CN112851842B - 一种小尺寸近红外二区荧光成像造影剂及其制备方法和应用 - Google Patents
一种小尺寸近红外二区荧光成像造影剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于纳米生物医学成像技术领域，涉及一种小尺寸（8~50纳米）近红外二区荧光成像造影剂及其制备方法和应用，该小尺寸造影剂由四臂星型分子刷聚合物在水溶液中自组装而成，该星型分子刷聚合物以共轭红外二区荧光染料为核，具有四条聚甲基丙烯酸寡聚乙二醇酯的亲水性侧链。该聚合物在水溶液中能组装成为粒径为8~50纳米的小尺寸近红外二区荧光成像造影剂。本发明制备的小尺寸近红外二区荧光成像造影剂相对于现有的近红外二区荧光成像造影剂具有优异的水溶性、小的分子尺寸、长体内血液循环时间以及高肿瘤积累，在近红外二区具有良好的荧光成像效果。
Description
技术领域
本发明属于纳米生物医学成像技术领域，具体涉及一种小尺寸的近红外二区荧光成像造影剂及其制备方法和应用。
背景技术
近红外窗口(650-1700纳米)中的荧光成像已广泛应用于生物科技领域，例如肝功能的评估，监测炎性关节炎中的治疗反应，非特异性肿瘤靶向和图像介导肿瘤治疗等。近红外窗口按照光的波长又可分为近红外一区(650-1000纳米)和近红外二区(1000-1700纳米)。
近红外二区荧光成像与近红外一区荧光成像相比具有很低的自发荧光，光吸收和在生物组织的散射特性。因此，近红外二区荧光成像对血管、肿瘤等疾病等具有信号强、背景噪音低和分辨率高的优势。近年来，多种有机的近红外二区荧光成像造影剂(例如：共轭聚合物纳米粒子和基于共轭小分子的纳米粒子)被应用于近红外二区成像中。近红外二区荧光成像造影剂的典型制备方法是基于有机共轭分子或聚合物的物理纳米沉淀法。然而，这类造影剂存在荧光亮度低、尺寸大(50-200纳米)、体内循环时间短(1-3个小时)和稳定性差的问题，从而严重阻碍了近红外二区荧光成像效果。
发明内容
目的：本发明提供一种小尺寸近红外二区荧光成像造影剂及其制备方法和应用，旨在提高近红外二区荧光成像造影剂的水溶性、高稳定性、高亮度以及延长体内循环时间，实现更好的荧光成像效果。
技术方案：为解决上述技术问题，本发明采用的技术方案为：
本发明提供一种四臂星型分子刷聚合物，所述聚合物的结构式如下：
其中：四条水溶性侧链的重复单元数n为5-15。
进一步地，所述聚合物核为近红外二区荧光染料，结构为4,9-双(5-(9,9-双(6-溴己基)-9H-芴-2-基)噻吩-2-基)-6,7-双(4-(己氧基)苯基)-[1,2,5]噻二唑[3,4-g]喹喔啉，四条水溶性侧链为聚甲基丙烯酸寡聚乙二醇酯。
进一步地，所述聚合物的合成路线为：
本发明还提供一种利用上述的四臂星型分子刷聚合物制备小尺寸近红外二区荧光成像造影剂的方法，将所述四臂星型分子刷聚合物直接溶于水中，得到小尺寸近红外二区荧光成像造影剂。
进一步地，所述四臂星型分子刷聚合物水溶液的浓度为10～300毫克/毫升。
本发明还提供一种上述的方法制备得到的小尺寸近红外二区荧光成像造影剂，所述小尺寸近红外二区荧光成像造影剂的粒径为8～50纳米。
本发明还提供一种上述的造影剂作为红外二区荧光成像造影剂的应用。
本发明还提供一种上述的造影剂在制备血管成像肿瘤疾病诊疗药物中的应用。
有益效果：本发明设计并合成了一种小尺寸的近红外二区荧光成像造影剂，该造影剂由四臂星型分子刷聚合物在水溶液中组装而成。四臂星型分子刷聚合物的核为4,9-双(5-(9,9-双(6-溴己基)-9H-芴-2-基)噻吩-2-基)-6,7-双(4-(己氧基)苯基)-[1,2,5]噻二唑[3,4-g]喹喔啉，四个水溶性侧链为聚甲基丙烯酸寡聚乙二醇酯。本发明制备方法简单，具有近红外二区成像荧光效果，可作为造影剂实现对肿瘤的近红外二区荧光成像。较现在报道的近红外二区荧光成像造影剂具有更高的水溶性、小尺寸、高亮度以及较长的体内循环时间，从而极大地提高了活体血管和肿瘤的成像质量。
附图说明
图1为本发明实施例1所得造影剂TQFP-5的透射电镜照片；
图2为本发明实施例2所得造影剂TQFP-10的透射电镜照片；
图3为本发明实施例3所得造影剂TQFP-15的透射电镜照片
图4为本发明实施例1所得造影剂TQFP-5的动态光散射测得的流体力学直径；
图5为本发明实施例2所得造影剂TQFP-10的动态光散射测得的流体力学直径；
图6为本发明实施例3所得造影剂TQFP-15的动态光散射测得的流体力学直径；
图7为本发明实施例1,2,3所得造影剂TQFP-5/10/15的吸收与荧光光谱图谱；
