CN115403503A - 七甲川花菁素类染料偶联物、制法、药物组合物和应用 - Google Patents
七甲川花菁素类染料偶联物、制法、药物组合物和应用 Download PDFInfo
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- CN115403503A CN115403503A CN202211070160.4A CN202211070160A CN115403503A CN 115403503 A CN115403503 A CN 115403503A CN 202211070160 A CN202211070160 A CN 202211070160A CN 115403503 A CN115403503 A CN 115403503A
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Abstract
本发明公开了一种七甲川花菁素类染料偶联物、制备方法、药物组合物和应用。该类偶联物的结构如下：
还涉及其立体异构体、药学上可接受的盐或它们的混合物。该类偶联物和药物组合物可有效抑制肿瘤细胞，并且无明显肠道毒性，安全有效。可制备为针对肿瘤的诊断剂、治疗剂，能精准靶向肿瘤细胞并在一定波长的近红外光激发下释放出活性药物DON，发挥化疗、光疗和靶向治疗的多种肿瘤治疗机制。制备方法简便、易操作。
Description
技术领域
本发明涉及一种七甲川花菁素类染料偶联物、制备方法、药物组合物和应用，尤其涉及一种可制备为肿瘤诊断剂、治疗剂的七甲川花菁素类染料偶联物、制备方法、药物组合物和应用。
背景技术
线粒体是细胞内物质能量代谢的主要场所，癌细胞中的线粒体存在结构和功能的完整性，且癌细胞对谷氨酰胺的摄取高于对葡萄糖的摄取。因此，无论在有氧还是缺氧条件下，癌细胞通过糖酵解迅速获得丙酮酸、乳酸等生物大分子构筑细胞结构，其能量主要通过谷氨酰胺代谢来获得。
谷氨酰胺通过丙氨酸-丝氨酸-半胱氨酸转运体(ASCT2)转运进细胞内，并在线粒体中由谷氨酰胺酶(GLS1/2)催化生成谷氨酸，谷氨酸进一步氧化脱氨生成α-酮戊二酸(α-KG)并进入三羧酸循环(TCA)，进一步参与线粒体中核苷酸、ATP、谷胱甘肽等的合成。谷氨酰胺能够以上述代谢方式满足细胞增殖对能量和生物量的需求。研究表明，胶质母细胞瘤、白血病、淋巴瘤、肺癌、三阴性乳腺癌和胰腺癌等癌细胞在生长过程中均表现出对谷氨酰胺的高度依赖即“谷氨酰胺成瘾”，当谷氨酰胺消耗殆尽后癌细胞便迅速死亡。
6-Diazo-5-oxo-L-正亮氨酸(DON)是一种与谷氨酰胺结构类似的非天然氨基酸，由于其反应性重氮基团，DON已被证明能烷基化多种以谷氨酰胺为底物的酶并抑制其活性，如谷氨酰胺酶(GLS1)、NAD合成酶、CTP合成酶和FGAR转氨酶等等。在临床前研究中，DON在体外可显著抑制具有“谷氨酰胺成瘾”的人癌细胞的生长，减小肿瘤体积，提高体内生存率。DON不仅有着出色的临床前数据，在后续的几项临床研究中也展现出了优异的抑制效果。例如，在晚期成年人患者和儿童患者的血液系统恶性肿瘤或实体肿瘤中，DON使得>50％肿瘤抑制或病情稳定。然而，DON在具有高活性的同时，也有着严重的全身毒性，尤其是在胃肠道的大量积累造成了不可接受的胃肠道毒副作用，极大地限制了其在临床上的应用。
为了降低DON的全身毒性并提高靶向性，人们通过前药策略改善其药代动力学特性和组织分布。对DON重氮酮进行衍生化，生成高度不稳定的化合物(如酮)，或者转化为无活性的化合物(如环重氮亚胺)。一方面，重氮酮的不稳定性使得反应必须在温和的条件下进行，这在很大程度上限制了合成路线的选择；另一方面，虽然能在一定程度上限制DON的全身毒性，但如脱靶效应依然存在。
发明内容
发明目的：针对现有DON药物及DON前药存在抗肿瘤活性有限、毒副作用明显等不足，本发明旨在提供一种针对肿瘤具有诊断、治疗多种功效的七甲川花菁素类染料偶联物、制备方法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的偶联物选自：
