CN113717543B - 一种七甲川菁近红外染料及其应用 - Google Patents
一种七甲川菁近红外染料及其应用 Download PDFInfo
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Abstract
本发明公开了一种七甲川菁近红外染料及其应用；该七甲川菁近红外染料具有更好的体内代谢特点，在肝脏、肠等器官滞留时间短，在肿瘤中的滞留时间几乎不变，靶向作用依旧保持，从而更适合用于肿瘤精准诊断，具备一定的临床应用前景，应用于外科肿瘤切除过程中手术导航。
Description
技术领域
本发明属于非特异性分子肿瘤靶向诊断试剂技术领域，具体涉及一种具有肿瘤聚集且滞留时间长，而正常组织如肝脏、肠等部位迅速清除的七甲川菁近红外染料及其应用。
背景技术
随着居民生活水平的提高，生存条件的改变，环境污染加重，饮食习惯的改变，恶性肿瘤也越来越常见，每年绝大多数恶性肿瘤因其无法治愈而剥夺了无数患者的生命，因此针对恶性肿瘤的治愈仍然是一项巨大的挑战。近年来，我国恶性肿瘤的发病率和死亡率出现了逐年上升的趋势，随之而来的是高额的治疗费用以及无数患者生命的剥夺。对于恶性肿瘤的临床治疗，主要有手术切除和化疗；化疗主要采用化疗药物对肿瘤进行杀伤，能够延长患者短期的生存期，但是伴随而来的是严重的不良反应，给患者造成不可挽回的身体及心理损伤；随着各种先进设备的出现，如核磁共振成像、超声造影、Spect/CT等，能精准的定位肿瘤，找出病灶所在部位，再以近红外成像设备和近红外荧光探针，借用近红外成像设备，能更好的区分肿瘤部位和正常组织，从而更精确的切除肿瘤，保留正常组织。
吲哚菁绿(ICG)是一种经FDA获批的用于临床术中导航的近红外荧光染料，具有良好的安全性，外科医生手术使用过程基本都是手术前一天静脉注射给药，经一天代谢后，等待肝脏、肠等组织代谢完全后进行手术，ICG肿瘤靶向机制为EPR被动靶向集聚于肿瘤部位。NIR-04(CN 111196896 A)是在ICG母核的基础上进行修饰得到的ICG衍生物，经活体验证发现，其靶向作用比ICG更强，肿瘤滞留时间相比ICG于大大延长，同时我们以NIR-04为候选化合物进行体内安全性、体内代谢、荷瘤鼠肿瘤靶向性进行研究，发现NIR-04在肝脏中积聚，并且难以代谢清除，从而不适合临床使用。
因此我们对NIR-04在结构不改变的基础上，进一步修饰，旨在开发出肝脏不滞留或滞留时间短的近红外荧光染料。
发明内容
针对现有技术的不足，本发明的第一个目的是提供一种七甲川菁近红外染料；该染料在体内代谢更优、不在肝脏等器官长时间滞留而且具有肿瘤特异性靶向性；本发明的第二个目的是提供该近红外荧光染料的应用。
本发明解决其技术问题采用的技术方案是：
一种结构式Ⅰ所示的七甲川菁近红外荧光染料，
其中，X选自SCH2CH2COOH、SCH2COOH、SCH2CH2CONH(CH2CH2O)n-CH2CH2NH2或SCH2CH2CONH(CH2CH2O)mCH2CH2COOH，n、m选自0-10。
本发明的结构式Ⅰ以下简称YQ-04-X，X选自SCH2CH2COOH、SCH2COOH、SCH2CH2CONH(CH2CH2O)n-CH2CH2NH2或SCH2CH2CONH(CH2CH2O)mCH2CH2COOH，n、m选自0-10。
优选的，所述近红外荧光染料选自如下I-1或I-2：
所述YQ-04-SCH2CH2COOH(又称Ⅰ-1)的合成方法如下：在偶极非质子性溶剂中，化合物Ⅱ(又称NIR-04)与3-巯基丙酸、碱反应得YQ-04-SCH2CH2COOH。
所述YQ-04-SCH2CH2CONH(CH2CH2O)nCH2CH2NH2(又称Ⅰ-2)的合成方法如下：
a)在偶极非质子性溶剂中，化合物Ⅱ与3-巯基丙酸、碱反应得YQ-04-SCH2CH2COOH；
b)在2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、碱和极性溶剂的存在下将YQ-04-SCH2CH2COOH，和NH(CH2CH2O)nCH2CH2NH2或NH(CH2CH2O)nCH2CH2NHBoc反应，得YQ-04-SCH2CH2CONH(CH2CH2O)nCH2CH2NH2或YQ-04-SCH2CH2CONH(CH2CH2O)nCH2CH2NH2Boc(n＝0-10)；
c)将步骤b)的YQ-04-SCH2CH2CONH(CH2CH2O)nCH2CH2NH2Boc(n＝0-10)在TFA作用下脱Boc，得YQ-04-SCH2CH2CONH(CH2CH2O)nCH2CH2NH2。
本发明还保护前文所述的七甲川菁近红外荧光染料YQ-04-X的钠盐、钾盐、钙盐形式。
本发明还保护前文所述的七甲川菁近红外荧光染料或其药学上可接受的盐在制备肿瘤精准诊断试剂中的应用。
优选的，所述药学上可接受的盐为钠盐、钾盐或钙盐。
优选的，所述的肿瘤为肝癌、乳腺癌、肺癌或宫颈癌。
