CN114591729B - 一种近红外IIb荧光探针、纳米粒子及其制备方法和应用 - Google Patents
一种近红外IIb荧光探针、纳米粒子及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种近红外IIb荧光探针,该荧光探针基于DPP(吡咯并吡咯二酮)共轭聚合物DT‑R,并公开了该荧光探针及其纳米粒子的制备方法。所制得的纳米粒子最大发射峰位于近红外二区(NIR‑II)范围,且最长发射波长可延伸至近红外IIb区(NIR‑IIb)。本发明提供的纳米粒子可在808nm激光激发下实现NIR‑IIb的小鼠血管成像,具有高的成像分辨率及信噪比,在血管监测和修复等方面有广泛的应用前景。
Description
技术领域
本发明属于生物光学诊疗领域,更具体地,涉及一种近红外IIb荧光探针、纳米粒子及其制备方法和应用。
背景技术
荧光成像(FLI)与各种传统成像方式相比,如正电子发射断层扫描(PET)、X射线计算机断层扫描(CT)和核磁共振成像(NMRI),具有其独特的优势,包括高时空分辨率和实时快速检测,近年来正成为主流的成像方式之一。到目前为止,FLI已经成熟或初步应用于高分辨率血管成像、胃肠道成像和成像引导的临床肿瘤切除术。近年来,位于900-1700nm的发射波长,即第二近红外(NIR-II),吸引了国内外研究人员的广泛和深入研究。与传统的成像范围,包括可见区(400-700nm)和第一近红外窗口(NIR-I,700-900nm)相比,NIR-II成像表现出更深的穿透力(~10mm),出色的高时间和空间分辨率,以及由于减少自发荧光和光子散射而产生的高信噪比(SBR)。NIR-II区间可以进一步细分为三个子区间NIR-IIa’(1000-1300nm)、NIR-IIa(1300-1400nm)和NIR-IIb(1500-1700nm),且随着波长的增加其成像分辨率和穿透深度可以进一步提高。目前,设计构筑了许多无机纳米材料如量子点和稀土纳米粒子用于NIR-IIb荧光成像。尽管它们拥有高的荧光亮度,但其潜在的长期生物毒性问题极大地限制了它们的临床实际应用。因此,设计开发出新型高效有机NIR-IIb荧光造影剂成为目前研究的热点及难点。
发明内容
本发明的目的是针对以上不足,提供一种近红外IIb荧光探针及其纳米粒子,该近红外IIb荧光探针具有高亮度,可用于NIR-IIb荧光成像,且易合成、毒性低,绿色安全。
为实现上述目的,本发明是通过以下技术方案实现的:
本发明提供了一种近红外IIb荧光探针,该荧光探针基于DPP(吡咯并吡咯二酮)共轭聚合物DT-R,所述DT-R的结构式如下:
优选的,所述式1中的R基团可选自H、F、Cl、Br、I或NO2,可选结构如下:
本发明还提供了上述近红外IIb荧光探针的制备方法,即所述共轭聚合物DT-R的合成包括以下步骤:
将2,5-双(2-辛基十二烷基)-3,6-双(5-(三甲基锡)噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮、R取代的4,7-双(5-溴噻吩-2-基)苯并[c][1,2,5]噻二唑衍生物及催化剂Pd(PPh3)4以1:1:1的摩尔比溶于有机溶剂甲苯,氮气保护下回流反应,冷却,沉降即得到目标聚合物。所述不同取代的4,7-双(5-溴噻吩-2-基)苯并[c][1,2,5]噻二唑衍生物可以为H取代、F取代、Cl取代、Br取代、I取代或NO2取代。该合成方法反应步骤仅为一步反应,条件比较简单,容易合成。
本发明还提供了一种上述近红外IIb荧光探针的纳米粒子,是基于式1所述的DPP共轭聚合物DT-R,利用两亲性聚合物F127及纳米共沉淀法制备得到的。
上述近红外IIb荧光探针的纳米粒子,在水溶液中,最大吸收波长在NIR-I区,最大发射波长在NIR-II区。
上述近红外IIb荧光探针的纳米粒子,在水溶液中,其发射波长尾峰能够延伸至1500~1700nm。
本发明还提供了上述近红外IIb荧光探针的纳米粒子的制备方法,包括以下步骤:
将式1所述DPP共轭聚合物DT-R和F127溶解于有机溶剂中,超声下加入超纯水中,超声后,除去有机溶剂得到纳米粒子。
优选的,所述DT-R和F127的质量比为1:20,所述有机溶剂与超纯水的体积比为1:10,有机溶剂可以为四氢呋喃,超声时间为5min,除去有机溶剂采用氮气流,时间为30min。
本发明还提供了一种上述近红外IIb荧光探针在制备808nm激光激发的NIR-IIb区域活体血管成像中的造影剂中的应用,是指将其纳米粒子作为808nm激光激发的NIR-IIb区域活体血管成像中的造影剂,具有高的成像分辨率及信噪比,在血管监测和修复等方面有广泛的应用前景。
