CN107057398B - 一种七甲川菁荧光染料及其肿瘤精准诊断和治疗的应用 - Google Patents
一种七甲川菁荧光染料及其肿瘤精准诊断和治疗的应用 Download PDFInfo
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Abstract
本发明一种具有肿瘤特异性的七甲川菁近红外荧光染料及其应用,所述的近红外荧光染料为ICG‑03,该染料能够被多种人缘肿瘤细胞自发吸收和累积,特异性聚集于肿瘤部位,而不是正常细胞,从而可用于肿瘤精准诊断。所述的分子,具有好于ICG的光学特性,可进行光动力学治疗,和肿瘤成像,稳定性好。本发明的七甲川菁近红外荧光染料可用于肿瘤的精准诊断和治疗。
Description
技术领域
本发明涉及近红外荧光染料领域,具体涉及一种七甲川菁荧光染料近红外荧光染料,可进行肿瘤靶向光动力学治疗。本发明还公开了其合成方法,以及在肿瘤精准诊断和治疗中的应用。
背景技术
目前,癌症已成为危害我国居民健康的最大的罪魁祸首,严重威胁着人类的健康。临床上用于治疗肿瘤的方法有外科手术法、化学药物治疗、放射性治疗等。其中,光热光动治疗技术是一种新兴的无副作用的治疗技术,它是利用一类具有良好光热转换效率的光热试剂在近红外光的照射下,将一部分能量以热量形式释放,并产生活性氧分子。光热治疗与传统治疗方法相比,具有以下优势作为一种非侵入式的治疗手段,毒、副作用低,简便易行,患者几乎无不适感,无风险,适用于各种人群。光热光动治疗既可以作为主要治疗方式,也可以作为协同治疗方式,在治疗膀胱、食道、头颈部、脑部、肺部、前列腺、腹腔内腔、胸腺和皮肤的癌症或恶性肿瘤方面得到运用。
近红外荧光探针被赋予了无损在位连续监测生物体内各参数的潜能,也在生物医学检测领域蕴藏着巨大的应用前景,必将在体内特异性分子的识别,尤其是肿瘤特异性分子的诊断中发挥重要的作用。
吲哚菁绿是是一种具有近红外特征吸收峰的三碳花菁染料,吸收范围600-850nm,分子量为775道尔顿,它具有摩尔消光系数高、荧光量子产率和光热转换效率高,熔点低以及最大吸收波长可调谐范围大等特点,是美国食品药物监督局(FDA)唯一批准用于临床的近红外造影剂。具有光热,光声和光动力响应,在光照环境下会加速分解,ICG在水溶液中的不稳定性及在血浆中的快速清除率限制了它在荧光成像、目标组织定位方面的应用。吲哚菁绿具有浓度依赖的聚集,较差的稳定性,非特异性的蛋白结合以及缺少靶向,因此在生物体内会快速降解,限制了其在肿瘤治疗方面的进一步应用。
事实上利用荧光染料进行肿瘤的检测和诊断还面临一系列的问题,如常用的肿瘤成像是用与肿瘤特异性的靶向片断化学结合,形成特异性菁染料标记复合物,这些靶向片断包括代谢底物,还有一些膜表面分子等。但这些方法用于肿瘤成像均有其局限性,因为靶向片段只能检测到部分特异性肿瘤细胞,这些细胞具有明确的表面分子特性,仅是多样性肿瘤细胞中的少部分。而且化学结合可能会改变靶分子的特异性和亲合力。因此有必要发展简单且可直接用于非侵入性肿瘤成像的新型染料。
发明内容
本发明公开了能有效靶向肿瘤细胞的近红外染料,这种染料能大量蓄积在肿瘤细胞,从而起到活体诊断功能,最终通过光照达到杀伤肿瘤细胞的效果。这种染料可制备成光学疗法的抗癌制剂。
本发明的目的在于提供新的具有药用价值的式(I)的化合物,其光热作用和光动力学均可杀伤癌细胞,可用于制备新型的抗癌制剂。
本发明的目的还在于提供具有式(I)的化合物的药理作用方式,其结合小窝蛋白2,促进高表达肿瘤细胞的摄取。
本发明另一个目的在于提供一种含有式(I)的化合物作为有效成分的光学影像诊断制剂。
本发明合成了一种式(I)化合物:
结构式I的近红外染料是吲哚菁绿的衍生物,因此,本发明的结构式I的近红外染料其生物相容性及体内安全性与其它近红外探针相比具有了明显的优势。
本发明的结构式I化合物以下简称ICG-03,它的最大吸收峰约在780nm,对应的最大荧光发射峰约为830nm。其紫外吸收光谱见图3,荧光光谱见图3。
由于ICG-03近红外染料带两个不同活性羧基,在活化后,可分别与带氨基的生物活性分子反应,通过控制反应物配比可调节其标记比例,因而在探针设计中具有明显的优势。ICG-03可作为该类生物活性分子在生物体内代谢过程研究的示踪剂,以及可作为肿瘤检测和早期诊断的造影剂。
ICG-03不溶于乙醚等非极性试剂,在水等强极性试剂中溶解度低,易溶于乙腈、甲醇等极性试剂中。含有羧基官能团,可与蛋白质和核酸等生物活性分子上的氨基发生缩合,进而可以对它们进行标记。此外,由于ICG-03在700到900纳米之间有强的近红外荧光发射(荧光发射峰约为830nm),并且此波段近红外光能穿透深层组织。因此,标记有ICG-03的蛋白质和核酸等生物活性分子可充当活体组织成像的探针。这些充分表明,ICG-03在活体组织成像以及在位活体检测等研究领域有着潜在的广泛的应用前景。
本发明解决的问题在于提供一种具有肿瘤特异性靶向的近红外荧光染料及其应用,这种染料能够被肿瘤细胞自发吸收和累积,特异性聚集于肿瘤部位,具有了肿瘤特异性靶分子和成像的双重功能,可用于临床肿瘤检测和诊断。
本发明是通过以下技术方案来实现:
一种具有肿瘤特异性靶向的近红外荧光染料,该近红外荧光染料的化学结构式为I
所述的具有肿瘤特异性靶向的近红外荧光染料在制备肿瘤诊断试剂中的应用。所述的肿瘤诊断试剂是能够与肿瘤细胞特异性结合,并诱发荧光的肿瘤诊断试剂。所述的肿瘤诊断试剂是靶向内吞小窝蛋白2高表达的肿瘤细胞或肿瘤组织。所述的肿瘤诊断试剂是显示肿瘤形成部位的诊断试剂。所述的肿瘤诊断试剂是用于在活体成像仪中对肿瘤细胞或组织显示近红外荧光的肿瘤诊断试剂。
本发明的化合物是肿瘤特异性靶向的近红外荧光染料。尽管不希望受理论约束,发明人相信本发明化合物的抗癌作用是基于其光动力学和光热效应。
药物组合物:可以任何本文所述适应症,包括抑制脑胶质瘤细胞、乳腺癌细胞增殖的治疗有效量,任选地与药学上可接受的添加剂、载体或赋形剂组合,来制备基于式I化合物,或其药学上可接受的盐或前药,包括酯的药物组合物。治疗有效量可随着要治疗的感染或病况、其严重性、所应用的治疗方案、所用药剂的药动学性质以及受治疗的患者而改变。
本发明还包括药物制剂,该制剂包含作为活性成分的式(I)化合物或其酯或前药或药学上可接受的载体。上述药学上可接受的载体是指药学领域常规的药物载体,是指一种或几种惰性的、非毒性的固体或液体填充物、稀释剂,助剂等,它们不逆向与活性化合物或病人发生作用。
本发明组合物的剂型可以是片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂、注射液等药剂学上常用的剂型。口服用药片和胶囊含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂。
本发明药物组合物的各种剂型可以按照药学领域中熟知的方法进行制备。
与现有技术相比,本发明具有以下有益的技术效果:
本发明提供的具有肿瘤特异性靶向的近红外荧光染料,为七甲川菁染料,自发荧光非常低。这种染料能够被肿瘤细胞自发吸收和累积,特异性聚集于肿瘤部位,而不是正常细胞,从而成为肿瘤特异性靶分子成像。当荷瘤裸鼠注射ICG-03结合成像可观察到这种染料能够被肿瘤组织特异性吸收,因此说明该染料具有成像和靶分子的双重功能。
本发明提供的ICG-03染料为基础的近红外活体成像技术克服了肿瘤细胞的异质性,可依据肿瘤细胞高表达的特点设计具有共性的特异性靶分子结合物,通过观察染料与其它肿瘤细胞的特异性结合从而将近红外活体成像技术应用于更多肿瘤的早期预警和快速诊断。