本发明将DON通过ROS敏感键与花菁类染料NIR-03进行偶联，得到染料-药物的治疗诊断试剂。该偶联物能精准靶向肿瘤细胞并在一定波长的近红外光激发下释放出活性药物DON。一方面，该治疗诊断试剂极大程度上减少了DON在胃肠道的积累，降低了其胃肠道毒副作用；另一方面，该治疗诊断试剂涵盖了包括化疗、光疗和靶向治疗在内的多种癌症治疗策略。
进一步地，上述偶联物还包含其立体异构体、药学上可接受的盐或它们的混合物。
其中，其药学上可接受的盐为其与以下酸形成的盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
作为本发明涉及的第二方面，当偶联物为DON-TK-NIR时，所述制备方法如下：
当偶联物为DON-CC-NIR时，所述制备方法如下：
进一步地，将上述偶联物与相应的酸成盐完全后，即得所述偶联物的药学上可接受的盐。
作为本发明涉及的第三方面，上述偶联物和/或其衍生物以及药学上可接受的载体形成药物组合物，制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第三方面，上述偶联物或者药物组合物可制备为肿瘤诊断剂或/和治疗剂。其中，所述诊断剂为肿瘤的定位剂或/和显影剂；治疗剂具有ROS、光响应特性。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类偶联物和药物组合物可有效抑制肿瘤细胞，抑制IC50值至低于5μM，并且无明显肠道毒性，安全有效；
(2)该类偶联物和药物组合物应用广泛，可制备为针对肿瘤的诊断剂、治疗剂，能精准靶向肿瘤细胞并在一定波长的近红外光激发下释放出活性药物DON，发挥化疗、光疗和靶向治疗的多种肿瘤治疗机制；
(3)化合物制备方法简便、易操作。
附图说明
图1为本发明的偶联物的释药原理图；
图2是DON-TK-NIR溶液的紫外吸收和荧光发射谱图；
图3是DON-TK-NIR溶液在体外用活性氧探针DCFH-DA检测到的ROS生成速率情况；
图4是DON-TK-NIR溶液在激光照射下药物释放的HPLC谱图；
图5是DON-TK-NIR溶液在激光照射下药物释放的LC-MS谱图；
图6是DON-TK-NIR在不同细胞系中的摄取情况；
图7是DON-TK-NIR在不同细胞内结合激光照射之后ASCT2蛋白的表达；
图8是DON-TK-NIR在A549细胞内的亚细胞共定位；
图9是DON-TK-NIR在A549小鼠异种移植模型中荧光成像情况；
图10是Vehicle、DON、DON-TK-NIR、DON-CC-NIR在有无激光照射下对不同细胞系的细胞毒性；
图11是Vehicle、DON、DON-TK-NIR结合激光照射在A549小鼠异种移植模型中肿瘤体积抑制曲线和治疗结束肿瘤质量图；
图12是Vehicle、DON、DON-TK-NIR结合激光照射在A549小鼠异种移植模型中体重变化曲线图；
图13是Vehicle、DON、DON-TK-NIR结合激光照射在A549小鼠异种移植模型中治疗结束后的肿瘤图片；
图14是Vehicle、DON、DON-TK-NIR治疗结束后肿瘤及肠道的H&E染色切片。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1：七甲川花菁素类染料偶联物DON-TK-NIR的制备
称取5-氧代吡咯烷-2-羧酸(10.00g，77.45mmol)和对甲苯磺酸(1.35g，7.55mmol)，共同溶解于异丙醇中，升温至85℃反应3h，反应结束后冷却至室温，蒸发溶剂。将粗产物溶解于乙酸乙酯中，有机层分别用饱和NaHCO3和饱和NaCl溶液洗涤3次，收集合并有机层，用无水Na2SO4干燥并真空浓缩，得到1a。产率为85％。
称取化合物1a(10.00g，58.48mmol)并溶解在无水THF中，冷却至-78℃后，滴加LiHMDS(1M in THF，55.56mmol)并在-78℃搅拌反应20分钟。然后，将在40mL无水THF中的准确称取Fmoc-Cl(22.63g,87.77mmol)，溶于无水THF中并缓慢滴加到反应溶液中继续搅拌反应2h。反应结束后，向反应液中加入饱和NH4Cl溶液以淬灭反应。所得溶液用乙酸乙酯洗涤3次，收集合并有机层，用无水Na2SO4干燥并真空浓缩，得到白色粉末状固体1b，产率为83.6％。
