CN116410198A - 一种硫/硒醚连接的两性离子喜树碱纳米前药应用于癌症诊疗 - Google Patents
一种硫/硒醚连接的两性离子喜树碱纳米前药应用于癌症诊疗 Download PDFInfo
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Abstract
本发明提供了式(Ⅰ)所示的化合物可以在水溶液中自组装成稳定的纳米级颗粒，该纳米前药物的能够实现对正常组织较小的毒性和良好的代谢能力，可以实现精准、优异的肿瘤定位和抑制效果，并具有高安全性，在抗癌药物的制备和癌症、皮肤病的诊断和治疗方面具有广阔前景。
Description
技术领域
本发明涉及一种新型的两性离子荧光探针与抗肿瘤药物相连制备的两性离子的前药化合物及其应用，具体通过硫醚/硒醚键连接两性离子罗丹明(RhB)和喜树碱(CPT)，构建了一种肿瘤异质性激活前药物，该药物可基于其两亲结构在水中自组装成稳定的纳米前药，属于化学制药领域。
背景技术
据数据得知，2023年中国确诊的癌症患者数量达到306.5万，而死于癌症的人数增加到220.5万，癌症发病率不断上升，对人们的身体健康有着极大的威胁。近年来，原有的手术、化疗等治疗方式因药物选择性差、给人带来的副作用过大，促使人们研发新型的抗癌药物解决原有治疗方式存在的选择性差、利用度差等问题。基于荧光探针的前药物被研发出来用于更精准地治疗癌症，其可以精确定位药物路径，可观测药物在动物以及人体内的路径，具有非常宽的动态响应范围以及极高的灵敏性等优点。
该药物是通过硫醚/硒醚键连接两性离子罗丹明(RhB)和喜树碱(CPT)，因RhB疏水，CPT亲水，二者可自组装成纳米级药物。该药物的连接键根据肿瘤的微环境(较正常细胞质，其pH值低，酶表达异常，具有炎症反应性和异质性)设计，其对高水平的GSH和H2O2具有响应性，故该药物可定位到肿瘤位置，穿过肿瘤组织细胞间隙，同时在肿瘤部位富集。Rhb和CPT的连接键(硫醚/硒醚键)可在肿瘤部位断键，释放出Rhb和CPT，Rhb释放后产生荧光，可以更好的追踪药物的路径，而CPT则为抗癌药物，精确到达肿瘤区域，进行抗癌治疗。
普通抗癌药物需要有聚合物包裹，从而使药物具有定向性，达到抗癌的目的，因聚合物包裹，其可能会存在药物泄露、载荷率较低、释放不同步等缺点。而此药物为纳米级别药物，无需聚合物包裹，可精确定位肿瘤位置，明确药物路径，故可以有效解决普通抗癌药物的缺点，抗癌效果和效率的双重提高，使其具有十分广阔的市场前景，对抗癌药物发展也具有重大意义。
发明内容
前药可以在水中自组装成稳定的纳米颗粒，减少与体内成分的非特异性结合，从而不影响荧光成像，并且能够实现对正常组织较小的毒性和良好的代谢能力。为后续氧化还原反应纳米前药系统的合理设计提供了思路，有助于下一代肿瘤治疗纳米药物的材料选择和结构设计，可应用于体内癌症的诊断治疗。
据此，本发明一方面提供一种由具有式(Ⅰ)所示结构的化合物，将两性离子荧光探针和抗肿瘤药物通过硫醚/硒醚键连接，设计了一种氧化还原刺激响应型纳米前药物。
由于肿瘤(特别是实体瘤)组织的血管丰富，并缺失淋巴回流系统，会造成本发明所述的纳米前药在肿瘤位置被动高渗透性和滞留性。这种纳米结构在实体瘤组织的高通透效应和滞留效应被称为EPR效应(enhanced permeability and retention effect)。这种被动靶向肿瘤的能力，可以自组装形成稳定的纳米粒子，实现被动靶向肿瘤。
本发明提供了式(Ⅰ)所示化合物将两性离子荧光探针与抗肿瘤药物相连，制备出的前药化合物可以同时具有诊断和治疗双重作用，有利于我们对药物的释放进行实时监测，观察药物在体内的分布情况。这种对氧化还原敏感的纳米前药，可以有效应用于肿瘤的诊断治疗，具备极大的市场价值和广阔的应用前景。
附图说明：