目前国内和国际上已开展的近红外肿瘤成像研究主要采取的方法是将与肿瘤特异性的靶向片断化学结合,形成特异性菁染料标记复合物,但均有其局限性,因为靶向片段只能检测到具有特异性标志的肿瘤细胞,这些细胞具有明确的表面分子特性,仅是多样性肿瘤细胞中的少部分。而本发明提供的ICG-03染料为基础的近红外活体成像技术克服了肿瘤细胞的异质性,是具有广谱特异性的肿瘤标志,能够实现染料与更多肿瘤细胞特异性结合。
附图简要说明:
图1七甲川菁荧光染料的质谱
图2七甲川菁荧光染料的氢谱
图3七甲川菁荧光染料的光谱性质
图4七甲川菁荧光染料与ICG的光稳定性比较
图5七甲川菁荧光染料与ICG的体外成像和光热性质比较
图6七甲川菁荧光染料与ICG的体内成像和光热性质比较
图7七甲川菁荧光染料光动力学特性a)U87细胞在不同状态下光动力学检测效果b)深色为凋亡细胞,浅色为正常细胞,在不同条件下的杀伤效果
图8七甲川菁荧光染料的细胞增殖抑制试验
图9七甲川菁荧光染料的荷瘤小鼠的治疗效果
图10七甲川菁荧光染料的动物靶向性a)和细胞靶向性b)
图11ICG-03染料的合成过程
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
本发明化合物I的制备
1、将苯肼对磺酸(5g)加入到甲基异丙基酮的甲醇溶液中(8.55/15毫升),加热这种溶液到117℃,搅拌5h后,溶剂蒸发。再加入50毫升乙醚到油状产物中,得到一个粉红色的粉末,即(3)号化合物。然后,将棕红色粉粉(6g)加氢氧化钠(1.5克)溶液中,溶剂为甲醇(10毫升)和异丙醇(10毫升),该溶液在82℃搅拌15分钟后,冷却至室温,大量的(3)号化合物分离出来,用于下一步的纯化。m/z=261.27,核磁共振谱(500兆赫,氯仿)δ7.90(d,2H)7.49(s,H)2.10(s,3H)1.44(s,6H)
2、化合物3(6克)和1-(溴甲基)苯(4.77毫升)溶解在36毫升甲苯。将混合物搅拌在氮气保护下回流5h,当混合物冷却,除去溶剂并将固体滤掉,用甲苯洗涤,最后在高真空下干燥,得到(4)号化合物。m/z=352.1,核磁共振谱(500兆赫,氯仿)δ9.30(s,H)7.98(s,H)7.80(s,H)7.23(d,5H)4.72(s,H)4.53(s,H)1.44(s,6H)。
3、包含三氯氧磷(17.5毫升)的20毫升二氯甲烷溶液逐滴加入到二甲基甲酰胺溶液中(20毫升),二氯甲烷需冰浴下。30分钟后,加入5克环己酮(化合物5),混合物在80℃加热回流搅拌3h,在冰水浴中,保持它过夜后产生黄色固体(6)号化合物。m/z=172.61,核磁共振谱(500兆赫,氯仿)δ9.87(s,2H)3.53(s,H)2.48(d,4H)2.18(s,H)1.90(s,H)1.83(s,2H)1.73(s,H)。
4、化合物4(8.53克),化合物6(2克)溶解在50毫升乙醇。将混合物搅拌,回流8h,冷却后得到的粗粉(7)号化合物,再溶于乙醇。m/z=840.38,核磁共振谱(500兆赫,氯仿)δ9.30(s,H)7.98(s,H)7.88(s,1H)7.80(s,H)7.34(s,H)7.28(s,5H)7.23(d,5H)7.02(s,H)6.45(s,H)6.09(s,H)5.45(s,H)5.25(d,2H)4.84(d,3H)2.60(s,4H)1.79(s,6H)1.46(d,8H)。
