CN111961072B - 一种溶酶体靶向的红外二窗发射荧光染料及其制备方法和应用 - Google Patents
一种溶酶体靶向的红外二窗发射荧光染料及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于生物荧光检测材料技术领域,具体涉及一种溶酶体靶向的红外二窗发射荧光染料及其制备方法和应用。本发明将苯胺衍生物和五元杂环共轭衍生物连接到氮杂氟硼烷母体结构上,实现了材料红外二窗的发射。该目标荧光染料不仅具有良好的光稳定性、热稳定性、化学稳定性,还表现出优异的光热性能、光声成像、肿瘤光热治疗的性质,同时,本发明提供的溶酶体靶向的红外二窗发射荧光染料的制备方法,其设计、合成具有理论基础的支持,且制备方法简单、合成条件温和、原料丰富、目标产物收率高,这为设计、合成高效的诊疗试剂具有重要的指导意义。
Description
技术领域
本发明属于生物荧光检测材料技术领域,具体涉及一种溶酶体靶向的红外二窗发射荧光染料及其制备方法和应用。
背景技术
溶酶体是细胞内一种重要的细胞器,在细胞的正常生命活动中发挥至关重要的作用:细胞内大分子的降解和再循环利用、细胞内和细胞外各种材料的降解以及损伤细胞器的再回收等。溶酶体具有高度动态的特性,他们的形态和空间分布是不断变化的,而其数量和形态的变化往往能够代表细胞所处的生命活动状态。溶酶体异常通常会引发多种疾病(如痛风、溶酶体贮积症或矽肺等),并且病变过程中常伴随溶酶体数量、大小、形状、结构等方面的变化。因此,发展非侵害性、长时程的荧光染料对溶酶体进行特异性成像不仅能够实时监测溶酶体在细胞生命活动过程中所发生的各种变化,而且对进一步了解溶酶体的生理学和病理学作用具有重要意义。
荧光染料作为检测标记因其灵敏度高、操作方便等特点而逐渐取代放射性同位素,并广泛应用于荧光免疫、荧光探针、细胞染色等领域。以荧光染料为核心的荧光显微成像具有高时空分辨能力,通过染色标记细胞的各类细胞器和生物膜,使细胞内各个细胞器之间的空间关系一目了然。目前,用于活细胞溶酶体特异性染色的荧光染料已成为荧光显微成像领域的研究热点之一,相应的染料已经得到了广泛报道。但是,多数用于溶酶体成像的荧光染料仍存在很大不足,例如短波长激发和发射(一般为600-650nm)而限制了它们在体内的实际应用,这也引发了许多问题,包括体内自发荧光的干扰、成像试剂的光漂白、对生物样品的光损伤现象等。
近年来,由于近红外二窗成像生物(NIR-II,1000-1700nm)窗口具有深部的组织穿透、高的信号背景比(SBR)、高的最大允许暴露激光等优点,其得到了广泛的研究关注。目前报道的二窗成像造影剂有:过渡金属硫化物/氧化物的开发半导体、单壁碳纳米管、量子点(QDs)、贵金属和半金属纳米颗粒(NPs)、有机高分子纳米材料、小分子有机荧光团等。然而,由于无机材料和有机高分子纳米材料的长期毒性和排泄时间未知限制了它们的临床应用。因此,设计具有良好生物相容性的、溶酶体靶向的红外二窗发射荧光染料面临着挑战。
发明内容
因此,本发明要解决的技术问题在于克服现有技术中的红外二窗发射荧光染料的长期毒性以及排泄时间长等缺陷,从而提供一种溶酶体靶向的近红外二窗发射荧光染料及其制备方法和应用。
为此,本发明提供如下技术方案:
本发明提供一种溶酶体靶向的近红外二窗发射荧光染料,具有如下式所示结构:
其中,所述Ar选自
所述R,R1独立的选自具有1-16个碳原子的直链或支链烃基,具有6-16个碳原子的芳香环取代基中的一种。
进一步地,所述R、R1独立的选自具有1-16个碳原子的直链或支链烷基、烯基、炔基,具有6-16个碳原子的芳香环取代基中的一种。
进一步地,所述R、R1独立的选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环戊基、环己基、苯基或苄基中的一种;
优选的,所述所述R、R1独立的选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基中的一种。