图1本发明所提供的化合物Ⅰ的合成路线；
图2HeLa细胞和L929细胞在不同培育条件下的荧光显微镜成像图；
图3静脉注射纳米前药后7小时内小鼠主要器官和肿瘤的荧光成像图；
图4小鼠在不同条件下治疗20天以后的图片；
图5小鼠静脉注射RhB-S-CPT、RhB-Se-CPT和游离CPT后的药代动力学研究(P<0.05)；
图6小鼠静脉注射RhB-C-CPT后的药代动力学研究(P<0.05)；
图7通过H&E染色检测的小鼠器官和肿瘤切片的光学图像；
图8不同浓度GSH和H2O2存在下化合物Ⅰ的药物释放(P<0.05)。
具体实施方式：
本发明的方法与技术通常依据本领域已知的传统方法进行，除非另有说明。与本文中描述的生物学、药理学、及医学与医药化学相关的命名法，及实验方法与技术是本领域已知且常用的。化学合成法、化学分析法、医药制法、调配法与传送法，及检测或测试法均采用标准技术。
除非另有说明，否则本文中所使用的科学与技术术语应具有那些本领域普通技术人员通常理解的含义。
本发明的化合物的实例如下述化合物Ⅰ：
如图1所示，化合物Ⅰ的合成包括以下步骤：
1)化合物1的合成：磺胺B钠盐(580mg,1.0mmol)溶于无水二氯甲烷(25mL)，0℃氮气气氛中。然后在搅拌下慢慢加入草酰氯(430μL,5.0mmol)和催化量无水二甲基甲酰胺(12μL)。得到的混合物在室温下继续反应16小时。溶剂在真空中浓缩，干燥，然后直接进行下一个反应(产率为98.0％)。
2)化合物2的合成：将化合物1溶于无水二氯甲烷(20ml)，在0℃氮气气氛中溶解。将N-叔丁氧羰基-1,2-乙二胺(160mg,1.0mmol)、DMAP(6.1mg,0.05mmol)、三乙胺(420μL,3.0mmol)溶于二氯甲烷(20mL)中，依次滴入化合物1溶液中。反应在室温下持续了13小时。反应结束后，混合溶液用5％盐酸溶液(50mL)，去离子水(50mL)洗涤，并在无水硫酸钠上干燥。有机相浓缩，粗产物以二氯甲烷/甲醇(体积比80:1至20:1)为洗脱液，硅胶柱层析纯化得到紫色固体化合物(产率为46.0％)。1H NMR(400MHz,DMSO-d6):δ(ppm):8.41(s,1H),8.03(t,1H),7.92(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.06-6.94(m,6H),6.87(t,1H),3.64(q,8H),3.02(q,2H),2.88(q,2H),1.38(s,9H),1.22(t,12H)。
3)化合物3的合成：将化合物2(300mg,0.43mmol)溶于二氯甲烷(30mL)中。然后，慢慢加入三氟乙酸(3ml)，在0℃搅拌3小时。反应结束后，用真空浓缩法去除溶剂和残留的三氟乙酸。粗产物溶于二氯甲烷(60ml)，用饱和碳酸钠溶液(25ml)洗涤两次。有机溶剂在无水硫酸钠上干燥，浓缩得到红色固体化合物(RhB-NH2)(产率为63.4％)。1H NMR(400MHz,CDCl3):δ(ppm):8.42(s,1H),7.93(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.08-6.94(m,6H),3.65(q,8H),2.87(t,2H),2.62(t,2H),1.23(t,12H)。
4)化合物4的合成：Se(520mg,6.8mmol)在去离子水(100mL)中0℃溶解。然后，在上述溶液中加入硼氢化钠(250mg,2.6mmol)，在0℃搅拌10分钟。然后，在上述溶液中加入第二种Se(520mg,6.8mmol)，在50℃搅拌15分钟。然后将溶液冷却至室温。然后，在上述溶液中加入溴乙酸(920mg,6.6mmol)，在25℃搅拌3小时。反应结束后，收集水相，用乙酸乙酯提取三次。在真空下浓缩除去溶剂，得到黄色固体化合物(产率为40.0％)。
