CN112409384B - 双噻吩噻二唑受体近红外二区荧光分子及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种双噻吩噻二唑电子受体近红外二区荧光分子及其制备方法和应用,属于纳米生物医学成像技术领域。本发明首先使用双噻吩噻二唑作为电子受体单元,分别与噻吩芴、螺芴、噻吩螺芴等三种供体单元进行Stille偶联反应,得到一类双噻吩噻二唑结构为受体的近红外二区荧光小分子。该类荧光小分子可通过控制给体的种类,方便控制与调节近红外二区荧光强度。再将该近红外二区荧光分子与两亲性甲氧基‑聚乙二醇‑磷脂自组装,得到的水溶性近红外二区荧光造影剂有很好的荧光亮度,可作为造影剂实现在近红外二区的小鼠活体血管及肿瘤成像。
Description
技术领域
本发明涉及一种荧光小分子,尤其涉及一种双噻吩噻二唑电子受体近红外二区荧光分子及其制备方法和应用,属于纳米生物医学成像技术领域。
背景技术
近红外二区(NIR-II,1000-1700纳米)荧光成像的穿透深度及成像的信噪比要优于常用的近红外(650-900纳米)荧光成像。目前已经有多种基于无机材料、有机小分子和共轭聚合物的NIR-II荧光成像造影。其中有机小分子具有生物相容性好、易于体内代谢的优势而广受关注。但目前,基于有机共轭小分子的NIR-II荧光造影剂主要基于苯并噻二唑和喹喔啉两种电子受体。苯并噻二唑电子受体的合成较为繁琐,提纯过程较为复杂。喹喔啉受体结构又存在分子量大的缺点。因此,开发一种新型的有机共轭NIR-II荧光小分子用于制备造影剂变得越来越迫切。
发明内容
本发明为了解决苯并噻二唑和喹喔啉两种电子受体近红外二区荧光成像小分子造影剂存在的缺陷,以双噻吩噻二唑为电子受体开发了一类近红外二区荧光小分子及相关水溶性造影剂的制备方法,以及采用该造影剂在活体血管和肿瘤等的近红外二区荧光成像的用途。
本发明所采取的技术方案为:双噻吩噻二唑电子受体近红外二区荧光分子,聚合物结构式为:
其中,R为下列结构式中的一种:
上述的双噻吩噻二唑电子受体近红外二区荧光分子的制备方法,以双噻吩噻二唑为电子受体结构单元,与供体单元进行Stille偶联反应,所述供体单元为噻吩芴、螺芴、噻吩螺芴中的一种。
优选地,所述受体结构单元为
其中R为噻吩芴的单元结构如下:
螺芴的单元结构如下:
噻吩螺芴的单元结构如下:
优选地,所述荧光分子的合成路线为:
其中,R可为下列结构式中的一种:
一种利用上述近红外二区荧光小分子制备造影剂的方法,包括以下步骤:
将近红外二区荧光小分子溶于四氢呋喃中,得到近红外二区小分子的四氢呋喃溶液;
将两亲性聚合物甲氧基-聚乙二醇-磷脂溶于水中,得到两亲性聚合物甲氧基-聚乙二醇-磷脂的水溶液;
在超声条件下将近红外二区小荧光的四氢呋喃溶液注射到两亲性聚合物甲氧基-聚乙二醇-磷脂的水溶液中,得到近红外二区荧光造影剂;
采用透析法或旋转蒸发除去多余的四氢呋喃。
优选地,所述两亲性聚合物甲氧基-聚乙二醇-磷脂的分子量为5000,其水溶液浓度为1~5毫克/毫升。
优选地,所述近红外二区荧光小分子有机溶液的浓度为0.2~0.5毫克/毫升。
上述的制备方法所得的造影剂作为红外二区荧光成像造影剂的应用。
上述的制备方法所得的造影剂在制备血管成像肿瘤疾病诊疗药物中的应用。
本发明所达到的有益效果:本发明设计、合成、制备了一种双噻吩噻二唑受体近红外二区荧光分子造影剂,是由基于双噻吩噻二唑为电子受体结构单元的近红外二区荧光分子与两亲性聚合物甲氧基-聚乙二醇-磷脂(分子量:5000)自组装而成的。可作为近红外二区荧光成像造影剂实现对活体内血管和肿瘤部位的高质量的近红外二区荧光成像。而且,通过改变双噻吩噻二唑受体近红外二区荧光分子中供体的结构,制备了一系列近红外二区的荧光分子,增加了近红外二区成像造影剂的种类与选择空间。