5、将3-巯基丙酸(219μL)添加到化合物7(1克)的二甲基甲酰胺溶液20毫升。在黑暗条件下,将三乙胺(350μL)逐滴加入到混合物中,搅拌24小时,加入300毫升乙醚后,icg-03即可得到,最后经柱层析纯化。m/z=910.06,核磁共振谱(500兆赫,氯仿)δ8.69(d,2H)7.82(s,2H)7.62(d,2H)7.35(m,12H)6.32(d,2H)5.50(s,4H)3.18(s,2H)2.89(s,3H)2.40(s,3H)1.75(s,13H)0.82(s,1H)。
实施例2
不同细胞系及人源荷瘤裸鼠模型对ICG-03染料的吸收
将对数生长期的U87(脑胶质瘤细胞)、MCF7(乳腺癌细胞)、HepG2(人肝癌细胞),A549(人肺癌细胞),MDA-MB-231(人乳腺癌细胞株)、Panc1(人胰腺癌细胞株)和L02(人正常肝细胞)经过胰酶消化处理,将细胞分别转接到激光共聚焦培养皿中,细胞密度约为3×105个/cm2。之后将共聚焦培养皿置于恒温细胞培养箱中(37℃,5%O2)培养24小时。待细胞贴壁后,分别加入经过滤膜过滤的0.2mL ICG-03溶液,孵育2小时。然后将细胞用冷的PBS溶液(pH7.4)洗涤两次用于激光共聚焦显微镜的双通道荧光成像。
在表观上观察肿瘤细胞内ICG-03的荧光强度,进而反映出其肿瘤细胞靶向能力,从而比较ICG-03对不同肿瘤细胞系的靶向能力大小。如图10-b所示,孵育2h后,在U87、MDA-MB-231、A549以及MCF-7细胞内可以观察到ICG-03的红色荧光信号,且在U87中的信号强度最大;与之相比,在相同时间点,HepG2以及Panc1细胞系内的ICG-03荧光信号明显低于上述肿瘤细胞,几乎没有信号输出,其结果与下述体内肿瘤靶向性相符。
为了考察ICG-03肿瘤的靶向能力,将通过无损在位近红外荧光成像技术,实时检测ICG-03在U87(脑胶质瘤细胞)、MCF7(乳腺癌细胞)、HepG2(人肝癌细胞),A549(人肺癌细胞),MDA-MB-231(人乳腺癌细胞株)、panc1 cells(人胰腺癌细胞株)荷瘤鼠体内的动态分布。选用765nm波长的激光光源,作为激发光源照射小鼠全身,并用高灵敏度的近红外电感耦合照相机获到荷瘤小鼠体内的荧光信号,由于ICG-03的最大发射波长约在820nm左右,所以选800nm的长通滤光片滤除其他散射光干扰,之后用计算机软件捕获成像的荧光图片。用150μL氨基甲酸乙酯(20mg/mL)分别将U87(脑胶质瘤细胞)、MCF7(乳腺癌细胞)、HepG2(人肝癌细胞),A549(人肺癌细胞),MDA-MB-231(人乳腺癌细胞株)、panc1 cells(人胰腺癌细胞株)荷瘤鼠麻醉,固定于夹板上。给药前预先采集荷瘤鼠的背景荧光图。将200μL ICG-03(0.5mg/mL)溶液通过尾静脉注射到麻醉的荷瘤鼠体内,在给药后不同时间点分别采集荷瘤小鼠的荧光成像图。
为了进一步探究ICG-03的靶向能力,本实例构建了六种小鼠肿瘤模型,均于腋下接种肿瘤细胞U87、MDA-MB-231、A549、MCF-7、HepG2以及Panc1,分别于尾静脉注射相同浓度的ICG-03溶液,通过小动物近红外成像系统来观察其在肿瘤部位的荧光强度,进而反应出其肿瘤靶向能力。如图10-a所示,静脉注射的ICG-03探针2h后,小鼠全身均能检测出较强的荧光信号;在注射12h后,U87、MDA-MB-231、A549以及MCF-7荷瘤鼠的肿瘤部位的荧光信号达到最大值,而其他器官无明显的荧光信号;在注射后24h时,肿瘤内仍能检测到明显的荧光信号;相比之下,HepG2以及Panc1荷瘤鼠在注射后12h,肿瘤部位未能观察到荧光信号。注射了ICG-03的U87、MDA-MB-231、A549以及MCF-7荷瘤鼠的T/N值在0~24h时内有较大的变化,且在12小时内达到最大值,其中肿瘤组织和周围正常对照组织荧光信号比值可达~9.7(U87),而通常的肿瘤部位与正常组织荧光信号比值达到3即可认为具有肿瘤主动靶向作用,显示其具有重要潜在应用前景,而HepG2以及Pane1荷瘤鼠的T/N值无明显的变化。
