CN116574087A - 一种近红外七甲川菁光敏染料偶联物及其制备方法和应用 - Google Patents
一种近红外七甲川菁光敏染料偶联物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及生物化学材料的技术领域，具体涉及一种近红外七甲川菁光敏染料偶联物及其制备方法和应用。本发明的近红外七甲川菁光敏染料偶联物具有长波长的近红外吸收功能。本发明的近红外七甲川菁光敏染料偶联物的制备方法简单，易于调节。本发明近红外七甲川菁光敏染料偶联物复合纳米颗粒具有特异性肿瘤靶向、水溶性与生物相容性，能主动靶向到肿瘤部位，在正常组织中不集聚或短时间清除干净，从而不影响其临床应用。本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒能成功靶向肿瘤部位并长时间滞留，在808nm近红外激光照射下，能达到活体诊断与治疗的作用，具备一定的临床应用前景，应用于临床术中导航。
Description
技术领域
本发明涉及生物化学材料的技术领域，具体涉及一种近红外七甲川菁光敏染料偶联物及其制备方法和应用。
背景技术
目前，癌症是除心血管疾病外严重危害我国居民健康的罪魁祸首之一，严重危害着人类的健康。临床上对于肿瘤的治疗主要有外科手术切除、化疗药物、放疗药物等。传统的治疗方法，包括放疗、化疗和手术局部切除，都与高复发率、低特异性、严重副作用和耐药性有关。为了获得精确的治疗和较小的副作用，光疗技术是一种很有前途的癌症治疗方法，因为它具有特定的光诱导诊断和对癌细胞的靶向细胞毒性，具有高时空准确性和非侵入性。特别是近红外二区 (NIR-II，1000-1700 nm) 的荧光成像 (FLI) 能够深入到组织中，而对组织的干扰和光损伤最小。另一方面，光动力疗法 (PDT) 和光热疗法 (PTT) 通过利用光诱导的活性氧 (ROS) 生成和产热，可以同时作为癌症治疗策略来应用。
白蛋白是血清蛋白的主要成分，它可以结合和传递各种小分子药物，已成为纳米医学中利用最多的蛋白质。由于白蛋白具有完全的生物相容性、良好的生物降解性和非免疫原性，它被广泛用作临床药物输送的纳米载体。因此，越来越多的与蛋白质相关的纳米平台被构建用于治疗，包括白蛋白结合的紫杉醇 (PTX) 、甲氨蝶呤-白蛋白复合物以及白蛋白结合的阿霉素 (DOX) 的前体。因此，在小分子药物输送中构建白蛋白纳米复合材料用于光疗具有重要意义。
到目前为止，一些高选择性的酪氨酸激酶小分子抑制剂已经作为抗癌药物进行了临床研究。其中，我们发现克唑替尼是一种FDA批准的口服ATP竞争性抑制剂。克唑替尼能特异性靶向肿瘤组织，激活通路进一步导致肿瘤细胞凋亡，起到肿瘤治疗作用，在开发具有肿瘤特异性的荧光探针过程中，具有肿瘤特异性杀伤作用的抗肿瘤药物具备一定的研究价值，可用于特异性荧光探针的开发，进一步扩大药物的应用价值，用于外科手术导航切除肿瘤。
发明内容
本发明的目的之一在于提供一种近红外七甲川菁光敏染料偶联物，具有长波长的近红外吸收。
本发明的目的之二在于提供一种近红外七甲川菁光敏染料偶联物的制备方法，制备方法简单，易于调节。
本发明的目的之三在于提供一种复合纳米颗粒的制备方法，使用牛血清白蛋白(BSA) 对其进行包裹以提高其水溶性与生物相容性。
本发明的目的之四在于提供一种复合纳米颗粒的应用。
本发明实现目的之一所采用的方案是：一种近红外七甲川菁光敏染料偶联物，其结构式如下：
。
本发明实现目的之二所采用的方案是：一种所述的近红外七甲川菁光敏染料偶联物的制备方法，包括以下步骤：惰性气氛下，将化合物2和化合物3在一定温度下进行反应，反应完全后纯化产物制得所述近红外七甲川菁光敏染料偶联物；所述化合物2为；
所述化合物3为。