进一步地,所述溶酶体靶向的红外二窗发射荧光染料具有如下式之一所示的结构:
本发明还提供一种上述的溶酶体靶向的红外二窗发射荧光染料的制备方法,合成路线如下:
依次通过醛酮的迈克加成消除反应、加成反应、加成消除反应、配位反应得到。
进一步地,所述步骤I的反应时间为10-16h,反应温度为室温;
所述步骤II的反应时间为20-24h,反应温度为60-85℃;
所述步骤III的反应时间为20-48h,反应温度为85-140℃;
所述步骤IV的反应时间为3-6h,反应温度为0℃或者室温;反应结束后用甲醇或乙醇淬灭反应。
进一步地,所述步骤I在碱金属氢氧化物的水溶液和低碳醇的混合溶液中进行反应;
优选的,所述碱金属氢氧化物为氢氧化钠或氢氧化钾;
优选的,所述低碳醇为甲醇或乙醇。
进一步地,所述步骤II中所用的溶剂为甲醇或乙醇,优先的为乙醇;
所述步骤III中所用的溶剂为甲醇、乙醇、正丁醇或者乙酸,优选的为乙醇;
所述步骤IV中所用的溶剂为二氯甲烷或者四氢呋喃,优选的为二氯甲烷。
进一步地,所述步骤I的反应溶剂为乙醇和氢氧化钠水溶液的混合溶液;优选的,二者的体积比为2-5:1;
所述步骤II的反应溶剂为乙醇和乙二胺的混合溶液;优选的,二者的体积比为5-10:2;
所述步骤III的反应溶剂为正丁醇和醋酸铵的混合溶液;优选的,二者的用量比为2-5mL:5g;
所述步骤IV中反应在弱碱性条件下进行,溶剂为二氯甲烷,弱碱性条件由氮氮二异丙基乙胺提供;优选的,二者的体积比优选为15:2。
本发明还提供一种上述溶酶体靶向的红外二窗发射荧光染料在光热成像、光热成像或红外二窗荧光成像、小鼠肿瘤光热治疗中的应用。
本发明技术方案,具有如下优点:
1.本发明提供的溶酶体靶向的红外二窗发射荧光染料,将苯胺衍生物和五元杂环共轭衍生物连接到氮杂氟硼烷母体结构上,实现了材料红外二窗的发射。该目标荧光染料生物相容性好,不仅具有近红外二窗的荧光发射、良好的光稳定性、热稳定性、化学稳定性,还表现出优异的光热性能、光声成像、肿瘤光热治疗的性质。
2.本发明提供的溶酶体靶向的红外二窗发射荧光染料的制备方法,其设计、合成具有理论基础的支持,且制备方法简单、合成条件温和、原料丰富、目标产物收率高,这为设计、合成高效的诊疗试剂具有重要的指导意义。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明实施例1中制备得到的化合物5-1的1H-NMR图;
图2为本发明实施例1中制备得到的化合物5-1的13C-NMR图;
图3为本发明实施例1中制备得到的化合物5-1的吸收和发射光谱图;
图4为本发明实施例1中制备得到的化合物5-1与吲哚菁绿(ICG)的光稳定性对比图;
图5为本发明实施例1中制备得到化合物5-1的热稳定性效果图;
图6为本发明实施例1中制备得到化合物5-1的光热效果图;
图7为本发明实施例1中制备得到化合物5-1的光声信号效果图;
图8为本发明实施例1中制备得到化合物5-1的激发波长依赖的发射光谱图;
图9为本发明实施例1中制备得到化合物5-1溶酶体靶向的细胞成像图;
图10为本发明实施例1中制备得到化合物5-1纳米粒子的细胞毒性实验数据。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明,并不局限于所述最佳实施方式,不对本发明的内容和保护范围构成限制,任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品,均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者,按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规试剂产品。
实施例1
本实施例提供一种溶酶体靶向的红外二窗发射荧光染料的制备方法,合成路线如下所示:
具体步骤包括:
化合物2-1的合成:
在1.46g 1-1(约10mmol)、1.91g(约10mmol)对乙胺基本乙酮和30mL的纯乙醇混合溶液中,缓慢加入10mL氢化钠水溶液(含2.00g氢氧化钠)。常温反应12h后,抽滤。得到黄色固体,冷乙醇洗涤,真空干燥。得到2.59g的化合物2-1(产率约81%)。
化合物2-1的核磁:1H NMR(400MHz,CDCl3)δ(ppm)=8.04(d,J=6.4Hz,2H),7.77(dd,J=15.2,2.4Hz,1H),7.66(dd,J=15.6,3.2Hz,1H),7.59(d,J=7.6Hz,1H),7.51(d,J=8.0Hz,1H),7.38–7.33(m,1H),7.26–7.22(m,1H),6.96(d,J=1.2Hz,1H),6.68(d,J=7.2Hz,2H),3.44(q,J=6.4Hz,4H),1.22(t,J=5.2Hz,6H)。
化合物3-1的合成:
3.19g 2-1(约10mmol)、15mL硝基甲烷、8mL二乙胺和20mL纯乙醇的混合液在回流条件(80℃)下反应过夜,通过硅胶柱层析分离法(展开剂乙酸乙酯:石油醚=4:1,v/v)2.93g化合物3-1(产率约77%)。
化合物3-1的1H NMR(400MHz,CDCl3)δ(ppm)=7.85(d,J=7.6Hz,2H),7.48(d,J=7.6Hz,1H),7.42(d,J=8.0Hz,1H),7.26–7.17(m,2H),6.64–6.59(m,3H),4.94–4.82(m,2H),4.50–4.44(m,1H),3.53–3.36(m,6H),1.20(t,J=6.4Hz,6H)。
化合物4-1的合成:
化合物3-1、50g醋酸铵固体、20mL正丁醇的混合物,加热回流(120℃)24h。反应液减压过滤、冷乙醇洗涤,所得化合物4-1直接用于下步反应。
化合物5-1的合成:
在0.134g(0.2mmol)4-1、15mL干燥二氯甲烷、2mL氮氮二异丙基乙胺的混合液中,缓慢加入3mL的三氟化硼乙醚,常温反应4小时。反应结束后,用乙醇猝灭过量的三氟化硼乙醚,利用旋蒸仪减压除去低沸点溶剂,减压抽滤得到的固体,用冷乙醇洗涤。利用薄层层析法分离(展开剂二氯甲烷:石油醚=1:4,v/v)得到蓝色固体产物5-1 0.109g(产率约76%)。
蓝色固体产物5-1的核磁:1H NMR(400MHz,CDCl3)δ(ppm)=8.18(d,J=3.6Hz,4H),7.77–7.66(m,4H),7.57(d,J=8.0Hz,2H),7.38–7.28(m,4H),6.76(s,4H),3.48(q,J=12.8Hz,8H),1.26(t,J=7.2Hz,12H)。
13C NMR(151MHz,CDCl3)δ(ppm)=156.08,155.11,150.65,149.64,132.08,129.47,125.24,123.19,121.54,118.39,116.23,111.43,111.13,108.36,44.60,12.81。
通过核磁共振氢谱和碳谱(图1和2)证明了化合物5-1的正确性。
实施例2
本实施例提供一种溶酶体靶向的红外二窗发射荧光染料的制备方法,合成路线如下所示:
具体步骤包括:
化合物2-2的合成:
在1.62g 1-2(约10mmol)、1.91g(约10mmol)对乙胺基本乙酮和30mL的纯乙醇混合溶液中,缓慢加入10mL氢化钠水溶液(含2.00g氢氧化钠)。常温反应12h后,抽滤。得到黄色固体,冷乙醇洗涤,真空干燥。得到3.02g的化合物2-2(产率约90%)。
化合物3-2的合成:
3.35g 2-2(约10mmol)、15mL硝基甲烷、8mL二乙胺和20mL纯乙醇的混合液在回流条件(75℃)下反应过夜,通过硅胶柱层析分离法(展开剂乙酸乙酯:石油醚=4:1,v/v)3.29g化合物3-2(产率约83%)。
化合物4-2的合成:
3.29g化合物3-2、50g醋酸铵固体、20mL正丁醇的混合物,加热回流(130℃)24h。反应液减压过滤、冷乙醇洗涤,所得化合物4-2直接用于下步反应。
化合物5-2的合成:
