CN110079117B - 近红外第二窗口激发/发射的荧光染料及制备方法和应用 - Google Patents
近红外第二窗口激发/发射的荧光染料及制备方法和应用 Download PDFInfo
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- CN110079117B CN110079117B CN201910322674.6A CN201910322674A CN110079117B CN 110079117 B CN110079117 B CN 110079117B CN 201910322674 A CN201910322674 A CN 201910322674A CN 110079117 B CN110079117 B CN 110079117B
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Abstract
本发明属于生物材料技术领域，具体为一种近红外第二窗口激发和发射的荧光染料及其制备方法和应用。本发明荧光染料为具有通式LZ染料结构的有机小分子七甲川菁染料荧光染料；本发明利用吲哚化合物与乙酰氯和缩合剂一锅法高效合成目标产物；该荧光染料水溶性好，并且连有活性基团如羧基、氨基、马来酰亚胺基团等，可对蛋白，多肽，氨基酸，DNA等进行修饰；该荧光染料可作为血管造影剂用于生物体血管成像，具有血液长循环功能，如用于对小鼠腿部，腹部及脑部血管的动态成像，实现对小鼠腿部缺血再灌注，动脉溶栓过程及脑部血脑屏障的开启和关闭的监控。
Description
技术领域
本发明属于生物材料技术领域，具体涉及一种近红外第二窗口激发/发射的荧光染料及其制备方法和应用。
背景技术
目前常见的分子影像技术如X线断层扫描成像(X-CT)，超声成像(UI)，正电子放射性断层成像(PET)和磁共振成像(MRI)已广泛用于对疾病等的医疗诊断。但是目前这些影像技术有其自身的缺点，如辐射，较差的空间分辨率，无法实现动态实时监测等。荧光成像由于实时、非侵入性、分辨率高、所需样品量少等优点，在生物技术领域等领域被广泛应用，尤其是有生物组织的荧光成像。在过去几年里，化学工作者们主要集中在近红外第一窗口(700nm～900nm)荧光成像方法的研究，但是由于生物组织在这个波段范围内有很强的吸收和散射，致使其信噪比和组织穿透深度都比较低。近期，一些研究工作集中在了近红外第二窗口(1000nm～1700nm)，在这个波段内，生物组织自身的吸收和散射弱，提高了成像质量和穿透深度。目前，一些无机材料如碳纳米管，稀土下转换纳米颗粒，量子点实现近红外第二窗口区的发射，但是它们的发射波长都位于近红外第一窗口内，同时含有重金属元素具有潜在的生物毒性，进入活体后代谢缓慢，且在水中溶解性差，这大大限制了它们的应用价值。相对于无机材料，有机染料具有相对分子量较小，易于代谢，同时也可以实现近红外第二窗口区的发射，利于临床转化。所以近红外第二窗口区的有机荧光染料引起了广泛的关注。近期，本发明课题组开发了具有近红外第二窗口激发和发射的有机小分子荧光染料FD-1080。同时，证明了相对于已报道的NIR-II材料所使用的激发波长(650-980nm)，1064nm作为激发波长具有更好的组织穿透深度和空间分辨率。但此类分子需要包裹在血清蛋白中实现近红外第二窗口荧光成像，同时代谢较快无法实现长时间检测。到目前为止，还未报道激发和发射都在近红外第二窗口区的七甲川菁染料实现长时间荧光成像用于监控小鼠腿部缺血再灌注，动脉溶栓过程及脑部血脑屏障的开启和关闭。
发明内容
本发明的目的在于提供一种制备工艺简单、生物相容性好，光稳定性高的近红外第二窗口激发和发射的荧光染料及其制备方法和应用。
第一，本发明在前人工作的基础上设计出一条新的合成七甲川菁类染料的方法，得到新的化合物结构，该方法和化合物结构未见文献报道，具体过程是利用吲哚化合物与乙酰氯和缩合剂一锅法高效率的合成目标化合物。
第二，本发明针对现有染料，例如吲哚菁绿(ICG)血液半衰期短(5min)等问题，合成了能实现长时间对血管等部位进行检测的荧光染料。该染料实现了对小鼠腿部缺血再灌注，动脉溶栓过程及脑部血脑屏障的开启和关闭的监控。
第三，本发明合成了一类水溶性好，并且连有活性基团如羧基，氨基，马来酰亚胺基团等，可对蛋白，多肽，氨基酸，DNA等进行修饰用于生物成像。
本发明提供的近红外第二窗口激发和发射的荧光染料，为有机小分子七甲川菁荧光染料，记为LZ染料，包括LZ和LZ-O，LZ-S或LZ-N，其化合物结构通式如下：
其中：
R1、R2、R3和R4各自独立选自H、C1-18烷基、R21、SO3R8、或COOR9；