惰性气氛下，将化合物2和化合物3溶解于溶剂后，在一定温度下进行反应，反应中可以添加一定量的碱剂，也可以不添加，当添加碱剂时，碱剂可以为三乙胺（TEA）或N-乙基二异丙胺(DIPEA)；溶剂为N,N-二甲基甲酰胺（DMF）或N,N-二甲基乙酰胺(DMAc)。
优选地，所述化合物2和化合物3的摩尔比为1 ： (1-2)，反应温度为60-80℃。
优选地，所述纯化的工艺为，将反应产物加入乙醚打浆过滤，滤饼经色谱柱层析。
优选地，所述色谱柱为十八烷基硅烷键合硅胶，粒径：75-150 μm。
优选地，所述柱层析的洗脱液为体积比1:1~4:1的甲醇和水的混合物。
本发明实现目的之三所采用的方案是：一种复合纳米颗粒的制备方法，包括如下步骤：在超声条件下，将近红外七甲川菁光敏染料偶联物的乙醇或甲醇溶液滴加至牛血清白蛋白的水溶液中，然后在50-70℃下搅拌即得所述复合纳米颗粒。
本发明实现目的之四所采用的方案是：一种所述的复合纳米颗粒的应用，将所述复合纳米颗粒应用于制备肿瘤诊断剂和治疗剂。
本发明实现目的之四所采用的另一种方案是：一种所述的复合纳米颗粒的应用，将所述复合纳米颗粒应用于制备NIR-II荧光成像造影剂。
本发明实现目的之四所采用的另一种方案是：一种所述的复合纳米颗粒的应用，将所述复合纳米颗粒应用于制备荧光成像指导的PDT/PTT联合治疗剂。
反应路线如下：
；
本发明具有以下优点和有益效果：
（1）本发明的近红外七甲川菁光敏染料偶联物具有长波长的近红外吸收功能。
（2）本发明的近红外七甲川菁光敏染料偶联物的制备方法简单，易于调节。
（3）本发明近红外七甲川菁光敏染料偶联物复合纳米颗粒具有特异性肿瘤靶向、水溶性与生物相容性，能主动靶向到肿瘤部位，在正常组织中不集聚或短时间清除干净，从而不影响其临床应用。本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒能成功靶向肿瘤部位并长时间滞留，在808 nm近红外激光照射下，能达到活体诊断与治疗的作用，具备一定的临床应用前景，应用于临床术中导航。
附图说明
图1是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒制备示意图；
图2是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒表征，其中图a为透射电镜，图b为DLS粒径分布；
图3是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒的吸收光谱；
图4是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒的荧光光谱；
图5是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒激光下的热成像图像；
图6是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒的体外单线态氧生产；
图7是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒在结直肠癌CT26荷瘤鼠中的体内成像；
图8是本发明的近红外七甲川菁光敏染料偶联物复合纳米颗粒肿瘤光疗动物实验验证；
图9是不同实验组小鼠的主要器官组织苏木精-伊红染色切片。
具体实施方式
为更好的理解本发明，下面的实施例是对本发明的进一步说明，但本发明的内容不仅仅局限于下面的实施例。
下面描述的实例中的实验方法，如无特殊说明，均为常规方法；所用的材料、试剂、仪器等，若无特殊说明，均可从商业途径得到。
实施例1近红外七甲川菁光敏染料偶联的制备