本发明还保护一种药物制剂，该制剂包含作为活性成分的前文所述的七甲川菁近红外荧光染料或其他前药形式以及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，是指一种或多种惰性的，非毒性的固体或液体填充物、稀释剂、助剂等，他们不与活性化合物或病人发生作用。
本发明的药物制剂的剂型可以为片剂、胶囊剂、丸剂、栓剂、软胶囊、口服液、混悬剂、注射剂等药剂学常用剂型。
本发明中的药物制剂可按照药学领域中熟知的方法制备。
有益效果
本发明在NIR-04结构基础上进行修饰，将氯原子进行取代，引入羧基、PEG等，在不改关键基团及溶解性的情况下，以期改善NIR-04在肝脏中滞留不清除的缺点，同时不影响其在肿瘤中的摄取及靶向性，同时为NIR-04后续应用，作为近红外荧光染料开发荧光探针，或者放射性核素标记提供更合适的连接位点；研究过程中，本发明关键性问题在于解决NIR-04肝脏无法代谢清除的同时不改变其靶向能力。
附图说明
图1为YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2的合成路线；
图2为ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2体内代谢情况，图A为各染料小鼠体内分布情况，图B为染料不同时间小鼠离体器官分布情况；
图3为NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2荧光数据，依次是图A、B、C；
图4为ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2乳腺癌Mcf7荷瘤鼠显像；
图5为ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2肝癌7721荷瘤鼠显像；
图6为ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2宫颈癌Hela荷瘤鼠显像；
图7为ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2肝癌Hepg2荷瘤鼠显像；
图8A为YQ-04-SCH2CH2COOH质谱图，B为其核磁氢谱图；
图9A为YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2质谱图，B为其核磁氢谱图；
图10为YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2Boc质谱图。
具体实施方式
以下结合实施例对本发明做进一步详细说明。所用试剂或者仪器设备未注明生产厂商的，均视为可以通过市场购买的常规产品。
实施例1 YQ-04-SCH2CH2COOH的合成
NIR-04(200mg,1.0eq)、HSCH2CH2COOH(55mg,2.0eq)和三乙胺(26mg，1.0eq)在二甲基亚砜(1ml)避光室温反应约3小时，以HPLC监测反应显示反应完全后，将反应液滴入乙酸乙酯中析出墨绿色絮状固体，过滤后再经纯化得墨绿色固体(100mg)，易吸潮，避光保存，其质谱和核磁氢谱数据如下：m/z＝847.47，1H NMR(300MHz,DMSO)δ8.78(dd,J＝23.1,14.1Hz,2H),7.74(s,1H),7.62(dd,J＝8.3,4.6Hz,2H),7.53(d,J＝8.0Hz,1H),7.41(dd,J＝15.2,7.9Hz,2H),7.27(t,J＝7.4Hz,1H),6.49(t,J＝14.5Hz,2H),4.46–4.24(m,4H),2.93(t,J＝10.9Hz,2H),2.67(s,4H),2.59(t,J＝6.7Hz,4H),2.31–2.17(m,2H),2.04(t,J＝10.6Hz,4H),1.79(s,2H),1.70(s,12H).其钠盐、钾盐可由碘化钠、碘化钾等在丙酮中与YQ-04-SCH2CH2COOH反应得到。
实施例2 YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2的合成一
YQ-04-SCH2CH2COOH(50mg,1.0eq),HATU(17mg，2.0eq)，NH2(CH2CH2O)2-CH2CH2NH2(18mg，2.0eq)，三乙胺(6mg，1.0eq)，在300ul二甲基亚砜中避光室温反应1小时，HPLC监测，反应完全后，将反应液滴入乙酸乙酯中，析出墨绿色絮状固体，过滤后再纯化得墨绿色固体(30mg)，避光保存，结构经质谱、核磁氢谱确证，质谱数据m/z＝977.35，m/z＝977.35，1HNMR(300MHz,DMSO)δ8.78(dd,J＝23.1,14.1Hz,2H),7.74(s,1H),7.62(dd,J＝8.3,4.6Hz,2H),7.53(d,J＝8.0Hz,1H),7.41(dd,J＝15.2,7.9Hz,2H),7.27(t,J＝7.4Hz,1H),6.49(t,J＝14.5Hz,2H),4.46–4.24(m,4H),2.93(t,J＝10.9Hz,2H),2.67(s,4H),2.59(t,J＝6.7Hz,4H),2.31–2.17(m,2H),2.04(t,J＝10.6Hz,4H),1.79(s,2H),1.70(s,12H).其钠盐、钾盐可由碘化钠、碘化钾等在丙酮中与YQ-04-SCH2CH2COCONH(CH2CH2O)2CH2CH2NH2反应得到。