称取化合物1b(10.00g,25.42mmol)并溶解在无水THF，冷却至-110℃后向溶液中缓慢滴加TMSCH2N2(2M in hexane，12mL，22.88mmol)并搅拌反应10分钟。滴加完毕后，再缓慢滴加入n-BuLi(2.5M in hexane，10mL，24.15mmol)并继续搅拌反应10分钟。反应结束后，向反应液中加入饱和NH4Cl溶液以淬灭反应。所得溶液用乙酸乙酯洗涤3次，收集合并有机层，用无水Na2SO4干燥并真空浓缩，得到白色粉末状固体1c。产率为38％。
称取化合物1c(0.80g,1.84mmol)和哌啶(1.35mL,18.4mmol)，共同溶解于DCM中，室温下搅拌反应30min。反应结束后蒸发溶剂，得到淡黄色固体1d。产率为38％。
称取4-肼基苯磺酸水合物(5.00g，26.57mmoL)和3-甲基-2-丁酮(5.4mL，79.71mmoL)，共同溶解于50mL乙酸中，升温至120℃并在氮气气氛保护下回流反应2h，反应结束后冷却至室温，析出粉红色固体，抽滤，滤饼用乙酸乙酯多次洗涤，真空干燥后得到中间产物2a。产率为98％。
称取上述中间产物2a(6.00g，25.10mmoL)和氢氧化钠(1.00g，25.10mmoL)，共同溶解于15mL甲醇/异丙醇(1：1)混合溶剂中，升温至85℃回流反应30min，反应结束后冷却至室温，加入50mL甲基叔丁基醚，析出褐色固体，抽滤，滤饼用甲基叔丁基醚多次洗涤，真空干燥后得到中间产物2b。产率为98％。
称取中间产物2b(6.00g，22.99mmoL)和溴化苄(2.38mL，22.99mmoL)，共同溶解于30mL甲苯中升温至125℃并在氮气保护气氛下回流反应6h，反应结束后冷却至室温，倒出上层溶剂，加入90mL甲基叔丁基醚打浆30min，抽滤，得紫红色固体粉末，真空干燥后得到中间产物2c。产率为92％。
称取环己酮(5.00g，50mmoL)、三氯氧磷(17.5mL，115mmoL)和DMF(20mL，273mmoL)，将DMF溶于20mL二氯甲烷中，降温至0℃，并在氮气气体保护下缓慢滴加三氯氧磷并控制温度在-5℃～0℃，再加入环己酮，升温至45℃回流反应2h，反应结束后将反应液缓慢倒入200mL冰水中淬灭过量三氯氧磷，该溶液在室温下快速搅拌2h，析出黄色晶体，抽滤，真空干燥后得到中间产物2d。产率为90％。
称取中间产物2d(3.00g，17.4mmoL)、中间产物2c(3g，8.52mmoL)和乙酸钠(1.75g，21.3mmoL)，将中间产物III和中间产物IV悬浮于45mL乙酸酐中，再加入乙酸钠，避光且在室温下搅拌反应过夜，析出绿色固体，抽滤，滤饼用甲基叔丁基醚多次洗涤，真空干燥后得到七甲川花菁染料2e。产率为78％。
称取3-巯基乙酸(5.20g，49mmoL)和丙酮(11.4g，196mmoL)，将3-巯基乙酸和丙酮置于三颈瓶中，通入干燥HCl气体至饱和，室温下搅拌反应4h，反应结束后将反应瓶置于-20℃降温析晶，析出橙红色固体，抽滤，滤饼分别用预冷的正己烷和水多次洗涤，得到纯白色固体粉末，真空干燥后得到中间产物3c。产率为90％。
称取(S)-2-氨基-6-重氮-5-氧代己酸异丙酯(0.4g，1.88mmoL)、3,3'-(丙烷-2,2-二基双(硫烷二基))二丙酸(0.71g，2.82mmoL)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(1.07，2.82mmoL)和N,N-二异丙基乙胺(DIPEA)(0.73g，5.64mmoL)，将中间产物V、HATU和DIPEA共同溶于15mL二氯甲烷中，室温下搅拌反应30min，再加入(S)-2-氨基-6-重氮-5-氧代己酸异丙酯，在室温下继续搅拌反应2h，反应结束后，用30mL二氯甲烷稀释反应液，并用饱和食盐水洗涤三次，合并有机相，用无水硫酸钠干燥，在温度不超过40℃的条件下蒸发溶剂，得到中间产物4a。产率为47％。