图8为本发明实施例1所得造影剂TQFP-10的小鼠血管及肿瘤成像；
图9为本发明实施例1所得造影剂TQFP-10的小鼠原位脑胶质瘤成像。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
四臂星型分子刷聚合物的合成路线如下：
四臂星型分子刷聚合物的合成方法：
将小分子可逆加成-断裂链转移聚合引发剂TQF-CTA(50毫克，0.02毫摩尔)，亲水聚合物单体接枝寡聚乙二醇甲醚甲基丙烯酸酯(OEGMA，0.8克，0.5毫摩尔)和偶氮二异丁腈(AIBN，0.3毫克，0.002毫摩尔)添加到2毫升1,4-二氧六环中，并在65摄氏度和氮气保护下搅拌6小时。然后，通过在乙醚中沉淀3次，得到星形聚合物刷TQFP，为绿色固体(1.2g，68％)。
调整步骤中亲水聚合物单体接枝寡聚乙二醇甲醚甲基丙烯酸酯聚合物链段(OEGMA)的比例，即可得到重复单元数n为5-15的四臂星型分子刷聚合物。
实施例1:
亲水聚合物单体接枝寡聚乙二醇甲醚甲基丙烯酸酯聚合物链段(OEGMA)重复单元数为5的四臂星型分子刷聚合物50毫克溶于5毫升水中自组装即可得造影剂。
如图1所示，测试造影剂在水溶液中的透射电镜图，可得该造影剂纳米粒子粒径为8-10纳米，且都为类球形。
如图4所示，测试造影剂在水溶液中的流体力学直径，可得该造影剂纳米粒子粒径为8纳米。
如图7所示，测试造影剂的吸收与发射光谱图，可以看出其紫外-近红外吸收在700-900纳米范围，而发射峰1000纳米以上，具有明显的二窗发射。
如图8所示，选用脑胶质瘤异质瘤肿瘤小鼠，尾静脉注射200微升，用近红外二区成像仪观察其小鼠血管及肿瘤位置的信号强度变化图。从图中可知造影剂的体内循环时间可达12小时。
如图9所示，选用脑胶质瘤原位瘤肿瘤小鼠，尾静脉注射200微升，用近红外二区成像仪观察其小鼠肿瘤位置的信号强度变化图，可以看出随着时间的延长脑肿瘤的成像越来越明显，在36小时到达最大值，随后随时间的延长信号强度开始减弱。
实施例2:
亲水聚合物单体接枝寡聚乙二醇甲醚甲基丙烯酸酯聚合物链段(OEGMA)重复单元数为10的四臂星型分子刷聚合物100毫克溶于5毫升水中自组装即可得造影剂。
如图2所示，测试造影剂在水溶液中的透射电镜图，可得该造影剂纳米粒子粒径为10-15纳米，且都为类球形。
如图5所示，测试造影剂在水溶液中的流体力学直径，可得该造影剂纳米粒子粒径为11纳米。
如图7所示，测试造影剂的吸收与发射光谱图，可以看出其紫外-近红外吸收在700-900纳米范围，而发射峰1000纳米以上，具有明显的二窗荧光发射。
实施例3:
亲水聚合物单体接枝寡聚乙二醇甲醚甲基丙烯酸酯聚合物链段(OEGMA)重复单元数为15的四臂星型分子刷聚合物1000毫克溶于5毫升水中自组装即可得造影剂。
如图3所示，测试造影剂在水溶液中的透射电镜图，可得该造影剂纳米粒子粒径为12-20纳米，且都为类球形。
如图6所示，测试造影剂在水溶液中的流体力学直径，可得该造影剂纳米粒子粒径为15纳米。
如图7所示，测试造影剂的吸收与发射光谱图，可以看出其紫外-近红外吸收在700-900纳米范围，而发射峰1000纳米以上，具有明显的二窗荧光发射。
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，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种四臂星型分子刷聚合物，其特征在于，所述聚合物的结构式如下：
其中：四条水溶性侧链的重复单元数n为5-15，所述聚合物核为近红外二区荧光染料，结构为4,9-双(5-(9,9-双(6-溴己基)-9H-芴-2-基)噻吩-2-基)-6,7-双(4-(己氧基)苯基)-[1,2,5]噻二唑[3,4-g]喹喔啉，四条水溶性侧链为聚甲基丙烯酸寡聚乙二醇酯，所述聚合物的合成路线为：
2.一种利用权利要求1所述的四臂星型分子刷聚合物制备小尺寸近红外二区荧光成像造影剂的方法，其特征在于，将所述四臂星型分子刷聚合物直接溶于水中，得到小尺寸近红外二区荧光成像造影剂；所述四臂星型分子刷聚合物水溶液的浓度为10～300毫克/毫升，所述小尺寸近红外二区荧光成像造影剂的粒径为8～50纳米。
3.根据权利要求2所述的方法制备得到的小尺寸近红外二区荧光成像造影剂。
4.根据权利要求3所述的造影剂作为红外二区荧光成像造影剂的应用。
5.根据权利要求3所述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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