将0.15 mmol化合物2加入到25 mL反应瓶中，加入3 mL无水N,N-二甲基甲酰胺(DMF) 搅拌溶解，氮气保护下，加入0.3 mmol化合物3和三乙胺，80℃搅拌2 h，反应结束。将反应液倒入25 mL乙醚中，析出蓝色固体，滤纸过滤，收集上层固体物质。十八烷基硅烷键合硅胶，粒径：75-150 μm，硅胶柱柱层析分离提纯，洗脱液为体积比1:1的甲醇和水的混合物，得50 mg蓝色金属色泽晶体为七甲川菁光敏染料偶联物，经核磁氢谱和质谱确证结构，1HNMR (600 MHz, MeOD) δ 7.90 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 12.8 Hz, 2H),7.65 (d, J = 2.8 Hz, 1H), 7.38 (s, 2H), 7.33 (m, 4H), 7.13 (dt, J = 7.8, 4.3Hz, 4H), 7.00 – 6.95 (m, 1H), 6.90 (dd, J = 10.3, 3.5 Hz, 1H), 6.05 – 5.91(m, 2H), 4.64 (s, 1H), 3.99 (t, J = 7.4 Hz, 4H), 3.82 – 3.56 (m, 4H), 3.50(d, J = 12.7 Hz, 1H), 3.22 – 3.18 (m, 2H), 2.67 – 2.46 (m, 6H), 2.37 (m, 4H),2.23 (t, J = 7.4 Hz, 8H), 1.85 (d, J = 6.3 Hz, 4H), 1.79 (s, 3H), 1.65 (s,12H), 1.48 – 1.46 (m, 2H). HRMS-ESI (m/z) Calcd for (C63H73Cl2FN7O5 +) ([M-Br]+):1096.5029, found: 1096.5034.
实施例2近红外七甲川菁光敏染料偶联的制备
将0.15 mmol化合物2加入到25 mL反应瓶中，加入3 mL无水N,N-二甲基甲酰胺(DMF) 搅拌溶解，氮气保护下，加入0.3 mmol化合物3，80℃搅拌2 h，反应结束。将反应液倒入25 mL乙醚中，析出蓝色固体，滤纸过滤，收集上层固体物质。十八烷基硅烷键合硅胶，粒径：75-150 μm，硅胶柱柱层析分离提纯，洗脱液为体积比1:1的甲醇和水的混合物，得50 mg蓝色金属色泽晶体为七甲川菁光敏染料偶联物，经核磁氢谱和质谱确证结构，1H NMR (600MHz, MeOD) δ 7.90 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 12.8 Hz, 2H), 7.65 (d, J= 2.8 Hz, 1H), 7.38 (s, 2H), 7.33 (m, 4H), 7.13 (dt, J = 7.8, 4.3 Hz, 4H),7.00 – 6.95 (m, 1H), 6.90 (dd, J = 10.3, 3.5 Hz, 1H), 6.05 – 5.91 (m, 2H),4.64 (s, 1H), 3.99 (t, J = 7.4 Hz, 4H), 3.82 – 3.56 (m, 4H), 3.50 (d, J =12.7 Hz, 1H), 3.22 – 3.18 (m, 2H), 2.67 – 2.46 (m, 6H), 2.37 (m, 4H), 2.23(t, J = 7.4 Hz, 8H), 1.85 (d, J = 6.3 Hz, 4H), 1.79 (s, 3H), 1.65 (s, 12H),1.48 – 1.46 (m, 2H). HRMS-ESI (m/z) Calcd for (C63H73Cl2FN7O5 +) ([M-Br]+):1096.5029, found: 1096.5034.
