A和二苯胺衍生物反应得到化合物B,反应式如下:
步骤S2、由化合物B与不同的吸电子受体R通过Knoevenagel缩合反应生成目标化合物,反应式如下:
更加优选地,强双光子吸收的近红外聚集诱导荧光材料包括化合物DCMa、DCIs、DCFu和DCPy。
本发明还提供一种强双光子吸收的近红外聚集诱导荧光材料的用途,其中,所述强双光子吸收的近红外聚集诱导荧光材料用于生物成像。
具体地,所述强双光子吸收的近红外聚集诱导荧光材料可以对多种细胞的脂滴或线粒体进行特异性成像。具有高亮度、高光稳定性和高对比度等优势。所述强双光子吸收的近红外聚集诱导荧光材料可用于细胞和组织层次的大深度双光子荧光成像。
优选地,所用的多种细胞为癌细胞和正常细胞,所用双光子的光源为900nm的飞秒激光器。
另外,所述强双光子吸收的近红外聚集诱导荧光材料在可见光照射下可以有效地产生单线态氧用于癌症细胞的光动力杀伤。
优选地,所用的可见光的光源为低功率的白炽灯,所用癌细胞为HeLa细胞。
实施本发明可以达到以下有益效果:本发明提出了强双光子吸收的近红外聚集诱导荧光分子设计合成新策略,实现了该类分子在近红外发射和聚集诱导发光之间的完美平衡,可广泛应用于生物成像和细胞靶向的光动力治疗中;本发明合成得到的材料表现出聚集诱导发光的性质,固体荧光量子产率高达30%;本发明合成得到的材料表现出近红外发光的特性;本发明合成得到的材料表现出强双光子吸收的特性;本发明合成得到的材料表现出脂滴和线粒体特异性成像的特性;本发明合成得到的材料表现出强单线态氧产生的特性。
附图说明
图1为化合物2的核磁共振氢谱;
图2为化合物2的核磁共振碳谱;
图3为化合物2的高分辨质谱;
图4为化合物3的核磁共振氢谱;
图5为化合物3的核磁共振碳谱;
图6为化合物3的高分辨质谱;
图7为化合物DCMa核磁共振氢谱;
图8为化合物DCMa核磁共振碳谱;
图9为化合物DCMa高分辨质谱;
图10为化合物DCIs的核磁共振氢谱;
图11为化合物DCIs的核磁共振碳谱;
图12为化合物DCIs的高分辨质谱;
图13为化合物DCFu的核磁共振氢谱;
图14为化合物DCFu的核磁共振碳谱;
图15为化合物DCFu的高分辨质谱;
图16为化合物DCPy核磁共振氢谱;
图17为化合物DCPy核磁共振碳谱;
图18为化合物DCPy高分辨质谱;
图19为(A)化合物DCMa、DCIs、DCFu和DCPy在甲苯中的吸收光谱。(B)DCMa在不同溶剂中的荧光溶剂化效应;(C)DCMa在不同溶剂中的紫外吸收;(D)DCMa在不同溶剂中的荧光光谱;
图20为化合物DCMa、DCFu和DCPy在不同溶剂中的(A)紫外吸收和(B)荧光光谱;
图21为化合物DCMa、DCIs、DCFu和DCPy的HOMO和LUMO能级图;
图22为化合物DCMa、DCIs、DCFu和DCPy的双光子吸收截面,溶剂:二氧六环(DCMa、DCIs和DCFu)和四氢呋喃(DCPy);浓度:1×10-4M;
图23为(A)DCMa的聚集诱导发光曲线图;(B)化合物DCMa、DCIs、DCFu和DCPy的荧光强度(I/I0)与水含量关系图;(C)化合物DCMa、DCIs、DCFu和DCPy的聚集体(fw=99%)的荧光光谱;(D)化合物DCMa、DCIs、DCFu和DCPy的固体荧光光谱;
图24为化合物DCMa在丙酮/水混合溶剂中的吸收光谱;
图25为化合物DCIs在丙酮/水混合溶剂中的吸收光谱和荧光光谱;
图26为化合物DCPy在DMSO/水混合溶剂中的吸收光谱和荧光光谱;
图27为化合物DCFu在丙酮/水混合溶剂中的吸收光谱和荧光光谱;
图28为化合物DCMa、DCIs、DCFu和DCPy荧光寿命曲线;
图29为化合物DCMa、DCIs、DCFu和DCPy在水含量99%混合溶剂中形成的聚集体的DLS粒径分布;
