CN107096027A - 一种pH控制识别肿瘤细胞的光敏剂及其制备方法和应用 - Google Patents
一种pH控制识别肿瘤细胞的光敏剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于光敏剂技术领域，具体涉及一种光敏剂及其合成方法以及在激光激发下的光动力学治疗方法，该光敏试剂对pH值敏感，在微酸性的肿瘤细胞中具有显著的光动力学效果。本发明的优点是：该化合物具有pH敏感的性质，可以通过对细胞微环境的响应，实现对肿瘤细胞的识别。在肿瘤细胞中，化合物在弱酸性环境中实现光动力学疗法。而在正常的细胞中，由于正常细胞是弱碱性，几乎没有光动力学反应。
Description
技术领域
本发明属于光敏剂技术领域，具体涉及一种光敏剂及其合成方法以及在激光激发下的光动力学治疗方法，该光敏试剂对pH值敏感，在微酸性的肿瘤细胞中具有显著的光动力学效果。
背景技术
光动力学疗法(PDT)是用光敏药物和激光活化治疗肿瘤疾病的一种新方法。用特定波长照射肿瘤部位，能使选择性聚集在肿瘤组织的光敏药物活化，引发光化学反应破坏肿瘤。新一代光动力学疗法(PDT)中的光敏药物会将能量传递给周围的氧，生成活性很强的单线态氧。单线态氧能与附近的生物大分子发生氧化反应，产生细胞毒性进而杀伤肿瘤细胞。与传统肿瘤疗法相比，PDT的优势在于能够精确进行有效的治疗，这种疗法的副作用很小。
肿瘤的微环境显酸性，已成为区分肿瘤的重要标志物，这是由于肿瘤细胞的糖酵解的调控失常引起的。在肿瘤细胞中，其细胞內液pH是略大于7.4，而其细胞外液的pH在6.5以下，这是由于肿瘤细胞的质子泵源源不断的向细胞外排除质子导致的。相对于肿瘤细胞，正常细胞的细胞外液和细胞內液都呈弱碱性(pH 7.2-7.4)，而其细胞外液的pH略高于细胞内液的pH。另外，据报道肿瘤细胞的溶酶体的酸性(pH 5.5-6.5)比正常细胞的(pH 4.5-5.5)更小。
发明内容
本发明的目的在于提供一种新的光敏剂及其合成方法，该光敏试剂对pH值敏感，在微酸性的肿瘤细胞中具有显著的光动力学效果。
本发明的另一目的是提供该光敏剂的应用，根据普通细胞和肿瘤细胞pH值的不同可以识别肿瘤细胞并实现光动力学治疗。
本发明所涉及的光敏剂记为pH-PDT，其结构式如下：
其中R1为二乙胺基、二甲胺基、N-甲基乙胺基、胺基、吡啶、吗啉或吡嗪，
R2，R3，R4为溴、碘或氢。
pH控制识别肿瘤细胞的光敏剂的合成如下：
其中，化合物1中的R1为二乙胺基、二甲胺基、N-甲基乙胺基、胺基、吡啶、吗啉或吡嗪。
(1)制备化合物2：
A、称取1eq的化合物1溶于300mL的干燥的甲苯中；
B、氮气保护下，慢慢滴加体积约2-1:2.5的2,5-二甲基吡咯；
C、加入1-2滴三氟乙酸启动反应，继续反应6-12小时；
D、待反应一段时间后，加入二氯二氰基苯醌4-5eq，继续反应4小时；
E、向反应体系加入4-5eq的三乙胺和三氟化硼乙醚螯合物，继续反应12小时。
F、反应完成后，向反应体系加入少量水淬灭反应，用二氯甲烷，多次萃取水相，合并有机相，有机相用无水硫酸镁干燥。
G、过滤上述溶液，去滤液，真空除去溶剂，得粗产物，薄层层析得化合物2。
(2)制备化合物3
A、量取乙醇80-100mL；
B、加入摩尔比为1-1:5的化合物2和化合物N-碘代马莱酰亚胺或碘/碘酸或相应的溴代试剂，混合液搅拌加热至30-60℃，反应12小时；
C、反应完成后，过滤得到固体，用乙醚洗涤，烘干得到固体化合物3。