实施例3 YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2Boc的合成
YQ-04-SCH2CH2COOH(50mg,1.0eq),HATU(17mg，2.0eq)，NH2(CH2CH2O)2-CH2CH2NH2Boc(18mg，1.2eq)，三乙胺(12mg，2.0eq)，在300ul二甲基亚砜中避光室温反应1小时，HPLC监测，反应完全后，将反应液滴入乙酸乙酯中，析出墨绿色絮状固体，再经纯化得墨绿色固体(50mg)，避光保存。
实施例4 YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2的合成二
YQ-04-SCH2CH2COOH(50mg,1.0eq),HATU(17mg，2.0eq)，NH2(CH2CH2O)2-CH2CH2NH2Boc(18mg，1.2eq)，三乙胺(12mg，2.0eq)，在300ul二甲基亚砜中避光室温反应1小时，HPLC监测，反应完全后，将反应液滴入乙酸乙酯中，析出墨绿色絮状固体，再经纯化得墨绿色固体(50mg)，避光保存，其质谱数据：m/z＝1077.32，往得到的墨绿色固体中加入TFA(100ul)避光室温反应30min，HPLC监测，反应完全后，将三氟乙酸吹干，再经纯化后得墨绿色固体(20mg)，避光保存。
性能测试
1.ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2-CH2CH2NH2对不同人源细胞系接种的荷瘤鼠模型成像对比
为了考察NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2在体内分布情况，对ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2四种染料在BCR小白鼠体内及离体器官代谢情况研究，同时构建了四种皮下瘤荷瘤鼠模型(接种于腋下)，通过近红外荧光成像技术，实时监测ICG、NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2在Mcf7(乳腺癌)、7721(肝癌)、宫颈癌(Hela)、Hepg2(肝癌)体内的动态分布。实验过程中采用785nm激发，接受信号选取800nm-900nm波段(成像设备采用的是南京诺源医疗器械有限公司的FL-10A)，各染料按ICG 1.25mg/kg给药，给的分别是对应的钠盐形式。
实验结果显示，从ICR小白鼠体内0、2、4、6、9、12、24、48小时代谢图可知，从小鼠在体数据以及解剖结果可知，NIR-04、YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2与ICG相比代谢相近，需24小时才能完全从体内排出体外，而NIR-04尾静脉给药48小时后在肝脏中依旧有强的荧光信号，而YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2尾静脉给药后能迅速的从肝脏中代谢出来，经肠排出体外，不会在肝脏中滞留而影响其以后在手术过程中的切除产生假阳性，但是修饰后的NIR-04，YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2NH2等在乳腺癌(Mcf7，如图4)、宫颈癌(Hela，如图6)、肝癌(7721如图5、Hepg2如图7)荷瘤鼠表现出更长的肿瘤滞留时间(长达48小时，甚至更长)。修饰后的化合物YQ-04-SCH2CH2COOH、YQ-04-SCH2CH2CONH(CH2CH2O)2CH2CH2-NH2等经尾静脉给药后24小时后，荷瘤鼠体内只剩肿瘤部位有荧光信号，肝脏、肠、肺等均无荧光信号，而NIR-04尾静脉给药后经过24小时代谢，除了肿瘤部位有荧光信号，肝脏部位也有很强的荧光信号，因此不利于在后期往临床转化方面应用。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求为保护范围。
Claims (4)
1.一种七甲川菁近红外荧光染料，所述近红外荧光染料为如下I-2：
2.权利要求1所述的七甲川菁近红外荧光染料或其药学上可接受的盐在制备肿瘤精准诊断试剂中的应用。
3.根据权利要求2所述的应用，其特征在于，所述药学上可接受的盐为钠盐、钾盐或钙盐。
4.根据权利要求3所述的应用，其特征在于，所述的肿瘤为肝癌、乳腺癌、肺癌或宫颈癌。
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