称取中间产物4a(0.34g，0.77mmoL)、HATU(0.44g，1.16mmoL)、DIPEA(0.3g，2.31mmoL)和无水哌嗪(0.33g，2.31mmoL)，将中间产物I、HATU和DIPEA溶解于15mL二氯甲烷中，室温下搅拌反应30min，再加入无水哌嗪，在室温下继续搅拌反应1h，反应结束后，用30mL二氯甲烷稀释反应液，并用饱和食盐水洗涤三次，合并有机相，用无水硫酸钠干燥，在温度不超过40℃的条件下蒸发溶剂，得到中间产物4b产率为51％。
称取中间产物4b(0.2g，0.39mmoL)和中间产物2e(0.41g，0.58mmoL)，共通溶解于15mL DMF中，室温下搅拌反应2天，反应结束后，将反应液中加入45mL甲基叔丁基醚，析出蓝色固体，抽滤，滤饼用甲基叔丁基醚多次洗涤，真空干燥后得到七甲川花菁素类染料偶联化疗药物DON-TK-NIR(4c)。产率为10％。
1H NMR(300Hz,MeOD):δ7.80-7.87(m,4H),7.51(d,J＝12Hz,2H),7.27-7.41(m,10H),7.13(d,J＝9Hz,2H),5.89(d,J＝12Hz,2H),5.28(s,4H),4.98(m,1H),4.37(q,J＝6Hz,1H),3.72(s,6H),2.96(t,J＝9Hz,4H),2.83(t,J＝4Hz,2H),2.33-2.62(m,8H),1.73(m,23H),1.34(s,3H),1.24(d,J＝6Hz,6H)ppm.
HRMS(ESI+):calcd for C66H78N7O11S4 -[M-H]-,1272.4648；found,1272.4484.
实施例2：七甲川花菁素类染料偶联物DON-CC-NIR的制备
称取(S)-2-氨基-6-重氮-5-氧代己酸异丙酯(0.4g，1.88mmoL)、壬二酸(0.53g，2.82mmoL)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(1.07，2.82mmoL)和N,N-二异丙基乙胺(DIPEA)(0.73g，5.64mmoL)，将中间产物V、HATU和DIPEA共同溶于15mL二氯甲烷中，室温下搅拌反应30min，再加入(S)-2-氨基-6-重氮-5-氧代己酸异丙酯，在室温下继续搅拌反应2h，反应结束后，用30mL二氯甲烷稀释反应液，并用饱和食盐水洗涤三次，合并有机相，用无水硫酸钠干燥，在温度不超过40℃的条件下蒸发溶剂，得到中间产物5a。产率为44％。
称取中间产物5a(0.29g，0.77mmoL)、HATU(0.44g，1.16mmoL)、DIPEA(0.3g，2.31mmoL)和无水哌嗪(0.33g，2.31mmoL)，将中间产物V、HATU和DIPEA溶解于15mL二氯甲烷中，室温下搅拌反应30min，再加入无水哌嗪，在室温下继续搅拌反应1h，反应结束后，用30mL二氯甲烷稀释反应液，并用饱和食盐水洗涤三次，合并有机相，用无水硫酸钠干燥，在温度不超过40℃的条件下蒸发溶剂，得到中间产物5b。产率为47％。
称取中间产物5b(0.2g，0.39mmoL)和中间产物2e(0.41g，0.58mmoL)，共通溶解于15mL DMF中，室温下搅拌反应2天，反应结束后，将反应液中加入45mL甲基叔丁基醚，析出蓝色固体，抽滤，滤饼用甲基叔丁基醚多次洗涤，真空干燥后得到七甲川花菁素类染料偶联化疗药物DON-CC-NIR(5c)。产率为12％。
1H NMR(300MHz,MeOD):δ7.66-7.74(m,4H),7.39(d,J＝12Hz,2H),7.13-7.25(m,10H),6.99(d,J＝9Hz,2H),5.14(s,4H),5.74(s,2H),4.85-4.89(m,1H),4.19-4.23(m,1H),3.55(s,6H),2.00-2.38(m,12H),1.79(m,2H),1.57(s,20H),1.11-1.32(m,12H)ppm.