在0.141g(0.2mmol)4-2、15mL干燥二氯甲烷、2mL氮氮二异丙基乙胺的混合液中,缓慢加入3mL的三氟化硼乙醚,常温反应4小时。反应结束后,用乙醇猝灭过量的三氟化硼乙醚,利用旋蒸仪减压除去低沸点溶剂,减压抽滤得到的固体,用冷乙醇洗涤。利用薄层层析法分离(展开剂二氯甲烷:石油醚=1:4,v/v)得到蓝色固体产物5-2 0.140g(产率约93%)。
实施例3
本实施例提供一种溶酶体靶向的红外二窗发射荧光染料的制备方法,合成路线如下所示:
具体步骤包括:
化合物2-3的合成:
在1.73g 1-3(约10mmol)、1.91g(约10mmol)对乙胺基本乙酮和30mL的纯乙醇混合溶液中,缓慢加入10mL氢化钠水溶液(含2.00g氢氧化钠)。常温反应24h后,抽滤。得到黄色固体,冷乙醇洗涤,真空干燥。得到3.08g的化合物2-3(产率约91%)。
化合物3-3的合成:
3.46g 2-3(约10mmol)、15mL硝基甲烷、8mL二乙胺和20mL纯乙醇的混合液在回流条件(70℃)下反应过夜,通过硅胶柱层析分离法(展开剂乙酸乙酯:石油醚=4:1,v/v)3.30g化合物3-3(产率约81%)。
化合物4-3的合成:
3.30g化合物3-3、50g醋酸铵固体、20mL正丁醇的混合物,加热回流(110℃)24h。反应液减压过滤、冷乙醇洗涤,所得化合物4-3直接用于下步反应。
化合物5-3的合成:
在0.145g(0.2mmol)4-3、15mL干燥二氯甲烷、2mL氮氮二异丙基乙胺的混合液中,缓慢加入3mL的三氟化硼乙醚,常温反应4小时。反应结束后,用乙醇猝灭过量的三氟化硼乙醚,利用旋蒸仪减压除去低沸点溶剂,减压抽滤得到的固体,用冷乙醇洗涤。利用薄层层析法分离(展开剂二氯甲烷:石油醚=1:4,v/v)得到蓝色固体产物5-3 0.149g(产率约96%)。
实验例
1、吸收及其红外二窗发射性能测试
分别用分光光度计和发光光谱仪测试化合物在2mL DMSO溶液(10-6M)中的吸收和发射光谱,激发波长为808nm。通过吸收发射光谱(图3)对比,证明了化合物5-1具有近红外二窗的发射,其可以用做二窗成像造影剂。
2、光热稳定性测试
用808nm 0.5W cm-2激光照射本发明实施例1制备得到的化合物5-1或吲哚菁绿(ICG)的二甲基亚砜(DMSO)溶液(10-6M),用吸收光谱仪测试不同照射时间时,溶液的吸收,照射之前,溶液最大吸收波长处的吸收值为I0,其他照射时间下的吸收值为I。横坐标为照射时间,纵坐标为I/I0的比值。通过光稳定性(图4)对比,随着光照时间的延长,化合物5-1溶液的吸收强度基本没有变化,ICG溶液的吸收强度明显降低,证明了材料具有良好的抗光漂白性。
3、热稳定性测试
用808nm 0.5W cm-2激光照射化合物5-1或ICG的二甲基亚砜(DMSO)溶液(10-6M),用光热成像仪记录溶液的温度变化,当溶液温度达到最大值以后,停止照射。当溶液温度降到室温以后,重复上述过程。第一次的溶液最大温度变化为I0,其他重复过程的最大温度变化为I。横坐标为重复照射次数,纵坐标为I/I0的比值。通过光稳定性(图5)对比,随着重复次数的增加,化合物5-1溶液的温度变化基本没有变化,ICG的温度变化明显降低,证明了材料具有良好的抗热稳定性。
4、光热转换效果测试
用808nm 0.5W cm-2激光照射5-1的二甲基亚砜(DMSO)溶液(10-6M)和纯DMSO溶液,用光热成像仪记录溶液的温度变化,通过温度变化(图6)对比,随着光照时间增加,化合物5-1溶液的温度变化一直增大,纯DMSO溶剂的温度变化很小,证明了材料具有良好的光热转换效果。
5、光声信号测试
用光声成像系统测试化合物5-1的二甲基亚砜(DMSO)溶液(10-6M)和纯DMSO溶液的光声信号。激发波长为808nm。通过光声信号(图7)对比,化合物5-1溶液表现出明显的光声信号,纯DMSO溶剂基本没有光声信号,证明了材料具有良好的光声信号。
6、溶酶体靶向的证明实验