本发明涉及的光敏剂pH-PDT用于pH控制识别的肿瘤细胞的光动力学治疗研究。首先，考察了激光照射下光敏剂pH-PDT在不同pH值下的光动力学研究(图1)，发现该pH-PDT光敏剂在pH为5.6的酸性条件下具有光动力学效果。然后考察了光敏剂pH-PDT的细胞毒性(图2)，最后通过对正常细胞和肿瘤细胞的pH的识别进行光动力学治疗(图3)，发现化合物本身没有毒性并且在弱酸性环境中实现光动力学治疗。
本发明的优点是：该化合物具有pH敏感性质，可以通过对细胞微环境的响应，实现对肿瘤细胞的识别。在肿瘤细胞中，化合物在弱酸性环境中实现光动力学治疗。而在正常的细胞中，由于正常细胞是弱碱性，几乎没有光动力学反应。
附图说明
图1为化合物5在DMSO和PBS缓冲液体积比为2:8的不同pH的溶液中(pH＝5.52和7.65)的光动力学变化图，通过检测9,10-二甲基蒽的荧光光谱的消耗，间接表征单线态氧的产生。
图2为用MTT法测试化合物5在肝癌细胞(HePG-2，肿瘤细胞)和正常肝细胞(HL-7702，正常细胞)中12小时和24小时的细胞毒性。分别测试了化合物5浓度为0，0.25,0.5,1,1.25,2.5,5,10,12.5和25μM的细胞毒性，发现化合物5在没有光照下与细胞共孵育，细胞的存活率在90％以上，这说明化合物5对这两种细胞基本没有毒性。
图3为化合物5在HePG-2细胞和HL-7702的光照毒性。选用激光为532nm，激光功率密度为10mW/cm2。实验分组为纯空白组(C)，激光对照组(L)，材料对照组(0)，光照0.5分钟(0.5)，光照1分钟(1)，光照1.5分钟(1.5)，光照2分钟(2)，光照2.5分钟(2.5)，光照3分钟(3)，光照3.5分钟(3.5)和光照4分钟(4)。实验结果表明光照对正常细胞HL-7702几乎没有光动力学治疗效果，而在肿瘤细胞HePG-2具有光动力学治疗效果而且随着光照时间的延长光动力学治疗效果越好。
具体实施方式
实施例1：
制备化合物4：4-乙二胺苯甲醛(0.95g)，2,5-二甲基吡咯(1g)溶于300mL的无水甲苯中，氮气保护，加1滴三氟乙酸，常温搅拌过夜，加1.22g二氯二氰基苯醌反应4小时，加入三乙胺(4.2mL)和三氟化硼乙醚(5.26mL)继续反应12小时。反应完成后，向反应体系加入少量水淬灭反应，用二氯甲烷，多次萃取水相，合并有机相，有机相用无水硫酸镁干燥。过滤，取滤液，真空除去溶剂，得粗产物，薄层层析得纯品。1H-NMR(400MHz,CDCl3):7.02(d,2H,J＝6.3Hz),6.74(d,2H,J＝6.5Hz),5.96(s,2H),3.42(dd,4H,J＝7.3Hz),2.54(s,6H),1.51(s,6H),1.19(t,6H,J＝6.8Hz)。
实施例2：
制备化合物5：量取乙醇80-100mL，加入化合物2(100mg)和化合物N-碘代马莱酰亚胺(500mg)，混合液搅拌加热至60℃，反应12小时，反应完成后，过滤得到固体，用乙醚洗涤，烘干得到固体。1HNMR(400MHz,CDCl3):δ6.98(d,2H,J＝8.37),6.85(d,2H,J＝8.28),3.43(dd,4H,J＝8.20),2.64(s,6H),1.54(s,6H),1.20(t,6H,J＝4.78)。
实施例3：
制备化合物6：量取乙醇80-100mL，加入化合物2(100mg)、化合物碘(500mg)和碘酸(500mg)，混合液搅拌加热至60℃，反应12小时，反应完成后，过滤得到固体，用乙醚洗涤，烘干得到固体。1HNMR(400MHz,CDCl3):δ7.53(s,1H),7.05(d,1H,J＝8.40),6.71(d,1H,J＝8.20),3.29(dd,2H,J＝7.78),2.63(s,6H),1.55(s,6H),1.38(t,3H,J＝7.05)。