R5和R6各自独立选自(CH2)nR10、(CH2)mOR11、(CHR12CH2O)pR11或(CH2)qSO3R9；
R7为Cl、OR13、SR14、NHR15；
R8为H或M；M＝Na、K、N(R18、R19)；
R9为H、R16、R17、M、NH(CH2)yR20或C1-18烷基；
R10为H、SO3R9或COOR9；
R11为H或C1-18烷基；
R12为H或CH3；
R13、R14、R15为R5、C6H4(CH2)sCOR22、(CH2)tCOR22；
R18、R19为H、C1-18烷基、(CH2)mOR11、(CHR12CH2O)pR11；
R20为H、R16、R17、N3；
R22为OR9；
Y-为卤素负离子或者OTs-；
n、m、p、q、s、t、y为0-18的整数。
本发明中使用的术语“烷基”包括直链烷基和支链烷基；术语“卤素”包括氟、氯、溴和碘；OTs-指对甲苯磺酸根离子。
本发明上述化合物中，优选R1、R2、R3和R4各自独立选自H或R21。
本发明化合物的母体结构上取代基的作用是调节染料在有机溶剂或者水溶液中的溶解性。其中优选的技术方案为R5和R6各自独立选自(CH2)nR10。
最为优选地，R1、R2、R3和R4选自H或R21，R5和R6选自(CH2)3SO3，R7为Cl、OC6H4CH2COOH。即下述化合物LZ-1060，LZ-1092，LZ-1105，LZ-1118和LZ-O
本发明的另一个目的是提供上述化合物的制备方法，具体步骤如下：
(1)连有取代基R1、R2或R3、R4的2-苯基-吲哚，与磺酸内酯或R5或R6CH2Z反应，制得化合物Ⅰ，其反应式为下式所示；
其中，Z是卤素或者OTs，反应温度为80～140℃，反应时间为2～8小时，反应溶剂选自四氢呋喃、乙醇或乙腈，碱性化合物为氢化钠、氢化钾、氢氧化钠、氢氧化钾或氢氧化铯；吲哚化合物、磺酸内酯或R5CH2Z与碱性化合物的投料摩尔比为1:1.1:2～1:1.5:3(即1:(1:2～1.5):(2～3))；
(2)化合物Ⅰ与乙酰氯和缩合剂Ⅱ反应生成化合物LZ，其反应式为下式所示；
其中，反应溶剂为乙酸酐，反应温度为60～140℃，反应时间为2～8小时。化合物Ⅰ与乙酰氯和缩合剂Ⅱ的投料摩尔比1:0.45:0.22～1:0.55:0.27(即1:(0.45～0.55):(0.22～0.27))；
(3)化合物LZ与HOR13、HSR14或NH2R15反应生成化合物LZ-O，LZ-S或LZ-N，其反应式为下式所示；
其中，反应溶剂为N,N-二甲基甲酰胺、乙醇、甲醇或乙腈，反应温度为20～60℃，反应时间为0.2～4小时，三乙胺，氨水作为催化剂或不加碱性化合物。化合物LZ与HOR13、HSR14或NH2R15的投料摩尔比1:0.9～1:5(即1:(0.9～5))。
本发明制备得到荧光染料为七甲川菁荧光染料，记为LZ染料。
本发明的LZ染料可作为血管造影剂用于生物体血管成像中。
本发明的LZ染料作为血管造影剂，具有血液长循环功能，如用于对小鼠腿部，腹部及脑部血管的动态成像，可实现长时间(≥3h)荧光成像，实现对小鼠腿部缺血再灌注，动脉溶栓过程及脑部血脑屏障的开启和关闭的监控。
本发明中，以LZ-1105为例，在磷酸盐缓冲溶液中，最大吸收峰位于1041nm处，用1064nm的激光器激发，能够观察到1105nm处的荧光发射峰(图1)；在1064nm激光器的激发下，分别在纯水溶液、PBS缓冲溶液和裸鼠血液中，3小时内光稳定性保持不变(图2)；在二甲亚砜(DMSO)溶液中的荧光量子产率为3.89％(表1)。
附图说明
图1为1064nm近红外第二窗口激发，染料LZ-1105的吸收和荧光发射谱图。
图2为1064nm近红外第二窗口激发，染料LZ-1105在纯水，磷酸盐(PBS)缓冲液，裸鼠血液及血清中的光稳定性光谱图。
图3为1064nm近红外第二窗口激发，染料LZ-1105对小鼠脑部长时间血管成像。
图4为1064nm近红外第二窗口激发，染料LZ-1105对小鼠腿部长时间血管成像。
具体实施方式
实施例1：LZ染料的制备。具体步骤如下。
(1)化合物1的合成
称取2-苯基吲哚(386mg,2.0mmol)与60％氢化钠(84mg,2.1mmol)溶于10mL无水四氢呋喃溶液中，在冰浴下搅拌20min，随后加入1,4-丁磺酸内酯(272mg,2.0mmol)，温度升至100℃，反应2h，冷却至室温后加入异丙醇，可得白色沉淀，过滤得化合物1(663mg,95％)。
(2)化合物2的合成
