CN113773667B - 有机小分子近红外二区荧光染料及其制备方法和应用 - Google Patents
有机小分子近红外二区荧光染料及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种有机小分子近红外二区荧光染料，并公开了该染料及其纳米颗粒水溶液的制备方法和应用。本发明基于吡咯并吡咯二酮单元合成了一种新型有机小分子荧光材料，此设计合成步骤简单，结构特征明显。通过纳米共沉淀方法制得具有良好水溶性、生物相容性及靶向性的纳米颗粒，该纳米颗粒具有优良的近红外二区荧光成像、光声成像、光动力及光热转换性能，可用于近红外二区荧光成像/光声成像指导下的光热/光动力联合治疗试剂的制备，为单一波长激发的NIR‑II荧光成像引导的光疗开辟新的领域。
Description
技术领域
本发明属于生物医药工程技术领域，更具体地，涉及一种有机小分子近红外二区荧光染料及其制备方法和应用。
背景技术
目前，癌症治疗主要采用外科手术来切除肿瘤，同时辅以发射性疗法治疗，而对严重或扩散性的肿瘤则采用化学药物治疗。但由于化疗对治疗目标靶体的选择性差，在杀伤癌细胞的同时也会损伤正常组织和细胞，为此光动力疗法(PDT)以及光热疗法(PTT)开始被尝试用作治疗恶性肿瘤的新技术。光学动力治疗是以光/光敏剂/氧气彼此共同作用为基础的一种新型疾病治疗手段。其原理是利用摄入的药物发生光动力学以及酶化反应产生多种活性氧(ROS)，从而对蛋白质、核酸等生物大分子产生破坏作用，产生细胞毒性，造成细胞器损伤，导致细胞死亡，进而破坏靶组织以达到治疗目的。基于单线态氧的光动力治疗需要足够的氧气供给，这限制了该治疗方式在缺乏氧病灶的治疗。光热疗法(PTT)成为近几年发展起来的一种具有临床应用前景的肿瘤技术，其过程是利用光热诊疗试剂选择性地富集于病灶部位，然后利用组织穿透力较强、光毒性较低的近红外光对其进行照射，光热治疗试剂吸收光能并转化为热能，使其肿瘤部位温度升高，从而杀死肿瘤细胞，达到治疗肿瘤的目的。相比于传统的肿瘤治疗方法，PTT的优势包括：(1)可以选择性的让激光照射肿瘤部位，避免了全身效应，从而达到微创治疗的目的；(2)当肿瘤区域的温度达到42℃以上时，癌细胞会因为蛋白质变性等因素的影响而导致死亡，且肿瘤细胞比正常细胞对温度更加敏感，从而在一定温度范围内可以选择性地杀死癌细胞而正常细胞不受影响；(3)侵入性小。但是，单一的PTT治疗往往会导致热休克反应，因此，光热及光动力两种技术的联合治疗被视作是一种可行性的策略。然而，大多数已报道的光诊疗剂往往受到多种因素的限制，包括较差的生物相容性、较低的近红外吸收能力以及不理想的治疗效果。同时，肿瘤治疗过程中往往需要多次注射药物并进行光照，这导致许多不必要的副作用同时增加患者体内毒性。
随着纳米技术的不断发展，大量纳米材料被制备用于光热治疗中。其中，金纳米材料包括金纳米棒、纳米笼、纳米片和复合纳米结构是目前应用最广泛的光热治疗试剂。然而这些无机纳米材料固有的生物毒性和不可降解性一定程度上都限制了它们在临床上的实际应用。相比于无机纳米材料的生物毒性，有机材料因其具有与生物组织类似的元素组成，被认为是比无机纳米颗粒有更好的生物相容性。其中，小分子NIR-II荧光染料凭借其具有良好的生物相容性，优越的光学性能，快速的代谢能力是理想的候选方案。此外，小分子NIR-II有机荧光团的内在多功能性也赋予了它们的PTT和PDT效应。但是现有的NIR-II荧光染料大多结构复杂，合成困难。
基于此，有必要开发一种新型的有机小分子NIR-II荧光染料，为实现临床应用的高性能纳米诊疗试剂的设计开发提供全新的方向。
发明内容
本发明的目的是针对以上不足，提供一种新型的有机小分子近红外二区(NIR-II)荧光染料，并提供该染料及其纳米颗粒水溶液的制备方法，其纳米颗粒具有良好的水溶性和生物相容性和靶向性，同时具有近红外二区荧光成像能力，和良好的光热及光动力效果。
本发明的另一个目的在于提供了该新型有机小分子近红外二区(NIR-II)荧光染料在近红外二区荧光成像和光声成像中的应用，及其在近红外二区荧光成像指导下的光热/光动力联合治疗的试剂中的应用。
为实现上述目的，本发明是通过以下技术方案实现的：
一种有机小分子近红外二区荧光染料，该染料的主要成分为吡咯并吡咯二酮单元衍生物，其结构式为：
一种上述有机小分子近红外二区荧光染料的制备方法，包括以下步骤：
将4-溴邻苯二胺和2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮，与磷催化剂、钯催化剂混合，抽真空，通氮气，随后加入溶剂和碱性溶液，在85～95℃反应45～50h，将得到的粗产物旋干，旋粉提纯即得。
其合成路线为：