将染料溶于DMSO溶液中,配制成10-5mol/L的溶液,将2μL上述溶液加入2mL细胞培养介质中,由10%胎牛血清以及90%含青霉素(80U/mL)和链霉素(80μg/mL)的不完全DMEM(高糖)培养基所配成的DMEM培养液,以此作为培养基在37℃下培养SKOV3细胞1小时,通过激光共聚焦扫描显微镜,以488nm作为激发波长,可以在红光通道下观察到在细胞溶酶体上有较强的信号(化合物5-1具有激发波长依赖的发射如图8)。通过细胞成像实验(图9),证明了它可以靶向细胞溶酶体。
7、细胞毒性实验
利用自组装的方法,利用生物脂质体DSPE-mPEG5000对化合物5-1(质量比为40:2)组装,得到5-1纳米粒子。首先将SKOV3细胞悬液按150μL/孔接种到三块96孔板中,板最外一圈的每个小孔内加入150μL的PBS缓冲液以防止溶液蒸发而引起实验误差,然后将96孔板置于培养箱中使细胞贴壁生长。待细胞密度大约为104SKOV3细胞/孔时,用DMEM不完全培养液将5-1纳米材料稀释成浓度成不同浓度的溶液,按150μL/孔注入到96孔板的不同列中,同时每个浓度设置6组对照实验。将96孔板置于培养箱中孵育24h后,每个孔更换新鲜的DMEM不完全培养液并加入15μL已配好的MTT溶液(5mg/mL),置于培养箱中继续孵育4h后,轻轻吸去上层清液,然后每孔依次加入150μL的DMSO以溶解活细胞内的甲瓒结晶,静置30min后即可在酶标仪上测量每孔的吸光度(OD570:一般情况下默认测量波长为570nm处的OD值)。最后计算细胞的存活率(OD值越大,代表细胞的存活率越高)。细胞存活率(%)=(探针的平均OD570÷纯细胞的平均OD570)×100%,通过细胞毒性实验(图10),证明了5-1纳米材料具有低的细胞毒性,好的生物相容性。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (9)
3.根据权利要求2所述的溶酶体靶向的红外二窗发射荧光染料的制备方法,其特征在于,
所述步骤I的反应时间为10-16h,反应温度为室温;
所述步骤II的反应时间为20-24h,反应温度为60-85℃;
所述步骤III的反应时间为20-48h,反应温度为85-140℃;
所述步骤IV的反应时间为3-6h,反应温度为0℃或者室温;反应结束后用甲醇或乙醇淬灭反应。
4.根据权利要求3所述的溶酶体靶向的红外二窗发射荧光染料的制备方法,其特征在于,所述步骤I在碱金属氢氧化物的水溶液和低碳醇的混合溶液中进行反应;所述低碳醇为甲醇或乙醇。
5.根据权利要求4所述的溶酶体靶向的红外二窗发射荧光染料的制备方法,其特征在于,所述碱金属氢氧化物为氢氧化钠或氢氧化钾。
6.根据权利要求2所述的溶酶体靶向的红外二窗发射荧光染料的制备方法,其特征在于,所述步骤II中所用的溶剂为甲醇或乙醇;
所述步骤III中所用的溶剂为甲醇、乙醇、正丁醇或者乙酸;
所述步骤IV中所用的溶剂为二氯甲烷或者四氢呋喃。
7.根据权利要求2所述的溶酶体靶向的红外二窗发射荧光染料的制备方法,其特征在于:
所述步骤I的反应溶剂为乙醇和氢氧化钠水溶液的混合溶液;
所述步骤II的反应溶剂为乙醇和乙二胺的混合溶液;
所述步骤III的反应溶剂为正丁醇和醋酸铵的混合溶液;
所述步骤IV中反应在弱碱性条件下进行,溶剂为二氯甲烷,弱碱性条件由氮氮二异丙基乙胺提供。
8.根据权利要求7所述的溶酶体靶向的红外二窗发射荧光染料的制备方法,其特征在于:
所述步骤I的反应溶剂为乙醇和氢氧化钠水溶液的混合溶液,二者的体积比为2-5:1;
所述步骤II的反应溶剂为乙醇和乙二胺的混合溶液,二者的体积比为5-10:2;
所述步骤III的反应溶剂为正丁醇和醋酸铵的混合溶液,二者的用量比为2-5mL:5g;
所述步骤IV中反应在弱碱性条件下进行,溶剂为二氯甲烷,弱碱性条件由二异丙基乙胺提供,二者的体积比为15:2。
9.一种权利要求1所述的溶酶体靶向的红外二窗发射荧光染料在光热成像、光声成像或红外二窗荧光成像中的应用。
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