HRMS(ESI+):calcd for C66H78N7O11S2-[M-H]-,1208.5206；found,1208.4655.
实施例3：化合物DON-TK-NIR的光学性质考察
如图2所示，对花菁类染料NIR-03及其偶联体DON-TK-NIR的紫外吸收波长进行了考察。偶联药物之后，其最大紫外吸收波长由790nm蓝移至660nm。
将DON-TK-NIR溶解于纯水中并在660nm近红外光下照射5min，随后用氮气挥干溶剂，并用100μL甲醇复溶，通过LC-MS测定出峰位置及分子量。如图4所示，原药峰出现在第29min，近红外光照射5min后，原药峰完全降解，在洗脱时间7min～12min内出现新峰。通过HPLC-MS进一步评估了新峰的组分，证实洗脱时间为12min的峰是目标中间体DON-SH，显示质荷比(m/z)为324.1。其他洗脱峰可能是由于生成的[1O2]反应活性太高，生成较多副产物。
通过裸鼠皮下注射A549细胞建立小鼠肺癌异种移植模型，当肿瘤体积达到约100mm3时，分别通过尾静脉注射150μL DON-TK-NIR和NIR-03。在注射第1、2、4、6、10、12和24小时时通过Maestro体内成像系统分别在660nm的激发波长和600-750nm的荧光发射波长对小鼠进行成像。在注射第24小时后处死小鼠，收集心、肝、脾、肺、肾和肿瘤的组织并进行荧光成像。如图9所示，2h左右在肿瘤部位呈现强烈的荧光信号和清晰的肿瘤成像，随着时间延长荧光信号逐渐衰减。小鼠心、脾、肺、肾无荧光信号，说明无化合物残留，有着优良的体内安全性，而肿瘤部位荧光强烈，说明化合物有着优良的肿瘤靶向性。
实施例4：化合物DON-TK-NIR在溶液中ROS生成速率考察
如图3所示，通过活性氧探针DCFH-DA检测化合物DON-TK-NIR在溶液中的活性氧生成速率。准确配置DCFH-DA溶液(1mM in MeoH)、NaOH溶液(10mM)、NaH2PO4溶液(25mM)和DON-TK-NIR溶液(1mM in water)。将1mL DCFH-DA溶液加入到4mL NaOH溶液中，室温下避光反应30min，再加入20mL NaH2PO4溶液中和，继续搅拌10min，得到DCFH溶液。取1mL DCFH溶液，用660nm近红外光照射10min，每隔一分钟测定一次紫外吸收和荧光发射波长。另取1mL DCFH溶液和1mL DON-TK-NIR溶液，混合均匀，用660nm近红外光照射10min，每隔一分钟测定一次紫外吸收和荧光发射波长。从图3可以看出，仅DCFH溶液在近红外光激发下无紫外吸收和荧光发射，加入DON-TK-NIR溶液后，在530nm处出现一新的紫外吸收峰，为DCF的吸收峰，且随激发时间的增加其紫外吸收强度增加，说明化合物DON-TK-NIR在近红外光的激发下能高效率的生成ROS。
实施例5：偶联物对非小细胞肺癌细胞系A549的活性研究
将处于对数生长期的A549细胞以3000/well的密度接种于96孔板中，除空白组外其他给药组都另铺一块不施加光照的阴性板，并于37℃，5％CO2培养箱中孵育12h，弃去培养基并加入药物。药物与细胞共孵育12h后，对相应板施加光照，每孔照射2.5min，随后转入孵箱中继续孵育36h。弃去上清，每孔加入150μL MTT溶液，继续放入孵箱中培养4h，弃去上清，每孔加入150μL DMSO，并置于摇床上以100rpm的转速震荡5min，最后用酶标仪检测样品在490nm处的光密度吸光度值即OD值。设置不加药组为空白对照，按照以下公式计算细胞存活率：存活率＝(实验孔OD值/对照孔OD值)×100％。