附图说明
图1为本发明实施例1、2、3所得的近红外二区造影剂的透射电镜照片;
图2为本发明实施例1、2、3所得的近红外二区造影剂的动态光散射照片;
图3为本发明实施例1、2、3所得的近红外二区造影剂的吸收谱图;
图4为本发明实施例1、2、3所得的近红外二区造影剂的荧光谱图;
图5为本发明实施例1所得的近红外二区造影剂对小鼠全身血管系统的近红外二区成像图。
具体实施方式
下面结合实施例对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案,而不能以此来限制本发明的保护范围。
实施例1:
1.近红外二区荧光分子一的合成
双噻吩噻二唑结构电子受体,噻吩芴电子给体近红外二区荧光分子一的合成方法:
在50毫升的烧瓶中加入双噻吩噻二唑(15毫克,0.0323毫摩尔),(二亚苄基丙酮)二钯(0.6毫克,0.000651毫摩尔)和三苯基膦(0.8毫克,0.00258毫摩尔),接上回流管,在避光条件下对整个体系进行抽真空充氮气,然后将鼓泡完的噻吩芴(49.21毫克,0.0646毫摩尔)与氯苯(2毫升)混合液加入烧瓶中,在135℃下回流搅拌24小时。反应结束后,将冷却至室温的反应液用石油醚沉降,抽滤获得黏状深青色物体,随后经过硅胶柱层析分离得到近红外二区荧光小分子一。
合成路线为:
2.小分子一造影剂的合成
将0.5毫克双噻吩噻二唑结构电子受体,噻吩芴电子给体近红外二区荧光分子一溶于1毫升四氢呋喃中,再将40毫克两亲性聚合物甲氧基-聚乙二醇-磷脂(分子量:5000)溶于10毫升水中。在室温超声条件下,将溶解好的近红外二区荧光分子一的四氢呋喃溶液直接加入甲氧基-聚乙二醇-磷脂(分子量:5000)水溶液中,得到混合溶剂液体。再通过透析法将多余的四氢呋喃除去,即可得造影剂。
如图1所示,配制浓度为0.04毫克/毫升的小分子一造影剂水溶液,测试其透射电镜图,可得该造影剂纳米粒子粒径为20纳米到80纳米,且都为类球形。
如图2所示,配制浓度为0.05毫克/毫升的小分子一造影剂水溶液,根据动态光散射测定该造影剂纳米粒子的流体力学半径约为60纳米。
如图3与4所示,配制浓度为0.04毫克/毫升的小分子一造影剂水溶液,测试其吸收与发射光谱图,可以看出其紫外-近红外吸收峰在741纳米波段,而发射峰则在1051纳米波段,明显是二窗发射材料。
如图5所示,配制浓度为0.5毫克/毫升的小分子一纳米粒子水溶液,选用健康BALB/c小鼠,尾静脉注射150毫升造影剂后,使用近红外二区荧光成像仪对健康小白鼠的全身、头部、腹部以及腿部进行血管系统成像,可以清晰的观察到血管分布,分辨率较高。
实施例2:
1.近红外二区荧光分子二的合成
双噻吩噻二唑结构电子受体,螺芴电子给体近红外二区荧光分子二的合成方法:
在50毫升的烧瓶中加入双噻吩噻二唑(15毫克,0.0323毫摩尔),螺芴(55毫克,0.0908毫摩尔)与(二亚苄基丙酮)二钯(0.6毫克,0.000651毫摩尔)和三苯基膦(0.8毫克,0.00258毫摩尔),接上回流管,在避光条件下对整个体系进行抽真空充氮气,然后将鼓泡完的氯苯(2毫升)加入烧瓶中,在135℃下回流搅拌24小时。反应结束后,反应液用石油醚沉降,抽滤得青绿色物体,随后经过硅胶柱层析分离得到得到近红外二区荧光小分子二。
合成路线为:
2.小分子二造影剂的合成
将0.4毫克双噻吩噻二唑结构电子受体,螺芴电子给体近红外二区荧光分子二溶于1毫升四氢呋喃中,再将25毫克两亲性聚合物甲氧基-聚乙二醇-磷脂(分子量:5000)溶于10毫升水中。在室温超声条件下,将溶解好的近红外二区荧光分子二的四氢呋喃溶液快速加入甲氧基-聚乙二醇-磷脂(分子量:5000)水溶液中,得到混合溶剂液体。再通过透析法将多余的四氢呋喃除去,即可得造影剂。