实施例2与实施例1的差别在于反应中未添加碱剂（三乙胺），经核磁氢谱和质谱确证结构，均成功合成了化合物1近红外七甲川菁光敏染料偶联物。
实施例3近红外七甲川菁光敏染料偶联物复合纳米颗粒的制备
用1 mL 1×PBS (pH=7.2-7.4) 来溶解66 mg (BSA)。之后，将1 mM的化合物1溶解在甲醇中。用PBS将1 mM BSA和化合物1稀释至10 μM。接着，将10 μM的化合物1滴加到BSA溶液中。合并后的溶液涡旋10秒后加热70℃ 反应两小时后。然后加入双蒸水后使用超滤离心管 (30 kDa) 纯化。近红外七甲川菁光敏染料偶联物复合纳米颗粒保存在4℃。
实施例4近红外七甲川菁光敏染料偶联物复合纳米颗粒表征
采用Malvern Zetasizer Nano series ZS-90测量了近红外七甲川菁光敏染料偶联物复合纳米颗粒的水动力直径。透射电镜 (TEM) 采用Hitachi TEM (HT7700, Japan)对样品进行形貌观察。结果如图2a所示,可知纳米颗粒均匀地分布在水体中，图2b可知：纳米颗粒的平均粒径为156.3 nm。
实施例5近红外七甲川菁光敏染料偶联物复合纳米颗粒的光谱测定。
用万分之一分析天平精确称取七甲川菁光敏染料偶联物复合纳米颗粒，配成10mM的溶液备用。测试时稀释成4 μM的染料溶液﹐用ShimadzuUV-3600紫外荧光分光光度计和Lumina Fluorescence Spectrometer荧光光谱仪分别测定化合物的紫外吸收光谱和荧光发射光谱。近红外七甲川菁光敏染料偶联物复合纳米颗粒的吸收光谱如图2所示，从图中可以看出：水中的偶联物复合纳米颗粒在778 nm处显示出与DMSO中的光敏染料相似的明显吸光峰，这比水中的光敏染料明显更清晰。近红外七甲川菁光敏染料偶联物复合纳米颗粒的荧光光谱如图3所示，从图中可以看出：光敏染料在水中的荧光强度很弱，而偶联物复合纳米颗粒在水中的荧光强度与光敏染料在DMSO中都比较强，说明复合纳米颗粒在水中保护了光敏染料避免了聚集引起的淬灭。
实施例6近红外七甲川菁光敏染料偶联物复合纳米的光热效应
用PBS将七甲川菁光敏染料偶联物复合纳米配置成10 mM的储备液备用。从以上配置的储存液中各吸取一定量的母液加入PBS，配制成10 μM的样品工作液，分别加入1.5 mL离心管中。将装有检测液的离心管置于808 nm、1.0 W/cm2的近红外激光 (Laser) 下照射5分钟，每隔10秒记录温度的变化。近红外七甲川菁光敏染料偶联物复合纳米颗粒激光下的热成像图像如图4所示，从图中可以看出：药物在激光照射下能产生光热效应，且随着时间和激光强度的增加，产生的温度逐步累积，20 μM药物在5 min照射下能加热水升温至约50℃ 。
实施例7近红外七甲川菁光敏染料偶联物复合纳米颗粒体外单线态氧生产
于2 mL的浓度为10 μM的近红外七甲川菁光敏染料偶联物复合纳米颗粒溶液中分别加入DPBF探针 (100%甲醇溶液配制) ，使用DPBF的浓度为1.5 μM，甲醇含量为2%。再分别于1.0 W/cm2的808 nm激光下照射5分钟，随后立即测定在415 nm的吸收波谱强度来量化单线态氧的生成。近红外七甲川菁光敏染料偶联物复合纳米颗粒的体外单线态氧生产如图5所示，从图中可以看出：药物在激光照射下能产生活性氧，且随着时间和激光强度的增加，产生的活性氧逐步增加。
实施例8近红外七甲川菁光敏染料偶联物复合纳米颗粒的肿瘤靶向能力
利用CT26细胞建立了Balb/c小鼠 (雄性) 皮下荷瘤模型，经尾静脉给予近红外七甲川菁光敏染料偶联物复合纳米颗粒，利用小动物活体成像系统进行近红外荧光实时成像，观察不同时间点化合物在小鼠体内的代谢分布。近红外七甲川菁光敏染料偶联物复合纳米颗粒在结直肠癌CT26荷瘤鼠中的体内成像图如图6所示，从图中可以看出：药物在肿瘤部位相较于其他正常组织部位显示出更强的荧光，说明药物在肿瘤部位累积更多，证明药物具有良好的肿瘤靶向能力。