图30为化合物(A)DCMa和(B)DCFu在水含量99%混合溶剂中形成的聚集体的SEM图片;
图31为化合物DCMa、DCIs、DCFu和DCPy的单晶结构图;
图32为化合物(A)DCMa、(B)DCIs、(C)DCFu和(D)DCPy的晶体堆积图;
图33为化合物DCMa、DCIs、DCFu和DCPy的细胞毒性;
图34为化合物DCMa、DCIs、DCFu和DCPy对HeLa细胞的特异性成像以及与BODIPY505/515或Mito Green的共染成像:(A)明场;(B,C)共聚焦荧光成像;B1)DCMa、B2)DCIs、B3)DCFu、B4)DCPy、C1-C3)BODIPY 505/515和C4)Mito Green;D1-D4)B和C的合并图;激发波长:488nm,浓度:5×10-7M(DCMa、DCPy、Mito Green和BODIPY 505/515)和2.5×10-6M(DCIs和DCFu);
图35为化合物DCMa、DCIs、DCFu、DCPy、Mito Green和BODIPY 505/515的光稳定性;
图36为化合物DCMa和DCPy对HeLa细胞的双光子荧光成像;浓度:1×10-6M(DCMa)和5×10-7M(DCPy);
图37为化合物(A-F)DCMa(5μM)用于肝组织和DCPy(5μM)用于(H-M)肌肉组织和(O-T)心肌组织的不同深度的双光子荧光成像;(G)肝组织、(N)肌肉组织和(U)心肌组织的Z轴投影图像。双光子激发波长:900nm;
图38为化合物DCMa和DCPy通过小鼠尾静脉注射2小时后在主要小鼠器官的分布;
图39为化合物(A)DCMa通过小鼠尾静脉注射2小时后对肝组织的深度双光子荧光成像和(B)DCPy通过小鼠尾静脉注射2小时后对肾组织的深度双光子荧光成像;双光子激发波长:900nm;
图40为(A)在DCMa、DPIs、DCFu和DCPy存在下,H2DCF-DA的荧光强度随着白光照射时间的变化;浓度:10×10-6M(AIEgens)和5×10-6M(H2DCF-DA);(B)在DCMa、DPIs、DCFu、DCPy和Ce6存在下,ABDA的吸收光谱随着白光照射时间的变化。A0和A分别是ABDA在光照前和光照后在378nm的吸光度;浓度:10×10-6M(AIEgens)和5×10-5M(ABDA)。不同浓度的化合物(C)DCFu和(D)DCPy用于HeLa细胞的光动力杀伤;
图41为不同浓度的化合物Ce6用于HeLa细胞的光动力杀伤。
具体实施方式
为了对本发明的技术特征、目的和效果有更加清楚的理解,现对照附图详细说明本发明的具体实施方式。显然,所描述的实施方式仅仅是本发明一部分实施方式,而不是全部的实施方式。基于本说明书中记载的实施方式,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施方式,都属于本发明保护的范围。
本发明提供了多种具有强双光子吸收的近红外聚集诱导荧光材料,该荧光材料具有如下化学式(I)所示的结构:
其中,R为电子受体,且该电子受体选自如下结构式中的一种:
进一步地,所述R1、R2和R3选自以下结构式中的一种:
进一步地,在本发明中,上述强双光子吸收的近红外聚集诱导荧光材料通过以下方法制备而成,该制备方法包括以下步骤:
步骤S1:由化合物A和二苯胺衍生物反应得到化合物B,具体的反应式如下:
步骤S2:化合物B与不同的吸电子受体R通过Knoevenagel缩合反应生成目标化合物,具体的反应式如下:
进一步地,通过本发明的上述制备方法制备得到的强双光子吸收的近红外聚集诱导荧光材料包括化合物DCMa、DCIs、DCFu和DCPy。