如图1所示,配制浓度为0.04毫克/毫升的小分子二造影剂水溶液,测试其透射电镜图,可得该造影剂纳米粒子粒径为20纳米到80纳米,且都为类球形。
如图2所示,配制浓度为0.05毫克/毫升的小分子二造影剂水溶液,根据动态光散射测定该造影剂纳米粒子的流体力学半径约为90纳米。
如图3与4所示,配制浓度为0.04毫克/毫升的小分子二造影剂水溶液,测试其吸收与发射光谱图,可以看出其紫外-近红外吸收峰在715纳米波段,而发射峰则在1059纳米波段,明显是二窗发射材料。
实施例3:
1.近红外二区荧光分子三的合成
双噻吩噻二唑结构电子受体,噻吩螺芴电子给体近红外二区荧光分子三的合成方法:
在50毫升的烧瓶中加入双噻吩噻二唑(15毫克,0.0323毫摩尔),(二亚苄基丙酮)二钯(0.6毫克,0.000651毫摩尔)和三苯基膦(0.8毫克,0.00258毫摩尔)接上回流管,在避光条件下对整个体系进行抽真空充氮气,然后将已除氧的噻吩螺芴(62.4毫克,0.0908毫摩尔)与氯苯(2毫升)的混合液加入烧瓶中,在135℃下回流搅拌24小时。反应结束后,反应液用石油醚沉降,抽滤得黏状深青色物体,随后经过硅胶柱层析分离得到得到近红外二区荧光小分子三。
合成路线为:
2.小分子三造影剂的合成
将0.2毫克双噻吩噻二唑结构电子受体,噻吩螺芴电子给体近红外二区荧光分子三溶于1毫升四氢呋喃中,再将10毫克两亲性聚合物甲氧基-聚乙二醇-磷脂(分子量:5000)溶于10毫升水中。在室温超声条件下,将溶解好的近红外二区荧光分子三的四氢呋喃溶液快速加入甲氧基-聚乙二醇-磷脂(分子量:5000)水溶液中,得到混合溶剂液体。再通过透析法将多余的四氢呋喃除去,即可得造影剂。
如图1所示,配制浓度为0.04毫克/毫升的小分子三造影剂水溶液,测试其透射电镜图,可得该造影剂纳米粒子粒径为20纳米到80纳米,且都为类球形。
如图2所示,配制浓度为0.05毫克/毫升的小分子三造影剂水溶液,根据动态光散射测定该造影剂纳米粒子的流体力学半径约为83纳米。
如图3与4所示,配制浓度为0.04毫克/毫升的小分子三造影剂水溶液,测试其吸收与发射光谱图,可以看出其紫外-近红外吸收峰在771纳米波段,而发射峰则在1060纳米波段,明显是二窗发射材料。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变形,这些改进和变形也应视为本发明的保护范围。
Claims (7)
4.一种利用权利要求1所述近红外二区荧光小分子制备造影剂的方法,其特征在于:包括以下步骤:
将近红外二区荧光小分子溶于四氢呋喃中,得到近红外二区小分子的四氢呋喃溶液;
将两亲性聚合物甲氧基-聚乙二醇-磷脂溶于水中,得到两亲性聚合物甲氧基-聚乙二醇-磷脂的水溶液;
在超声条件下将近红外二区小荧光的四氢呋喃溶液注射到两亲性聚合物甲氧基-聚乙二醇-磷脂的水溶液中,得到近红外二区荧光造影剂;
采用透析法或旋转蒸发除去多余的四氢呋喃。
5.根据权利要求4所述的制备方法,其特征在于:所述两亲性聚合物甲氧基-聚乙二醇-磷脂的分子量为5000,其水溶液浓度为1~5毫克/毫升。
6.根据权利要求4所述的制备方法,其特征在于:所述近红外二区荧光小分子有机溶液的浓度为0.2~0.5毫克/毫升。
7.权利要求4-6任一项所述的制备方法所得的造影剂在制备血管成像肿瘤疾病诊疗药物中的应用。
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