优选地，上述制备方法，所述4-溴邻苯二胺、2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮、磷催化剂和钯催化剂的摩尔比为(3～5):1：(0.1～0.2)：(0.2～0.3)。
优选地，上述制备方法中，所述磷催化剂选用三(邻甲基苯基)磷，钯催化剂选用三(二亚苄基丙酮)二钯(Pd2(Dba)3)。
优选地，上述制备方法中，所述溶剂为无水甲苯，碱性溶液为1mol/L的K3PO4溶液。
一种上述有机小分子近红外二区荧光染料的纳米颗粒水溶液，是通过将所述的有机小分子近红外二区荧光染料与两亲性分子通过纳米共沉淀方法制得的，包括以下步骤：
将上述的吡咯并吡咯二酮单元衍生物和Pluronic F127溶解于四氢呋喃后，加入水，超声震荡3～5min；
去除溶液中的四氢呋喃，然后经水相滤膜过滤、离心机超滤，制得有机小分子近红外二区荧光染料的纳米颗粒水溶液。
上述方法制备的纳米颗粒水溶液，其最大光吸收波长为635nm±10nm。
上述方法制备的纳米颗粒水溶液，其最大荧光发射波长为1000nm±10nm。
一种上述的有机小分子近红外二区荧光染料在近红外二区荧光成像中的应用，所述应用是指该有机小分子近红外二区荧光染料的纳米颗粒水溶液作为近红外二区荧光成像造影剂。
一种上述的有机小分子近红外二区荧光染料在光声成像中的应用，所述应用是指该有机小分子近红外二区荧光染料的纳米颗粒水溶液作为光声成像造影剂。
一种上述的有机小分子近红外二区荧光染料在制备光热/光动力联合治疗试剂中的应用，所述应用是指该新型有机小分子近红外二区荧光染料的纳米颗粒水溶液用于制备肿瘤靶向光热/光动力联合治疗试剂。
与现有技术相比，本发明的有益效果为：
本发明基于吡咯并吡咯二酮单元合成了一种新型有机小分子NIR-II荧光材料，其设计合成步骤简单，结构特征明显。
本发明所述的有机小分子NIR-II染料通过简单的纳米共沉淀方法制备得到具有良好水溶性、生物相容性及靶向性的纳米颗粒，该纳米颗粒具有优良的近红外二区荧光成像能力、光声成像能力、光动力及光热转换性能，可以用于近红外二区荧光成像/光声成像指导下的光热/光动力联合治疗试剂的制备。
本发明的有机小分子NIR-II染料可以用于成像和光疗，对肿瘤细胞表现良好的抑制率，为单一波长激发的NIR-II荧光成像引导的光疗开辟新的领域，提供了新的策略，同时实现了肿瘤的有效治疗。
附图说明
图1为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的紫外谱图。
图2为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的荧光谱图。
图3为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒的DLS图。
图4为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的近红外二区荧光成像图。
图5为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的光声成像图。
图6为不同浓度的有机小分子NIR-II荧光染料的纳米颗粒水溶液在同一功率光照下的光热变化图。
图7为相同浓度的有机小分子NIR-II荧光染料的纳米颗粒水溶液在不同功率光照下的光热变化图。
图8为一定浓度的有机小分子NIR-II荧光染料的纳米颗粒水溶液在1W/m2光照下DPBF的414nm紫外吸收强度随时间变化图。
具体实施方式
下面将结合附图和具体实验方法对本发明做更详细地描述。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。
本发明的实施所使用的试剂皆为市购，所使用的仪器分别为：
近红外二窗荧光成像仪：NIRvana 640-Princeton instrument
红外热成像仪：TESTO869
激光器：MDL-IH-808-1.5W-PSU-II-LED
1.一种有机小分子近红外二区荧光染料，该染料的主要成分为吡咯并吡咯二酮单元衍生物，其结构式为：
所述有机小分子近红外二区(NIR-II)荧光染料的合成路线为：
具体制备步骤如下：
称取85mg的4-溴邻苯二胺和100mg的2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮(摩尔比5：1)，20mg三(邻甲基苯基)磷，10mg三(二亚苄基丙酮)二钯(Pd2(Dba)3)(摩尔比1:3)加入到两口烧瓶中，抽真空，通氮气。随后加入无水甲苯30mL，2mL的K3PO4溶液(1mol/L)，油浴锅内90℃反应48h，将得到的粗产物旋干，旋粉过柱子提纯，得到目标产物(约110mg，产率59.5％)。
2.上述有机小分子近红外二区荧光染料的纳米颗粒水溶液的制备方法如下：