进一步地,本发明还提供一种强双光子吸收的近红外聚集诱导荧光材料的用途,所述强双光子吸收的近红外聚集诱导荧光材料用于生物成像。
具体地,所述强双光子吸收的近红外聚集诱导荧光材料可以对多种细胞的脂滴或线粒体进行特异性成像,具有高亮度、高光稳定性和高对比度等优势。所述强双光子吸收的近红外聚集诱导荧光材料可用于细胞和组织层次的大深度双光子荧光成像。
优选地,所用的多种细胞为癌细胞和正常细胞,所用双光子的光源为900nm的飞秒激光器。
另外,所述强双光子吸收的近红外聚集诱导荧光材料在可见光照射下可以有效地产生单线态氧,用于癌症细胞的光动力杀伤。
优选地,所用的可见光的光源为低功率的白炽灯,所用癌细胞为HeLa细胞。
实施本发明可以达到以下有益效果:
本发明提出了强双光子吸收的近红外聚集诱导荧光分子设计合成新策略,实现了该类分子在近红外发射和聚集诱导发光之间的完美平衡,可广泛应用于生物成像和细胞靶向的光动力治疗中;
本发明合成得到的材料表现出聚集诱导发光的性质,固体荧光量子产率高达30%;
本发明合成得到的材料表现出近红外发光的特性;
本发明合成得到的材料表现出强双光子吸收的特性;
本发明合成得到的材料表现出脂滴和线粒体特异性成像的特性;
本发明合成得到的材料表现出强单线态氧产生的特性。
下文中以DCMa、DCIs、DCFu和DCPy化合物为例,对所述强双光子吸收的近红外聚集诱导荧光化合物的制备及其生物成像和细胞器靶向光动力治疗进行详细的描述。
DCMa、DCIs、DCFu和DCPy的合成路线如下所示:
化合物2的合成
将2,7-二溴-9-乙基咔唑(1)(2.84g,8.04mmol)溶于无水四氢呋喃(25mL)中,然后在丙酮干冰浴中冷却至-78℃。缓慢滴加正丁基锂(4.02mL,8.04mmol)的己烷溶液。-78℃下反应一小时后加入无水DMF(0.92mL)。-78℃下搅拌两小时后,将混合物置于室温下,缓慢加入HCl(2N)使反应淬灭。用二氯甲烷萃取溶液,有机相经过干燥、过滤和浓缩得到粗产物。粗产物进一步经过柱层析色谱(乙酸乙酯/正己烷)分离得到产物2(2.0g,82%)。
对化合物2的化学结构进行表征,得到表征数据:1H NMR(400MHz,CDCl3,ppm):δ10.17(s,1H),8.19(d,J=8.0Hz,1H),8.00(d,J=8.3Hz,1H),7.97(s,1H),7.77(dd,J=8.0Hz,1.2Hz,1H),7.62(d,J=1.5Hz,1H),7.40(dd,J=8.3Hz,1.6Hz,1H),4.41(q,J=7.2Hz,2H),1.48(t,J=7.3Hz,3H),如图1。13C NMR(100MHz,CDCl3,ppm):δ191.81,141.74,139.11,133.52,126.97,122.26,121.96,121.15,120.91,120.27,120.00,111.47,108.91,37.30,13.25,如图2。HRMS):m/z计算的分子量为[M]+C15H12BrNO 301.0102;测得的分子量为301.0101,如图3。
化合物3的合成
将化合物2(0.31g,1.02mmol)、二苯胺(0.26g,1.54mmol)和碳酸铯(0.50g,1.54mmol)溶于甲苯(5mL)中并通氮气保护。然后在溶液中加入醋酸钯(0.012g,0.054mmol)和三叔丁基膦(26μL,0.11mmol)。加热升温至120℃下反应24小时后冷却至室温。反应混合物用盐酸(1M)和水洗涤后干燥并浓缩。粗产物进一步经过柱层析色谱(乙酸乙酯/正己烷)分离得到产物3(0.35g,88%)。