实施例4：
配置化合物5在DMSO和PBS缓冲液体积比为2:8的不同pH的溶液(pH＝5.52和7.65)的浓度为5μM，加入5eq的9,10-二甲基蒽，通过激光光照诱导单线态氧的生成，而生成的单线态氧与9,10-二甲基蒽反应其荧光淬灭，并通过荧光光谱的变化监测这一过程。
实施例5：
我们用MTT法测试化合物5在肝癌细胞(HePG-2，肿瘤细胞)和正常肝细胞(HL-7702，正常细胞)中12小时和24小时的细胞毒性。分别测试了化合物5浓度为0，0.25,0.5,1,1.25,2.5,5,10,12.5和25μM的细胞细胞毒性。
实施例6：
我们在细胞层次测试了化合物5在HePG-2细胞和HL-7702的光照毒性。选用化合物5的浓度为1μM，激光为532nm，激光功率密度为10mW/cm2。实验分组为纯空白组(C)，激光对照组(L)，材料对照组(0)，光照0.5分钟(0.5)，光照1分钟(1)，光照1.5分钟(1.5)，光照2分钟(2)，光照2.5分钟(2.5)，光照3分钟(3)，光照3.5分钟(3.5)和光照4分钟(4)。用MTT法测试细胞的毒性。
由实施例合成出的化合物5具有pH敏感性质，在pH为弱酸和弱碱中变化明显。化合物5在pH为7.65的弱碱环境下光动力学效应比较弱，而在pH为5.52的弱酸性环境中光动力学效应较强。在肿瘤细胞中，化合物在弱酸性环境中可以在激光诱导下实现光动力学治疗。而在正常的细胞中，由于正常细胞是弱碱性，在激光诱导下几乎没有光动力学反应。本专利中保护的其他化合物在pH为5.0-6.5具有较强的光动力学性质，而在弱碱性的环境(pH＝7.0-8.0)中的光动力学性质较差。
上述实施例为本发明的优选例，并不用来限制本发明，凡在本发明的原则之内，所做的任何修改、变化、变通或替换方案，均在本发明的保护范围之内。
Claims (3)
1.一种pH控制识别肿瘤细胞的光敏剂，其特征在于结构式为：
其中，R1为二乙胺基、二甲胺基、N-甲基乙胺基、胺基、吡啶、吗啉或吡嗪；
R2，R3，R4为溴或碘或氢。
2.一种如权利要求1所述的pH控制识别肿瘤细胞的光敏剂的制备方法，其特征在于，合成路线及方法如下：
其中，化合物1中的R1为二乙胺基、二甲胺基、N-甲基乙胺基、胺基、吡啶、吗啉或吡嗪；
(1)制备化合物2：
A、称取1eq的化合物1溶于300mL的干燥的甲苯中；
B、氮气保护下，慢慢滴加体积约2-1:2.5的2,5-二甲基吡咯；
C、加入1-2滴三氟乙酸启动反应，继续反应6-12小时；
D、待反应一段时间后，加入二氯二氰基苯醌4-5eq，继续反应4小时；
E、向反应体系加入4-5eq的三乙胺和三氟化硼乙醚螯合物，继续反应12小时；
F、反应完成后，向反应体系加入少量水淬灭反应，用二氯甲烷，多次萃取水相，合并有机相，有机相用无水硫酸镁干燥；
G、过滤上述溶液，去滤液，真空除去溶剂，得粗产物，薄层层析得化合物2；
(2)制备化合物3
A、量取乙醇80-100mL；
B、加入摩尔比为1-1:5的化合物2和化合物N-碘代马莱酰亚胺或碘/碘酸，混合液搅拌加热至30-60℃，反应12小时，如为溴取代则使用相应的溴代试剂；
C、反应完成后，过滤得到固体，用乙醚洗涤，烘干得到固体化合物3。
3.一种如权利要求1所述的pH控制识别肿瘤细胞的光敏剂的应用，其特征在于，光热试剂对pH值敏感，可通过不同pH识别正常细胞与肿瘤细胞，对肿瘤细胞具有激光诱导下的光动力学治疗作用。
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