实施例9近红外七甲川菁光敏染料偶联物复合纳米颗粒在荷瘤小鼠上的肿瘤光疗应用
利用CT26细胞建立了Balb/c雄性小鼠皮下荷瘤模型，分为 (1) PBS组，(2) 单独给药七甲川菁光敏染料偶联物复合纳米颗粒组，(3) PBS加光照Laser组和 (4) 给七甲川菁光敏染料偶联物复合纳米颗粒加光照Laser组，每组5只。经尾静脉给给药，24小时后再分别只给予组别 (2) 和 (4) 肿瘤 1 W/cm2的808 nm激光照射5分钟，连续观察测量上述4组小鼠体重和肿瘤的体积大小变化。近红外七甲川菁光敏染料偶联物复合纳米颗粒的肿瘤光疗动物实验验证图如图7所示，从图中可以看出：给予药物组小鼠肿瘤增长速度放缓，而药物＋光照联合治疗组则显著抑制肿瘤生长，具有良好的肿瘤抑制效果。
实施例10不同实验组小鼠的主要器官组织苏木精-伊红染色切片。
PBS组和其他3个试验组小鼠处死后。然后将心脏、肝脏、脾脏、肺和肾脏收集起来并固定在4%的多聚甲醛中。然后按照标准流程进行石蜡包埋切片、苏木精伊红 (H&E) 染色。不同实验组小鼠的主要器官组织苏木精-伊红染色切片如图8所示，从图中可以看出：小鼠的主要脏器（心、肝、脾、肺、肾）未出现明显损伤，说明药物安全性良好。
以上所述是本发明的优选实施方式而已，当然不能以此来限定本发明之权利范围，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变动，这些改进和变动也视为本发明的保护范围。
Claims (10)
1.一种近红外七甲川菁光敏染料偶联物，其特征在于：其结构式如下：
2.一种如权利要求1所述的近红外七甲川菁光敏染料偶联物的制备方法，其特征在于：包括以下步骤：惰性气氛下，将化合物2和化合物3在一定温度下进行反应，反应完全后纯化产物制得所述近红外七甲川菁光敏染料偶联物；所述化合物2为
所述化合物3为
3.根据权利要求2所述的近红外七甲川菁光敏染料偶联物的制备方法，其特征在于：所述化合物2和化合物3的摩尔比为1：(1-2)，反应温度为60-80℃。
4.根据权利要求2所述的近红外七甲川菁光敏染料偶联物的制备方法，其特征在于：所述纯化的工艺为，将反应产物加入乙醚打浆过滤，滤饼经色谱柱层析。
5.根据权利要求4所述的近红外七甲川菁光敏染料偶联物的制备方法，其特征在于：所述色谱柱为十八烷基硅烷键合硅胶，粒径：75-150μm。
6.根据权利要求4所述的近红外七甲川菁光敏染料偶联物的制备方法，其特征在于：所述柱层析的洗脱液为体积比1:1～4:1的甲醇和水的混合物。
7.一种复合纳米颗粒的制备方法，包括如下步骤：在超声条件下，将近红外七甲川菁光敏染料偶联物的乙醇或甲醇溶液滴加至牛血清白蛋白的水溶液中，然后在50-70℃下搅拌即得所述复合纳米颗粒，所述近红外七甲川菁光敏染料偶联物为权利要求1所述的近红外七甲川菁光敏染料偶联物或者权利要求2-6中任一项所述的制备方法制备的近红外七甲川菁光敏染料偶联物。
8.一种如权利要求7所述的复合纳米颗粒的应用，其特征在于：将所述复合纳米颗粒应用于制备肿瘤诊断剂和治疗剂。
9.一种如权利要求7所述的复合纳米颗粒的应用，其特征在于：将所述复合纳米颗粒应用于制备NIR-II荧光成像造影剂。
10.一种如权利要求7所述的复合纳米颗粒的应用，其特征在于：将所述复合纳米颗粒应用于制备荧光成像指导的PDT/PTT联合治疗剂。
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