对化合物3的化学结构进行表征,得到表征数据:1H NMR(400MHz,CDCl3,ppm):δ10.12(s,1H),8.09(d,J=8.0Hz,1H),7.97(d,J=8.5Hz,1H),7.90(s,1H),7.72(dd,J=8.0Hz,1.2Hz,1H),7.31-7.27(m,4H),7.18-7.16(m,4H),7.10-7.04(m,3H),7.01(dd,J=8.5Hz,1.8Hz,1H),4.26(q,J=7.2Hz,2H),1.35(t,J=7.2Hz,3H),如图4。13C NMR(100MHz,CDCl3,ppm):δ191.95,147.67,147.28,142.36,139.40,132.34,128.70,127.84,123.91,122.50,121.47,121.31,119.08,116.71,116.56,108.24,102.90,37.02,13.21,如图5。HRMS:m/z计算的分子量为[M]+C27H22N2O 390.1732;测得的分子量为390.1729,如图6。
化合物DCMa的合成
将化合物3(0.39g,1.0mmol)和丙二腈(0.08g,1.2mmol)溶于无水乙醇(5mL)中。加热回流反应四小时后冷却至室温,生成红色沉淀化合物,经过过滤、乙醇洗涤和干燥得到粗产物。粗产物进一步经过乙腈重结晶得到晶态化合物DCMa(0.37g,85%)。
对化合物DCMa的化学结构进行表征,得到表征数据:1H NMR(400MHz,CDCl3,ppm):δ8.07(s,1H),8.04(d,J=8.2,1H),7.94(d,J=8.6,1H),7.89(s,1H),7.62(dd,J=8.2Hz,1.4Hz,1H),7.33 7.29(m,4H),7.19 7.18(m,4H),7.12 7.08(m,2H),7.06(d,J=1.7,1H),7.01(dd,J=8.6Hz,1.9Hz,1H),4.22(q,J=7.2,2H),1.37(t,J=7.2,3H).,如图7。13C NMR(100MHz,CDCl3,ppm):δ159.92,148.58,147.01,143.01,139.22,128.80,128.24,126.21,124.31,122.96,122.64,121.63,119.43,116.48,116.27,114.15,113.32,109.29,102.01,77.91,37.09,13.09,如图8。HRMS:m/z计算的分子量为[M]+C30H22N4 438.1844;得到的分子量为438.1860,如图9。
化合物DCIs的合成
将化合物3(0.39g,1.0mmol)和化合物5(0.2g,1.1mmol)溶于无水乙腈(8mL)中。加入一滴哌啶后,体系加热回流反应四小时。冷却至室温,生成红色沉淀化合物,经过过滤、乙腈洗涤和干燥得到粗产物。粗产物进一步经过乙腈重结晶得到红色晶态化合物DCIs(0.42g,75%)。
对化合物DCIs的化学结构进行表征,得到表征数据:1H NMR(400MHz,CDCl3,ppm):δ7.97(d,J=8.1Hz,1H),7.91(d,J=8.4Hz,1H),7.49(s,1H),7.37(d,J=8.1Hz,1H),7.297.25(m,5H),7.17 7.09(m,6H),7.05 7.02(m,2H),6.97(dd,J=8.5Hz,1.8Hz,1H),6.89(s,1H),4.23(q,J=7.2Hz,2H),2.62(s,2H),2.53(s,2H),1.36(t,J=7.2Hz,3H),1.10(s,6H),如图10。13C NMR(100MHz,CDCl3,ppm):δ168.66,153.74,147.43,146.67,141.58,140.00,137.99,131.66,128.62,127.28,124.21,123.60,122.38,122.19,120.71,119.53,118.91,117.51,116.67,113.13,112.44,106.41,103.41,77.04,42.36,38.63,36.84,31.46,27.44,13.20,如图11。HRMS:m/z计算的分子量为[M]+C39H34N4 558.2783;得到的分子量为558.2764,如图12。