5)化合物5的合成：将2,2'-硫代二乙酸(150mg,1.0mmol)溶于无水四氢呋喃(10mL)中，氮气气氛0℃。然后，在上述溶液中滴加草酰氯(105μL,1.2mmol)。混合物在35℃持续反应3小时。将溶剂和草酰氯在真空下浓缩脱除，得到黄色油即为2,2'-磺胺二酰二乙酰氯，无需进一步提纯即可用于下一步。
6)化合物6的合成：将化合物4(197mg,1.0mmol)用无水四氢呋喃(10mL)在氮气气氛为0℃下溶解。然后，在上述溶液中滴加草酰氯(105μL,1.2mmol)。混合物在35℃持续反应3小时。将溶剂和草酰氯在真空下浓缩脱除，得到黄色油即为2,2'-硒二乙酰氯，无需进一步提纯即可用于下一步。
7)化合物7的合成：在氮气气氛0℃下，将CPT(90mg,0.26mmol)和化合物5溶于无水二氯甲烷(20mL)中。然后，在上述溶液中加入4-二甲氨基吡啶(190mg,1.56mmol)，在0℃下搅拌4小时。混合物用清水(50毫升)清洗，并在无水硫酸钠上干燥。有机相浓缩，粗产物以二氯甲烷/甲醇(体积比200:1至80:1)为洗脱液，用闪柱层析纯化得到黄色固体化合物即为CPT-S-COOH(产率为60.1％)。1H NMR(400MHz,CDCl3)δ(ppm):8.40(s,1H),8.23(d,J＝8.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.82(t,1H),7.66(t,1H),7.37(s,1H),5.74(m,2H),5.31(s,2H),3.61(s,2H),3.54(s,2H),2.12(m,2H),0.93(t,3H)。
8)化合物8的合成：将CPT(90mg,0.26mmol)和化合物6溶于无水二氯甲烷(20mL)中，氮气气氛0℃。然后，在上述溶液中加入4-二甲氨基吡啶(190mg,1.56mmol)，在0℃下搅拌4小时。混合物用清水(50毫升)清洗，并在无水硫酸钠上干燥。有机相浓缩，粗产物以二氯甲烷/甲醇(体积比200:1至80:1)为洗脱液，用闪柱层析纯化得到黄色固体化合物即为CPT-Se-COOH(产率为58.2％)。
9)化合物I的合成：化合物7(48mg,0.1mmol)、化合物1(66mg,0.1mmol)和HBTU(37.9mg,0.2mmol)在无水二氯甲烷(25mL)中在0℃氮气气氛中溶解。然后，在上述溶液中加入N,N-二异丙基乙胺(129mg,0.2mmol)，在25℃搅拌5小时。混合物用5％ HCl(30mL)，水(30mL)洗涤，并在无水硫酸钠上干燥。有机相浓缩，粗产物以纯二氯甲烷，二氯甲烷/甲醇(体积比200:1至80:1)为洗脱液，用闪柱层析纯化，得到粉色固体RhB-S-CPT(产率为50.0％)1H NMR(400MHz,DMSO):δ(ppm):8.69(s,1H),8.40(s,1H),8.10(m,3H),8.01(t,3H),7.95(d,J＝4Hz,1H),7.93(d,J＝4Hz,1H),7.85(t,1H),7.83(t,1H),7.81(t,1H),7.71(s,1H),6.98(d,J＝4Hz,2H),6.90(d,J＝4Hz,2H),5.51(s,2H),5.29(s,2H),5.29(s,2H),3.69(s,2H),3.62(m,8H),3.29(s,2H),3.12(m,2H),2.88(t,2H),2.15(t,2H),1.22(m,12H),0.93(t,3H).13CNMR(100MHz,CDCl3):δ(ppm):168.55,168.12,166.49,155.69,154.60,145.41,132.47,130.31,129.61,128.66,127.52,127.14,126.87,113.25,112.94,95.38,94.51,66.53,66.13,44.87,41.53,38.37,33.92,32.56,30.91,30.66,30.42,29.17,28.68,28.64,21.67,13.11,11.62,6.61.MS:计算C53H54N6O12S3(M):1062.296；发现:1063.858(M+H+)。