称取5,6-亚甲基二氧-2-苯基吲哚(415mg,2.0mmol)与60％氢化钠(84mg,2.1mmol)溶于10mL无水四氢呋喃溶液中，在冰浴下搅拌40min，随后加入1,4-丁磺酸内酯(272mg,2.0mmol)，温度升至100℃，反应4h，冷却至室温后加入异丙醇，可得白色沉淀，过滤得化合物2(782mg,99％)
(3)七甲川菁荧光染料LZ-1060的合成
称取化合物1(1.50g,4.3mmol)与乙酰氯(172mg,2.2mmol)溶于20mL乙酸酐中，55℃条件下反应2h，随后加入2-氯-1-甲酰基-3-羟亚甲基环己烯(4)(787mg,2.2mmol)，升温至100℃下反应2h，冷却至室温，加入乙醚，可得沉淀，过滤得化合物LZ-1060染料(1.68g,93％)。
(4)七甲川菁荧光染料LZ-1092的合成
称取化合物2(1.70g,4.3mmol)与乙酰氯(172mg,2.2mmol)溶于20mL乙酸酐中，55℃条件下反应2h，随后加入2-氯-1-甲酰基-3-羟亚甲基环己烯(4)(787mg,2.2mmol)，升温至100℃下反应2h，冷却至室温，加入乙醚，可得沉淀，过滤得化合物LZ-1092染料(1.87g,92％)。
(5)七甲川菁荧光染料LZ-1105的合成
称取化合物1(1.50g,4.3mmol)与乙酰氯(172mg,2.2mmol)溶于20mL乙酸酐中，55℃条件下反应4h，随后加入2-氯-1-甲酰基-3-羟亚甲基环戊烯(3)(757mg,2.2mmol)，升温至100℃下反应4h，冷却至室温，加入乙醚，可得沉淀，过滤得化合物LZ-1105染料(1.51g,90％)。
(6)七甲川菁荧光染料LZ-1118的合成
称取化合物2(1.70g,4.3mmol)与乙酰氯(172mg,2.2mmol)溶于20mL乙酸酐中，55℃条件下反应4h，随后加入2-氯-1-甲酰基-3-羟亚甲基环戊烯(3)(757mg,2.2mmol)，升温至100℃下反应4h，冷却至室温，加入乙醚，可得沉淀，过滤得化合物LZ-1118染料(1.69g,91％)
(7)七甲川菁荧光染料LZ-O的合成
称取化合物LZ-1105(155mg,0.1mmol)与(30.4mg,0.2mmol)溶于10mL N,N-二甲基甲酰胺中，25℃条件下反应4h，加入乙醚，可得沉淀，过滤得化合物LZ-O染料(153mg,92％)
应用例：七甲川菁荧光探针LZ-1105对小鼠脑部长时间血管成像。具体步骤如下：
将麻醉的小鼠尾静脉注射150μL浓度为0.5mM的LZ-1105磷酸盐缓冲液，用1064nm外置激光器照射小鼠脑部，激光器功率密度为47mW/cm2(参见图3)。
七甲川菁荧光探针LZ-1105对小鼠腿部长时间血管成像。具体步骤如下：
将麻醉的小鼠尾静脉注射150μL浓度为0.5mM的LZ-1105磷酸盐缓冲液，用1064nm外置激光器照射小鼠左腿，激光器功率密度为47mW/cm2(参见图4)。
表1.LZ染料在不同溶剂中的光学性质
[a]相对荧光量子产率计算方法以IR-26化合物在1,2-二氯乙烷(0.05％)为标准。
Claims (3)
1.一种近红外第二窗口激发和发射的荧光染料，其特征在于，为有机小分子七甲川菁荧光染料，记为LZ染料，其化合物结构通式如下：
其中：
R5为Cl、OC6H4CH2COOH；
R1、R2、R3和R4选自H或R6；即为下述结构的化合物：LZ-1092、LZ-1105、LZ-1118和LZ-O；
2.一种如权利要求1所述的近红外第二窗口激发和发射的荧光染料的制备方法，其特征在于，具体步骤如下：
(1)连有取代基R1、R2或R3、R4的2-苯基-吲哚，与碱性化合物，与磺酸内酯反应，制得化合物Ⅰ，其反应式为下式所示：
其中，反应温度为80～140℃，反应时间为2～8小时，反应溶剂选自四氢呋喃、乙醇或乙腈，碱性化合物为氢化钠或氢氧化钠；吲哚化合物、磺酸内酯与碱性化合物的投料摩尔比为1:1.1:2～1:1.5:3；
(2)化合物Ⅰ与乙酰氯和缩合剂Ⅱ反应生成化合物LZ，其反应式为下式所示：
其中，反应溶剂为乙酸酐，反应温度为60～140℃，反应时间为2～8小时；化合物Ⅰ与乙酰氯和缩合剂Ⅱ的投料摩尔比1:0.45:0.22～1:0.55:0.27；
(3)化合物LZ与HOC6H4CH2COOH反应生成化合物LZ-O，其反应式为下式所示；
其中，反应溶剂为N,N-二甲基甲酰胺、乙醇、甲醇或乙腈，反应温度为20～60℃，反应时间为0.2～4小时，三乙胺、氨水作为催化剂或不加碱性化合物；化合物LZ与HOC6H4CH2COOH的投料摩尔比1:0.9～1:5。
3.如权利要求1所述的近红外第二窗口激发和发射的荧光染料在制备用于生物体血管成像的血管造影剂中的应用。
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