化合物DCFu的合成
将化合物3(0.38g,0.97mmol)和6(0.18g,0.97mmol)溶于无水乙醇(13mL)中。加热回流过夜后冷却至室温,生成紫色沉淀化合物,经过过滤、乙醇洗涤和干燥得到粗产物。粗产物进一步经过乙醇重结晶得到紫色晶态化合物DCFu(0.46g,85%)。
化合物DCFu的化学结构进行表征,得到表征数据:1H NMR(400MHz,CDCl3,ppm):δ7.98(d,J=8.2Hz,1H),7.96(s,1H),7.91(d,J=8.5Hz,1H),7.69 7.61(m,5H),7.59(dd,J=8.2Hz,1.2Hz,1H),7.30 7.26(m,4H),7.18 7.16(m,4H),7.08 7.04(m,3H),6.98(dd,J=8.5Hz,1.8Hz,1H),6.66(s,1H),4.24(q,J=7.2Hz,2H),1.35(t,J=7.2Hz,3H),如图13。13CNMR(100MHz,CDCl3,ppm):δ163.88,163.19,147.62,147.22,144.23,142.32,139.81,131.49,128.93,128.70,128.40,127.64,127.28,125.48,123.96,123.47,122.92,122.56,121.19,119.40,116.89,116.52,111.43,110.97,102.75,96.86,36.90,13.18,如图14。HRMS:m/z计算的分子量为[M]+C38H27N3O2 557.2103;得到的分子量为557.2127,如图15。
化合物DCPy的合成
将化合物3(0.5g,1.28mmol)和1,4-二甲基吡啶碘化物(7)(0.27g,1.16mmol)溶于无水乙醇(15mL)中。加入一滴哌啶后,体系加热回流反应四小时。冷却至室温,生成红色沉淀化合物,经过过滤、乙醇洗涤和干燥得到碘化物(0.56g,80%)。碘化物进一步溶解在丙酮(20mL)中,加入饱和的六氟磷酸钾(20mL)。搅拌三十分钟后,溶液浓缩得到粗产物。粗产物经过柱层析色谱(二氯甲烷/甲醇)得到红色晶态化合物DCPy(0.57g,99%)。
对化合物DCPy的化学结构进行表征,得到表征数据:1H NMR(400MHz,DMSO-d6,ppm):δ8.81(d,J=6.7Hz,2H),8.19 8.11(m,4H),8.07(d,J=8.4Hz,1H),7.93(s,1H),7.627.56(m,2H),7.31 7.28(m,4H),7.18(s,1H),7.06 7.01(m,6H),6.86(dd,J=8.4Hz,1.7Hz,1H),4.30(q,J=6.9Hz,2H),4.22(s,3H),1.23(t,J=7.1Hz,3H),如图16。13C NMR(100MHz,DMSO-d6,ppm):δ152.58,147.36,146.49,144.77,141.95,141.59,140.00,131.75,129.32,124.10,123.50,122.94,122.73,121.79,121.71,120.09,119.50,117.61,116.77,108.58,104.18,46.60,36.80,13.45,如图17。HRMS:m/z计算的分子量为[M]+C34H30F6N3P 625.2082;得到的分子量为625.2060,如图18。