体外释放CPT实验
分别选取0mM、1mM和10mM的GSH和H2O2与RhB-S-CPT和RhB-Se-CPT在37℃的2mL释放液中孵育，然后在不同的时间段，利用高效液相色谱测量所释放的药物吸收峰，从而进一步计算出药物释放速率(每组n＝3)。图(3)
10mM的GSH和H2O2与RhB-S-CPT和RhB-Se-CPT孵育后药物的释放速率非常快，2个小时GSH组药物释放就已经超过了40％，而H2O2组药物释放也接近40％。在第12小时，GSH组药物释放达到了92％左右，H2O2组也接近于80％左右，不添加GSH和H2O2时，药物基本没有释放，这证明了RhB-S-CPT和RhB-Se-CPT对氧化还原的敏感性和药物的高效释放。
体外细胞摄取实验
采用激光共聚焦扫描显微镜对HeLa细胞评估RhB-S-CPT和RhB-Se-CPT前药纳米粒的细胞摄取。实验所用的HeLa和L929细胞在添加10％FBS和1％青霉素/链霉素的常规培养基中培养(为保持所有细胞均保存在37℃、5％CO2的增湿大气中)。将Hela细胞以1×105个细胞的密度接种在玻璃底皿中，并培养24小时。然后去除培养基，用PBS溶液将细胞清理干净，再加入含5μM的化合物RhB-S-CPT和RhB-Se-CPT纳米粒子的培养基，在37℃下培养0.5小时或2小时。然后去除培养基，用PBS溶液清洗处理过的细胞三次，并用荧光染料Hoechst33342共同染色5分钟。洗净后用激光共聚焦显微镜(Nikon C2+)对细胞进行观察。在0.5小时，细胞对RhB-S-CPT和RhB-Se-CPT的摄取较少，只在细胞的周围有一点摄取，而2小时后，细胞对RhB-S-CPT和RhB-Se-CPT的摄取量明显增多，每个细胞核的周围都有大量化合物RhB-S-CPT和RhB-Se-CPT，这表明了细胞对化合物RhB-S-CPT和RhB-Se-CPT的摄取随时间逐渐增强。
细胞毒性实验
用HeLa和L929细胞体外评价RhB-S-CPT和RhB-Se-CPT纳米颗粒的细胞毒性。以游离CPT和生理盐水作为对照组。将HeLa细胞接种于96孔板中，每孔加入200μL培养基，培养12小时后，移除细胞培养基，将游离CPT和化合物RhB-S-CPT和RhB-Se-CPT在培养基中经过梯度稀释后(0.1μM至100μM)与细胞培养72小时未经处理过的细胞作为对照组，达到培育时间后，去除培养基，用PBS洗涤两次，然后用含有calcein-AM和EthD-1染料的PBS继续培育细胞30分钟。去除含有染料的培养基，继续用PBS洗涤一次，用荧光显微镜(Olympus IX73)对细胞进行拍摄(图2)。化合物对正常细胞的杀伤力是很小的，只会在癌细胞中激活药物来杀死肿瘤细胞，对细胞具有很强的选择性。
小鼠肿瘤成像实验
首先我们需要构建荷瘤小鼠肿瘤模型。将3×106的4T1细胞通过皮下注射至雌性裸鼠(6只6周龄，约15g)的侧面，每天观察小鼠肿瘤的体积大小，当肿瘤体积达到250mm3时即可进行体内实验。将裸鼠分为4组，静脉注射RhB-S-CPT和RhB-Se-CPT纳米粒(每组3个)。注射7h后将小鼠处死并进行解剖，取出小鼠的心、肝、脾、肺、肾和肿瘤，清理干净后，用小动物活体光学成像系统进行拍摄。如图3所示，图片中的内脏从左到右依次为小鼠的心、肝、脾、肺、肾和肿瘤。从图中我们可以观察到化合物RhB-S-CPT和RhB-Se-CPT确实可以在荷瘤小鼠的肿瘤部位被动靶向积累，并且在并且在不同的部位，荧光强度是不同的。在尾静脉注射12小时后肝脏部位是最亮的，说明这个部位前药胶束的富集量也是最多的。