按公式计算受试化合物抑制率，IC50由百分抑制率和对数浓度值作图求得，分析结果见表1。
表1.偶联物对非小细胞肺癌细胞系A549的抑制作用
| Cpd. | IC<sub>50</sub>(μM) | Cpd. | IC<sub>50</sub>(μM) |
| DON-TK-NIR | 1.51 | DON-CC-NIR | 24.66 |
如表1所示，所有测试偶联物对非小细胞肺癌细胞系A549均有抑制作用，其中DON-TK-NIR的IC50值为1.51μM，达到微摩尔浓度水平。
将处于对数生长期的A549细胞分别给药DON-TK-NIR和DON-CC-NIR，给药12h后在660nm近红外光下照射10min。DON-TK-NIR给药组，激光照射的区域TK链发生断裂触发药物释放，导致其荧光光谱发生变化；而DON-CC-NIR给药组，无论有无激光照射都不会触发药物释放，荧光光谱变化忽略不计。如图5所示，DON-TK-NIR给药组在圆形区域内外产生了不同的荧光，而DON-CC-NIR给药组在圆形区域内外荧光不变。
将处于对数生长期的A549细胞、H1975细胞和16HBE细胞以2×105/well的密度接种在12孔板中。待细胞贴壁后，用PBS洗涤两次，并与DON-TK-NIR溶液(10μM)在37℃下孵育4小时。孵育后，将细胞用PBS洗涤两次，然后用胰蛋白酶消化并重悬于400μL PBS中。使用流式细胞仪(BD Bioscience，U.S.A.)记录不同细胞中DON-TK-NIR的红色荧光。每个样品大约计数3×104个细胞。为了更直观地比较不同细胞对DON-TK-NIR的摄取差异，本实验还使用了共聚焦激光荧光显微镜，用AF660滤光片组分析DON-TK-NIR荧光，用AF660滤光片组分析DAPI荧光。如图6所示，DON-TK-NIR在A549细胞中摄取量最高，可能是由于A549细胞膜表面ASCT2表达量最高。
将A549细胞分别与DON和DON-TK-NIR在6孔板中孵育12小时后，用660nm激光照射10分钟，然后继续孵育24小时。用含有PMSF蛋白酶抑制剂混合物的NP40裂解缓冲液裂解细胞。将细胞裂解物在4℃离心10分钟，并使用增强的BCA蛋白质测定试剂盒测量上清液中的蛋白质含量。如图7所示，A549细胞中ASCT2表达量最高，该结果与细胞摄取结果相一致，说明了DON介导的化合物摄取与细胞ASCT2表达呈正相关。
将A549细胞以2×105/well的密度接种在20mm玻璃共聚焦培养皿中。将细胞在DMEM培养基中用DON-TK-NIR(10μM)处理4小时。在孵育的最后30分钟加入线粒体绿色荧光探针(200nM)和DAPI(500nM)染料。然后弃去培养基，用PBS(4×1mL)彻底清洗细胞。用共聚焦激光扫描显微镜(CLSM，LSM800，Zeiss，Germany)观察荧光图像。如图8所示，化合物DON-TK-NIR在细胞内显示出与线粒体共定位，有较强的线粒体靶向能力。
将处于对数生长期的A549细胞以3000/well的密度接种于96孔板中，除空白组外其他给药组都另铺一块不施加光照的阴性板，并于37℃，5％CO2培养箱中孵育12h。弃培养基并加入药物。药物与细胞共孵育12h后，对相应板施加光照，每孔照射2.5min，随后转入孵箱中继续培养36h。弃去上清，每孔加入150μL MTT溶液，继续放入孵箱中培养4h，弃去上清，每孔加入150μL DMSO，并置于摇床上以100rpm的转速震荡5min，最后用酶标仪检测样品在490nm处的光密度吸光度值即OD值。设置不加药组为空白对照，按照以下公式计算细胞存活率：存活率＝(实验孔OD值/对照孔OD值)×100％。如图10所示，DON-TK-NIR结合近红外光激发显示出对A549细胞优良的细胞毒性(IC50＝1.51μM)，而不施加光照组的细胞毒性远低于DON组，说明该偶联体极大程度降低了DON的毒性，只有在近红外光的激发下才能释放活性药物DON并发挥肿瘤细胞杀伤作用。