上述制得的强双光子吸收的近红外聚集诱导荧光材料可以用于生物成像和细胞器靶向的光动力治疗。
此外,该强双光子吸收的近红外聚集诱导荧光材料可以对多种细胞的脂滴或线粒体进行特异性成像,具有高亮度、高光稳定性和高对比度等优势。进一步地,所述强双光子吸收的近红外聚集诱导荧光材料可用于细胞和组织层次的大深度双光子荧光成像。此外,该双光子吸收的近红外聚集诱导荧光材料在可见光照射下可以有效地产生单线态氧用于癌症细胞的光动力杀伤。
对合成得到的DCMa、DCIs、DCFu和DCPy以及中间体的化学结构进行了核磁表征,结果如图1~图18所示。
光物理性质表征
我们首先对目标化合物的光物理性质进行了研究(图19)。DCMa、DCIs、DCFu和DCPy在甲苯中的最大吸收波长为480,491,528和496nm,这主要归因于该类分子的分子内电荷转移(ICT)效应。通过吸收光谱的比较,我们可以得出结论,这四种化合物中电子受体的吸电子能力为DCMa<DCIs<DCPy<DCFu。理论计算结果也显示这四种化合物中存在显著的ICT效应(图21)。此外,我们对四种化合物在不同溶剂中的光学行为进行了研究。结果显示,随着溶剂的极性增加,四种化合物的荧光发射均具有显著的溶剂化效应(图19,图20)。在强极性溶剂如DMSO中,化合物呈现出较弱的荧光,这主要是因为化合物在强极性溶剂中表现出的扭曲分子内电荷转移(TICT)效应。
鉴于四种化合物具有强的推拉电子结构,我们通过双光子激发荧光(TPEF)方法对化合物的双光子性质进行了研究。如图22,四种化合物在二氧六环中的双光子吸收光谱显示,四种化合物在800-1040nm范围内均具有优异的双光子吸收性质,最大双光子吸收截面值分别为394(DCMa)、548(DCIs)、887(DCFu)和390(DCPy)GM。这一结果显示,对于具有同样给电子基团的四种化合物,吸电子基团的吸电子能力的增强可以显著增强化合物的双光子吸收性质。值得注意的是,它们的双光子吸收截面值比文献中已报道的类似化合物具有较大程度的提高。这一结果也证实了我们的分子设计。
我们对化合物的聚集诱导荧(AIE)光行为也进行了研究(图23-图27,表1)。在纯有机溶剂如丙酮和DMSO中,四种化合物表现出较弱的荧光,随着体系中水含量的增加,四种化合物的荧光强度先呈现出下降的趋势,这主要是因为随着水含量的增加,溶液中溶剂的极性增强,由于分子的TICT效应,荧光强度逐渐降低。进一步增加水含量,四种化合物均形成聚集体,化合物的荧光显著增强。这一结果证实这四种化合物均具有典型的聚集诱导荧光性质。DCMa、DCIs、DCFu和DCPy的聚集体的荧光发射波长分别为665、709、755和698nm。鉴于它们优异的AIE性质,四种化合物在固体状态下表现出优异的固体荧光性质,固体发射波长分别为664、673、765和678nm。固体荧光量子产率分别为30%、14%、2%和7%。时间分辨荧光测试表明四种化合物的荧光寿命在2.62-10.05纳秒范围内(图28)。值得注意的是,四种化合物均具有较大的斯托克斯位移(Δν=187-244nm),这可以避免激发光和荧光发射间的相互干扰,对于生物成像应用具有重要意义。我们也通过动态光散射(DLS)测试对在混合溶液中形成的聚集体的尺寸进行了测试(图29)。DCMa、DCIs、DCFu和DCPy所形成的聚集体的尺寸分别为65、87、81和64nm。我们也利用扫描电子显微镜(SEM)对聚集体的形貌进行了观察,结果显示DCMa和DCFu所形成的聚集体为球状聚集体,尺寸大小跟DLS测试相吻合。
表1为化合物DCMa、DCIs、DCFu和DCPy的光物理性质;
表1
a)在甲苯溶液中测量;b)使用积分球确定;c)在总悬浮液中测量,fw=99%fw=99%;d)斯托克斯转移.