小鼠体内治疗实验
将3×106的4T1细胞皮下注射到雌性裸鼠(6 6周龄，约15g)的右后腿，每天观察小鼠肿瘤的体积大小，当接种的肿瘤大小达到100～150mm3时，将小鼠随机分为CPT、RhB-C-CPT、RhB-S-CPT和RhB-Se-CPT 4组，每组5只，每3天注射一次，在整个实验过程中对不同组的每只老鼠进行标记和单独跟踪，每隔一天测量并记录体重和肿瘤体积。第20天处死小鼠，取出小鼠肿瘤进行称重和拍照。此外，将不同组小鼠的心、肝、脾、肺、肾和肿瘤组织用福尔马林固定，通过H&E染色进行组织病理分析。如图3所示，通过对比明显看出，RhB-C-CPT组小鼠肿瘤在第20天已经大面积破裂了。CPT组小鼠肿瘤虽然比RhB-C-CPT组的要小，但是也出现了小程度的破裂，说明是有小部分游离药物进入了小鼠的肿瘤，但是含量可能不高，因此导致抑制效果也很一般。化合物RhB-C-CPT和RhB-Se-CPT则表现出了非常有效的抑制作用，小鼠在第20天肿瘤体积稍有增加，但增加程度远低于其它两组。这一结果和荧光成像结果也相互对应，说明化合物RhB-S-CPT和RhB-Se-CPT可以大量富集在肿瘤部位，并通过肿瘤微环境氧化还原刺激性响应来释放出高含量被激活的药物达到抑制肿瘤生长的效果。如图4所示，小鼠的心肝脾肺肾没有看到明显的组织学变化，表明化合物RhB-S-CPT和RhB-Se-CPT对主要器官和正常组织的毒性几乎可以忽略不计，表现出了良好的安全性。然而，通过H&E染色的肿瘤切片可以看出，化合物RhB-S-CPT和RhB-Se-CPT组的肿瘤出现了明显的凋亡和坏死，显示出良好的抗肿瘤作用。
体内药代动力学研究
利用小鼠评价RhB-S-CPT和RhB-Se-CPT纳米颗粒的药代动力学特征。将小白鼠随机分为游离CPT、RhB-C-CPT、RhB-S-CPT和RhB-Se-CPT三组，分别以相当于CPT的4mg/kg剂量通过尾静脉注射游离CPT、RhB-C-CPT、RhB-S-CPT和RhB-Se-CPT(每组3只)。在预先设置好的时间段内在小鼠尾部取血。每次取血10μL，将其置于50μL的细胞裂解液中并在0℃环境下保存，15分钟后，取50μL的二甲基亚砜加入裂解液中，继续保存在0℃环境中。待样品全部采集完毕后，用酶标仪测量吸光度并在标准曲线中找到对应的值，做出药代动力学曲线图，如图5、6所示。
游离CPT、RhB-C-CPT、RhB-S-CPT和RhB-Se-CPT在血浆中随时间的分布图，由图可知化合物RhB-Se-CPT还有RhB-C-CPT在血液中以较高的浓度保持了24小时，RhB-S-CPT也以相对较高的浓度保持了24小时，而游离CPT在24小时后浓度仅为化合物RhB-C-CPT和RhB-Se-CPT的七分之一。与游离CPT相比，化合物RhB-S-CPT和RhB-Se-CPT还有RhB-C-CPT在血液中的停留时间更久，因此有更多的可能性可以进入肿瘤细胞并富集在肿瘤内部，综合体内荧光成像和体内治疗实验结果，共同证明了化合物RhB-S-CPT和RhB-Se-CPT对肿瘤的有效被动靶向性。
以上实施例仅用以说明本发明的技术方案，而非对其进行限制；尽管参照实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
Claims (1)
1.一种由具有式(Ⅰ)所示结构的化合物，将两性离子荧光探针和抗肿瘤药物通过硫醚/硒醚键连接，设计了一种氧化还原刺激响应型两性离子纳米前药。
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