称取1mg有机小分子NIR-II染料和20mg Pluronic F127溶于1mL四氢呋喃(THF)中，将溶液放入细胞粉碎仪器中，迅速加入5mL水，超声环境中迅速震荡3min。鼓吹氮气去除溶液中的THF，然后使用水相滤膜过滤得到水溶液纳米颗粒，最后通过离心机超滤得到定量的纳米颗粒水溶液。其紫外吸收光谱如图1所示，荧光光谱图如图2所示，所得到的纳米颗粒的粒径大小如图3所示。
3.有机小分子NIR-II荧光染料的纳米颗粒水溶液用于近红外二区荧光成像
配制浓度为0.1mg/ml的上述纳米颗粒水溶液1ml，放置于小离心管中，在近红外二区荧光成像仪下，用波长为808nm的激光激发，得到近红外二区荧光成像，如图4所示，结果表明该纳米颗粒具有优异的红外二区荧光成像能力。
4.有机小分子NIR-II荧光染料的纳米颗粒水溶液用于光声成像
配置浓度为1mg/mL的纳米颗粒水溶液，溶于200μL小试管，在光声成像仪进行成像测试，结果如图5所示。
5.有机小分子NIR-II荧光染料的纳米颗粒水溶液光热/光动力测试
(1)纳米颗粒光热测试：
研究不同溶液浓度及不同光功率密度下纳米颗粒水溶液的光热性能。
分别配置浓度梯度为20μg/ml、40μg/ml、60μg/ml、80μg/ml和100μg/ml的纳米颗粒水溶液，使用激光(660nm，1W/cm2)照射，由红外相机记录溶液温度随时间变化的趋势，如图6所示，采用相同的激光功率照射下，纳米颗粒水溶液温度上随着浓度的增大而不断升高。
接着，分别用功率密度为0.25W/cm2、0.5W/cm2、0.75W/cm2及1W/cm2的激光(660nm)照射具有相同浓度的纳米颗粒溶液，并检测溶液温度随时间变化曲线，如图7所示，表明随着激光功率密度增加，纳米颗粒溶液温度增加越明显。
(2)光动力性能的测试：
在比色皿中加入纳米颗粒水溶液，再滴加入DPBF的乙醇溶液，分别用光功率密度为0.25W/cm2、0.5W/cm2及1W/m2的激光(730nm)间断照射，每次光照20s，并记录DPBF在414nm处的紫外吸收峰的变化，图8为1W/m2光照下DPBF特征峰414nm处的紫外吸收峰随时间的变化趋势。DPBF在414nm处的吸收峰随着激光的不断照射有明显降低，从而反映光照过程产生了单线态氧。另外随着光功率密度越大，DPBF在414nm处的吸收峰下降的幅度越大，表明该纳米颗粒具有较好的光动力性能。
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 (10)
1.一种有机小分子近红外二区荧光染料，其特征在于，该染料为吡咯并吡咯二酮单元衍生物，其结构式为：
2.一种权利要求1所述的有机小分子近红外二区荧光染料的制备方法，其特征在于，包括以下步骤：
将4-溴邻苯二胺和2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮，与磷催化剂、钯催化剂混合，抽真空，通氮气，随后加入溶剂和碱性溶液，在85～95℃反应45～50h，将得到的粗产物旋干，提纯即得。
3.根据权利要求2所述的有机小分子近红外二区荧光染料的制备方法，其特征在于，所述4-溴邻苯二胺、2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮、磷催化剂和钯催化剂的摩尔比为(3～5):1：(0.1～0.2)：(0.2～0.3)。
4.根据权利要求2所述的有机小分子近红外二区荧光染料的制备方法，其特征在于，所述磷催化剂为三(邻甲基苯基)磷，钯催化剂为三(二亚苄基丙酮)二钯。
5.根据权利要求2所述的有机小分子近红外二区荧光染料的制备方法，其特征在于，所述溶剂为无水甲苯，碱性溶液为1mol/L的K3PO4溶液。
6.一种权利要求1所述的有机小分子近红外二区荧光染料的纳米颗粒水溶液，其特征在于，是通过纳米共沉淀方法制得的，包括以下步骤：
将权利要求1所述的吡咯并吡咯二酮单元衍生物和Pluronic F127溶解于四氢呋喃后，加入水，超声震荡3～5min；
去除溶液中的四氢呋喃，然后经水相滤膜过滤、离心机超滤，制得有机小分子近红外二区荧光染料的纳米颗粒水溶液。
7.根据权利要求6所述的有机小分子近红外二区荧光染料的纳米颗粒水溶液，其特征在于，其最大光吸收波长为635nm±10nm。
8.根据权利要求6所述的有机小分子近红外二区荧光染料的纳米颗粒水溶液，其特征在于，其最大荧光发射波长为1000nm±10nm。
9.一种权利要求1所述的有机小分子近红外二区荧光染料在制备近红外二区荧光成像和/或光声成像的造影剂中的应用。
10.一种权利要求1所述的有机小分子近红外二区荧光染料在制备光热/光动力联合治疗试剂中的应用。
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