为了进一步探究化合物的结构和性质间的构效关系,我们得到了四种化合物的单晶结构(图31)。晶体结构显示,分子内咔唑单元平面性较好。对于四种化合物来说,咔唑与电子受体间具有较小的二面角,这表明分子具有良好的共轭结构。相对而言,分子内的二苯胺具有扭曲的结构,苯环的扭转角为28.98°-58.99°,二苯胺与咔唑间的夹角为26.98°-47.50°。结果显示,四种化物分子的推拉电子结构以及延长的π共轭体系不仅可以有效地红移化合物的发射波长,而且还可以增强化合物的非线性光学性质,这一结果跟它们的光学性质相吻合。此外,鉴于二苯胺的扭曲结构,二苯胺的存在可以有效地减少分子间的π-π相互作用,促进分子的AIE特性(图32)。在晶体堆积结构中,多种弱作用力限定了分子的构象并且限制了分子内的转动,这可以有效地减少分子在固态下的非辐射跃迁,使得分子在固体状态下发出高亮度近红外荧光。
生物应用和细胞器靶向光动力治疗
鉴于四种化合物具有优异的近红外AIE性质、强双光子吸收性质和大的斯托克斯位移,我们首先探索了它们在生物成像方面的应用。我们首先对四种化合物的细胞毒性进行研究,发现四种化合物在测试范围内均具有可以忽略的细胞毒性(图33)。进一步的细胞成像实验表明,三种中性AIE化合物(DCMa、DCIs和DCFu)可以特异性成像脂滴(lipiddroplet)(图34),这主要是由于亲脂性的AIE材料可以选择性地富集于脂滴。另外一种带正电荷的化合物DCPy可以特异性靶向线粒体(mitochondria),DCPy特异性靶向线粒体的特性主要来源于其携带正电荷的属性,与高负电位的线粒体有较强的静电相互作用,选择性地富集于线粒体内。光稳定性实验证实四种化合物均具有优异的光稳定性(图35)。鉴于化合物的双光子活性,DCMa和DCPy可用于脂滴和线粒体的双光子细胞和组织成像(图36和图37)。此外,通过小鼠尾静脉注射,AIE材料可应用于小鼠肝脏和肾脏器官内脂滴和线粒体的双光子荧光成像(图38和图39)。得益于近红外双光子激发和近红外发射,其成像深度可达150μm。
值得一提的是,在白光灯照射下,四种化合物均可以有效地产生单线态氧,其中,DCPy产生活性氧的能力最好,远远优异于常用的光动力治疗试剂Ce6(图40)。细胞存活率分析(MTT assay)显示,在低功率白光(4.2mW/cm-2)照射下,DCPy能够快速杀死癌细胞,其功效优于Ce6(图41)。
上面结合附图对本发明的实施方式进行了描述,但是本发明并不局限于上述的具体实施方式,上述的具体实施方式仅仅是示意性的,而不是限制性的,本领域的普通技术人员在本发明的启示下,在不脱离本发明宗旨和权利要求所保护的范围情况下,还可做出很多变形,这些均属于本发明的保护范围之内。
Claims (10)
1.一种具有强双光子吸收的近红外化合物,其特征在于,所述近红外化合物具有下式所示的结构:
其中,R为吸电子受体,R1和R2为H或为烷基、烷氧基、芳基或其他功能性官能团中的一种。
2.如权利要求1所述的强双光子吸收的近红外化合物,其特征在于,所述吸电子受体选自以下结构中的一种:
3.如权利要求2所述的强双光子吸收的近红外化合物,其特征在于,所述R1,、R2和R3选自以下结构中的一种:
4.一种制备如权利要求1~3中任意一项所述的强双光子吸收的近红外化合物的方法,其特征在于,所述方法包括以下步骤:
步骤S1、由化合物A和二苯胺衍生物反应得到化合物B,反应式如下:
步骤S2、由化合物B与不同的吸电子受体R通过Knoevenagel缩合反应生成目标化合物,反应式如下:
5.如权利要求4所述的制备强双光子吸收的近红外化合物的方法,其特征在于,所述方法还包括以下步骤:
由2,7-二溴-9-乙基咔唑的单醛基化反应得到化合物A,反应式如下:
6.一种如权利要求1~3中任意一项所述的强双光子吸收的近红外化合物在聚集诱导发光中的应用,其特征在于,所述化合物具有高亮度远红外和近红外荧光发射。
7.如权利要求6所述的强双光子吸收的近红外化合物在聚集诱导发光中的应用,其特征在于,所述化合物在近红外区域具有强双子吸收。
8.如权利要求6所述的强双光子吸收的近红外化合物在聚集诱导发光中的应用,其特征在于,所述化合物用于对细胞和组织中的脂滴或线粒体进行特异性成像。
9.如权利要求6所述的强双光子吸收的近红外化合物在聚集诱导发光中的应用,其特征在于,所述化合物在光照下有效地产生单线态氧。
10.如权利要求6所述的强双光子吸收的近红外化合物在聚集诱导发光中的应用,其特征在于,所述化合物用于光动力治疗杀伤癌细胞。
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