与现有技术相比,本发明的有益效果为:
本发明所述基于吡咯并吡咯二酮(DPP)共轭聚合物的近红外IIb荧光探针,具有高的荧光亮度,且易合成、结构修饰性好,毒性低,合成过程绿色安全。
本发明所述近红外IIb荧光探针的纳米粒子,其吸收位于NIR-I区,整个发射波长位于NIR-II区,且尾峰可延伸至NIR-IIb区,因此可以用于制备808nm激光激发的NIR-IIb高分辨率血管成像的造影剂,且其制备工艺简单,可重复性好。
附图说明
图1为实施例1所提供的一种NIR-IIb荧光探针的核磁共振氢谱图;
图2为实施例1所述的DT-H的纳米粒子的DLS和TEM图;
图3为实施例1所述的DT-H的纳米粒子在水溶液中的吸收和发射图谱;
图4为实施例1所述的DT-H的纳米粒子在水溶液中1400-1800nm的发射光谱图;
图5为实施例2所提供的一种NIR-IIb荧光探针的核磁共振氢谱图;
图6为实施例2所述的DT-NO2的纳米粒子的DLS和TEM图;
图7为实施例2所述的DT-NO2的纳米粒子在水溶液中的吸收和发射图谱;
图8为实施例2所述的DT-NO2的纳米粒子在水溶液中1400-1800nm的发射光谱图;
图9为实施例2所述的DT-NO2的纳米粒子在活体中的NIR-IIb活体成像图。
具体实施方式
下面将结合附图和具体实施例更详细地描述本发明的优选实施方式。
实施例1
一种基于吡咯并吡咯二酮(DPP)共轭聚合物的NIR-IIb荧光探针,其中共轭聚合物DT-H具有如下结构:
上述共轭聚合物DT-H的合成步骤包括:将2,5-双(2-辛基十二烷基)-3,6-双(5-(三甲基锡)噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮(0.05g,0.042mmol)、4,7-双(5-溴噻吩-2-基)苯并[c][1,2,5]噻二唑(0.0193g,0.042mmol),Pd(PPh3)4(5mg,0.0042mmol)和10mL甲苯在N2气氛下加入到50mL的预置反应管中,混合物回流7h,冷却至室温后,将反应溶液滴加到200mL甲醇溶液中,减压过滤收集混合物,得到最终产品DT-H(收率为58%),其核磁共振氢谱图如图1所示,图中6.5-8.0之间的峰为芳香环噻吩或苯环上的氢,0-2.0之间的峰为烷基链上的氢。其合成路线如下:
本实施例提供了一种上述近红外IIb荧光探针DT-H的纳米粒子,其制备方法包括:
步骤一:称取聚合物DT-H 0.5mg,10mg的F127溶于1mL四氢呋喃中,超声溶解;
步骤二:超声下将上述混合物溶液快速加入5mL超纯水中,并继续超声5min;
步骤三:除去所得溶液中的四氢呋喃,得到100μg/mL的DT-H纳米粒子溶液。
本实施例所述的DT-H的纳米粒子的DLS和TEM如图2所示,纳米粒子的直径为134nm,呈典型的球形形态;所述的DT-H的纳米粒子在水溶液中的吸收和发射图谱如图3所示,从图中可以发现,该纳米粒子的最大吸收为732nm,最大发射波长为1080nm,属于近红外二区范围;所述的DT-H的纳米粒子在水溶液中1400-1800nm的发射光谱图如图4所示,图中可以明显的观察到发射峰,该发射属于NIR-IIb的发射,表明其可用于NIR-IIb的活体成像。
实施例2
一种基于吡咯并吡咯二酮(DPP)共轭聚合物的NIR-IIb荧光探针,其中共轭聚合物DT-NO2具有如下结构:
上述共轭聚合物DT-NO2的合成步骤包括:将2,5-双(2-辛基十二烷基)-3,6-双(5-(三甲基锡)噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮(0.1g,0.084mmol)、4,7-双(5-溴噻吩-2-基)-5,6-二硝基苯并[c][1,2,5]噻二唑(0.04g,0.084mmol),Pd(PPh3)4(10mg,0.0084mmol)和10mL甲苯在N2气氛下加入到50mL的预置反应管中,混合物回流7h,冷却至室温后,将反应溶液滴加到200mL甲醇溶液中,减压过滤收集混合物,得到最终产品DT-NO2(收率为60%),其核磁共振氢谱图如图5所示,图中6.5-8.0之间的峰为芳香环噻吩或苯环上的氢,0-2.0之间的峰为烷基链上的氢。其合成路线如下:
本实施例提供了一种上述近红外IIb荧光探针DT-NO2的纳米粒子,其制备方法包括:
步骤一:称取聚合物DT-NO2 0.5mg,10mg的F127溶于1mL四氢呋喃中,超声溶解;