实施例6：偶联物对小鼠模型的活性研究
通过裸鼠皮下注射A549细胞建立小鼠肺癌异种移植模型。待肿瘤体积达到100mm3后，将所有小鼠随机分为4组。各组分别通过尾静脉注射PBS、DON(1.00mg/kg)、低剂量DON-TK-NIR(7.43mg/kg)和高剂量DON-TK-NIR(10.00mg/kg)，并在注射4h后在660nm近红外光下照射肿瘤部位10min。如图11所示，DON组和DON-TK-NIR两组与空白组相比都有着显著的肿瘤抑制作用，后者显示出更强的抑制效果。
如图12所示，虽然与空白组相比，给药组体重均有下降，但DON-TK-NIR两组比DON组体重变化幅度小且更加平稳，而DON组体重下降明显且持续下降。
治疗21天后处死小鼠，取各组小鼠肿瘤，图13可以看出，DON-TK-NIR组治疗效果显著，高剂量组和低剂量组均有三只小鼠肿瘤完全消失，而DON组由于药物毒性太大，死亡一只。
实施例7：偶联物对胃肠道的毒副作用
通过裸鼠皮下注射A549细胞建立小鼠肺癌异种移植模型。待肿瘤体积达到100mm3后，将所有小鼠随机分为4组。各组分别通过尾静脉注射PBS、DON(1.00mg/kg)、低剂量DON-TK-NIR(7.43mg/kg)和高剂量DON-TK-NIR(10.00mg/kg)，并在注射4h后在660nm近红外光下照射肿瘤部位10min。每天给药，21天后处死小鼠，取肿瘤组织及心、肝、脾、肺、肾及肠道。
如图14所示，从图中可以看出，DON组与空白组相比，虽然肿瘤细胞有着较大损伤但同时对肠道也有着严重损伤；而DON-TK-NIR高低剂量两组不仅肿瘤细胞有着严重损伤而且对肠道几乎没有损伤，说明该偶联体在保证与DON药效一致的同时极大程度上降低了DON对肠道的毒副作用，有着更好的治疗效果和体内安全性。
Claims (10)
1.一种七甲川花菁素类染料偶联物，其特征在于，选自：
2.根据权利要求1所述的偶联物，其特征在于，还包含其立体异构体、药学上可接受的盐或它们的混合物。
3.根据权利要求2所述的偶联物，其特征在于，其药学上可接受的盐为其与以下酸形成的盐：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
4.一种权利要求1所述的偶联物的制备方法，其特征在于，当偶联物为DON-TK-NIR时，所述制备方法如下：
5.一种权利要求1所述的偶联物的制备方法，其特征在于，当偶联物为DON-CC-NIR时，所述制备方法如下：
6.一种权利要求2或3所述的偶联物的制备方法，其特征在于，所述偶联物与相应的酸成盐完全后，即得所述偶联物的药学上可接受的盐。
7.一种药物组合物，其特征在于，所述药物组合物包含权利要求1～3任一所述的偶联物以及药学上可接受的载体。
8.一种权利要求1～3任一所述的偶联物或者权利要求7所述的药物组合物在制备肿瘤诊断剂或/和治疗剂中的应用。
9.根据权利要求8所述的应用，其特征在于，所述诊断剂为肿瘤的定位剂或/和显影剂。
10.根据权利要8所述的应用，其特征在于，所述治疗剂具有ROS或/和光响应特性。
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