实施例3
化合物的安全性试验
为了考察药物对正常组织的毒副作用,需要进行组织切片及病理学研究,6周龄的30大鼠,体重为200±10g,腹腔注射ICG-03染料10mg/kg,四周后处死大鼠,肉眼观察大鼠心、肝、脾、肺和肾有无变化,10%福尔马林固定组织,切片做HE染色。大鼠心、肝、脾、肺和肾有无明显变化,组织病理与正常对照大鼠无显著差别,该剂量约为小鼠成像检测使用剂量的100倍,小鼠体重为20g,小鼠实验剂量为0.1mg/kg,证明该剂量的安全性。结果表明,该染料对动物和细胞均没有毒性,用于临床肿瘤检测和诊断显示出良好的潜能。
实施例4
荷瘤裸鼠的光动力学和光热治疗
为了考察ICG-03和ICG的治疗效果和毒副作用,将U87荷瘤裸鼠随机分为5组(n=10),分别为生理盐水对照组、激光照射对照组、非光照的ICG-03(200μL,0.5mg/mL)、光照的ICG-03(200μL,0.5mg/mL)和光照的ICG(200μL,0.5mg/mL),并每隔2天进行一次光照,对其进行治疗。每只荷瘤裸鼠每两天尾静脉注射一次,每三天测量一次荷瘤裸鼠的体重并用游标卡尺测量荷瘤鼠肿瘤长度和宽度,治疗周期为15天。
小鼠体重、肿瘤大小变化情况及存活率的计算公式如下:
肿瘤体积=长度×(宽度)2×1/2;
存活率=Ns/Nt×100%,Ns和Nt分别代表15天后每组小鼠的存活数量和小鼠总数。
在之前的实例中,已经验证了ICG-03的肿瘤靶向性、高效的协同PDT/PTT作用特性,以及在细胞水平的抗肿瘤疗效。因此,在本部分实例中,将继续探索ICG-03的用于活体肿瘤治疗的效果。由于ICG-03可以自发的主动靶向聚集在体内的肿瘤部位,并且在近红外的激光照射下,发出荧光信号。因此,可以应用肿瘤部位的荧光信号,来指导治疗激光的照射部位,即靶向的肿瘤部位,用于光热及光动治疗,并提高光疗治疗的准确性。实验选择了皮下接种U87细胞的荷瘤裸鼠作为模型,随机分为五个实验组:生理盐水组、Laser组、ICG-03组、ICG-03&Laser组及ICG&Laser组。在给药的15天内,隔天给次药,并且每三天记录一次肿瘤的体积大小及小鼠的体重。在治疗后15天内,生理盐水对照组、仅光照组和ICG-03无光照组肿瘤体积迅速增长,没有表现出明显肿瘤抑制作用;相对而言,ICG&Laser组则表现出的轻微的抑瘤作用,因为ICG在光照的条件下,能产生一定的PDT/PTT效应,但是由于其光稳定性较弱,因此不能实现很好的光疗效果;而ICG-03&Laser组则表现出了突出的抗肿瘤效果,这是由于ICG-03在尾静脉注射后,在血液中分布,并由于主动靶向作用在肿瘤部位蓄积。当ICG-03进入肿瘤细胞后,在808nm的激光的照射下,ICG-03所产生的PDT/PTT效应定点在肿瘤内部发生作用,并且由于其较好的光稳定性,表现出了更有效的光疗效应,进而表现出更好的抑瘤作用。
治疗期间荷瘤鼠存活率变化曲线能反映出小鼠的生存状态。图9-b表明,ICG-03光照组小鼠存活率达到90%,相对于ICG光照组60%的存活率以及仅光照组50%的存活率大大提高,而对照组小鼠及ICG-03未光照组的存活率仅仅为30%。上述结果说明ICG-03介导的PDT/PTT协同治疗效果,可以显著提高荷瘤鼠的存活质量,延长小鼠的存活时间。
Claims (1)
1.结构式I如下的七甲川菁近红外荧光染料ICG-03在制备肿瘤的精准诊断和治疗制剂中的应用:
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