步骤二:超声下将上述混合物溶液快速加入5mL超纯水中,并继续超声5min;
步骤三:除去所得溶液中的四氢呋喃,得到100μg/mL的DT-NO2纳米粒子溶液。
本实施例所述的DT-NO2的纳米粒子的DLS和TEM如图6所示,纳米粒子的直径为118nm,为均匀分散的球形;所述的DT-NO2的纳米粒子在水溶液中的吸收和发射图谱如图7所示,从图中可以发现,纳米粒子的最大吸收和发射峰分别位于782nm和1090nm;所述的DT-NO2的纳米粒子在水溶液中1400-1800nm的发射光谱图如图8所示,图中可以明显的看到NIR-IIb发射峰,说明DT-NO2纳米粒子可作为NIR-IIb荧光成像造影剂;所述DT-NO2纳米粒子经尾静脉注射后小鼠的全身血管成像如图9所示,激发光源波长为808nm,采用的滤光片分别为980nm LP,1300-1400nm和1500nm LP,从成像图中可以发现,NIR-IIb区域(1500nm LP)的具有最佳的成像效果,小鼠全身血管清晰可见,表明纳米粒子具有出色的NIR-IIb荧光成像性能。
实施例3
一种基于吡咯并吡咯二酮(DPP)共轭聚合物的NIR-IIb荧光探针,其中共轭聚合物DT-F具有如下结构:
上述共轭聚合物DT-F的合成步骤包括:将2,5-双(2-辛基十二烷基)-3,6-双(5-(三甲基锡)噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮(0.1g,0.084mmol)、4,7-二(5-溴噻吩基-2-)-5,6-二氟-2,1,3-苯并噻二唑(0.04g,0.084mmol),Pd(PPh3)4(10mg,0.0084mmol)和10mL甲苯在N2气氛下加入到50mL的预置反应管中,混合物回流7h,冷却至室温后,将反应溶液滴加到200mL甲醇溶液中,减压过滤收集混合物,得到最终产品DT-F(收率为52%),其合成路线如下:
本实施例提供了一种上述近红外IIb荧光探针DT-F的纳米粒子,其制备方法包括:
步骤一:称取聚合物DT-F 0.5mg,10mg的F127溶于1mL四氢呋喃中,超声溶解;
步骤二:超声下将上述混合物溶液快速加入5mL超纯水中,并继续超声5min;
步骤三:除去所得溶液中的四氢呋喃,得到100μg/mL的DT-F纳米粒子溶液。
以上已经描述了本发明的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和技术原理的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的,这些修改和变更也应视为本发明的保护范围。
Claims (8)
1.一种近红外IIb荧光探针,其特征在于,该荧光探针基于DPP共轭聚合物DT-R,所述DT-R的结构式如下:
所述式1中的R基团为NO2。
2.一种权利要求1所述的近红外IIb荧光探针的制备方法,其特征在于,所述共轭聚合物DT-R的合成包括以下步骤:
将2,5-双(2-辛基十二烷基)-3,6-双(5-(三甲基锡)噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮、R取代的4,7-双(5-溴噻吩-2-基)苯并[c][1,2,5]噻二唑衍生物及催化剂以1:1:1的摩尔比溶于有机溶剂,氮气保护下回流反应,冷却,沉降即得到目标聚合物。
3.一种权利要求1所述的近红外IIb荧光探针的纳米粒子,其特征在于,是基于权利要求1所述的DT-R,利用两亲性聚合物F127及纳米共沉淀法制备得到的。
4.根据权利要求3所述的近红外IIb荧光探针的纳米粒子,其特征在于,所述纳米粒子在水溶液中,最大吸收波长在NIR-I区,最大发射波长在NIR-II区。
5.根据权利要求3所述的近红外IIb荧光探针的纳米粒子,其特征在于,所述纳米粒子在水溶液中,其发射波长尾峰能够延伸至1500~1700nm。
6.一种权利要求3所述的近红外IIb荧光探针的纳米粒子的制备方法,其特征在于,包括以下步骤:
将权利要求1所述DT-R和F127溶解于有机溶剂中,超声下加入超纯水中,超声后,除去有机溶剂得到纳米粒子。
7.根据权利要求6所述的近红外IIb荧光探针的纳米粒子的制备方法,其特征在于,所述DT-R和F127的质量比为1:20,所述有机溶剂与超纯水的体积比为1:10。
8.一种权利要求1所述的近红外IIb荧光探针在制备808nm激光激发的NIR-IIb区域活体血管成像中的造影剂中的应用。
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