CN112494650A - 一种血卟啉衍生物联合化学药物在肝癌治疗中的应用 - Google Patents
一种血卟啉衍生物联合化学药物在肝癌治疗中的应用 Download PDFInfo
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- CN112494650A CN112494650A CN202011567436.0A CN202011567436A CN112494650A CN 112494650 A CN112494650 A CN 112494650A CN 202011567436 A CN202011567436 A CN 202011567436A CN 112494650 A CN112494650 A CN 112494650A
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Abstract
本发明属于增加化疗药物敏感性的医药学领域，具体涉及一种血卟啉骈合维拉帕米片段血卟啉衍生物A2在肝癌逆转化疗药物的耐受与增敏的用途。血卟啉衍生物A2具有不同程度的增敏化疗药物抑制肝癌细胞增殖作用，表明血卟啉衍生物A2能够发展成为化疗药物的增敏剂或者逆转耐药剂，用于肝癌患者的治疗。
Description
技术领域
本发明属于增加化疗药物敏感性的医药学领域，具体涉及一种血卟啉骈合维拉帕米片段血卟啉衍生物A2在肝癌逆转化疗药物的耐受与增敏中的用途。
技术背景
恶性肿瘤是当今世界上严重影响人类健康并威胁人类生命的主要疾病之一，已成为导致人类死亡的第二大原因[1]。肝细胞肝癌(HCC)是我国常见的实体性肿瘤，病死率高居恶性肿瘤第二位，严重危害我国人民身体健康[2]。由于HCC起病隐匿、进展迅速，多数患者确诊时已为中晚期，错过手术治疗的最佳时机，这使得经导管肝动脉化疗栓塞术(transcatheter arterial chemoembolization,TACE)成为中晚期HCC患者的重要治疗方法[3]。化学药物和靶向药物治疗是延长中晚期HCC患者生存时间的重要手段，但其效果受到肿瘤耐药性的限制，针对多个随机临床对照试验结果的***分析显示，当前的HCC对于标准化疗方案的反应率只有50％左右，靶向药物索拉菲尼只能延长患者3个月的生存期[4]。其它治疗方式如抗血管生成治疗、免疫治疗等与化疗同样存在着治疗上最终严重耐受的缺陷。因此，探讨克服肿瘤细胞对化疗药物的耐药性，对于提高HCC的临床疗效仍有非常重要的意义，
维拉帕米(Verapamil，VER)是一种耐药逆转剂，VER是早期发现的可以改变细胞内化疗药物浓度而降低肿瘤耐药性的药物，实验研究表明，VER可以明显提高恶性肿瘤细胞对化学药物的敏感性[5]。该药物能够逆转肿瘤多药耐药(multiple drug resistance，MDR)的有效浓度为6.0-10.0μmol/L，但是当维拉帕米的静脉血药浓度超过1.0-2.0μmol/L就会出现心血管不良反应，如心率下降、血压下降、房室传导阻滞等[6]。因此，口服、静脉应用维拉帕米逆转肿瘤细胞多药耐药的应用受到限制。VER联合化疗药物靶血管灌注和瘤体局部注射有效，然而恶性实体肿瘤生长及转移部位的特殊性、介入治疗要求一定的设备和医生的技能，这样很多恶性实体肿瘤失去此有效方法，这些因素成为限制临床应用VER转肿瘤化疗药物耐受的主要原因。
血卟啉为暗红色结晶性粉末，易溶于甲醇，乙醇，己醇和氯仿等有机溶剂，难溶于水，***及稀无机酸。血卟啉盐溶于水。光敏物质，在肿瘤组织中选择性潴留，在有氧的条件下，光敏剂与分子氧及其他物质作用产生活性氧组分(reactive oxygen species,ROS)，如单线态氧和氧自由基,这些活性氧分子易与多种生物分子反应，引起脂类、蛋白质、核酸和其他细胞组分的损伤，破坏组织、细胞，最终杀灭肿瘤细胞和组织以达到治疗目的[7]。生物特性主要表现为特异性聚集，即为血卟啉及衍生物可以在肿肾、脾、皮肤、瘤、肝、骨等组织中选择性积聚并滞留。通常来说，癌细胞对血卟啉的亲和力比正常细胞大10倍，因此血卟啉在癌细胞中的浓度远大于正常的组织细胞[8]，癌细胞内的滞留时间比较长，在上述正常组织细胞中血卟啉及其衍生物数小时可清除，经过48-72小时之后，正常组织中的血卟啉己完全排出，此时它几乎全部滞留在癌细胞内。经过特定波长的光照射，从而到达治疗癌症目的[9]。但由于血卟啉极性较低，因此不能直接通过静脉给药，从而极大的限制了其在临床中的应用。
参考文献：
[1]Onrubia M,Cusido RM,Ramircz K.Bioprocessing of plant in vitrosystems for the mass production of pharmaceutically important metabolites:Paclitaxel and its derivatives[J].Curr.Med.Chem.2013,20:880–891.
[2]Chen W,Zheng R,Baade PD,Zhang S,Zeng H,Bray F,Jemal A,Yu XQ,HeJ.Cancer statistics in China.2015.CA Cancer J Clin.2016,66:115-32.
[3]Jeong SO,Kim EB,Jeong SW,Jang JY,Lee SH,Kim SG.Predictive Factorsfor Complete Response and Recurrence after Transarterial Chemoembolization inHepatocellular Carcinoma.Gut Liver.2017,11(3):409-416.
[4]Forner A,Llovet JM,Bruix J.Hepatocellular carcinoma.Lancet.2012,379(9822):1245-55.
[5]Kyrochristos ID,Glantzounis GK,Ziogas DE,Gizas I,Schizas D,Lykoudis EG,Felekouras E,Machairas A,Katsios C,Liakakos T,Cho WC,RoukosDH.From Clinical Standards to Translating Next-Generation Sequencing Researchinto Patient Care Improvement for Hepatobiliary and Pancreatic Cancers.Int JMol Sci.2017,18(1).pii:E180.
[6]Krawczenko A,Bielawska-Pohl A,Wojtowicz K,Jura R,Paprocka M,WojdatE,
U,Klimczak A,Grillon C.Expression and activity of multidrugresistance proteins in mature endothelial cells and their precursors:Achallenging correlation.PLoS One.2017,12(2):e0172371.
[7]Liu N,Huang H,Liu S,Li X,Yang C,Dou Q,Liu P J.Calcium channelblocker verapamil accelerates gambogic acid-induced cytotoxicity viaenhancing proteasome inhibition and ROS generation.Toxicol In Vitro.2014,28(3):419-25.
[8]Sun X,Yin Q,Chen D,Dong X,Zhou L,Zhang H,Fan P.Determination ofverapamil in dog serum and tissues by reversed-phase high performanceliquidchromatography.Se Pu.2004,22(3):255-7.
[9]Moan J,Berg K,Photochemotherapy of cancer:experimentalresearch.Photochemistry and Photobiology.1992,55(6):931-948.
发明内容
本发明的目的之一在于提供一种用于治疗肝癌的药物组合物，由药学上有效剂量的血卟啉衍生物A2和化疗药物，以及药学上可接受的载体制得。
所述血卟啉衍生物A2由血卟啉和维拉帕米片段骈合形成，其具有如下结构：
所述维拉帕米片段为3,4-二甲氧基苯乙胺，其结构如下：
优选的，所述化疗药物为阿霉素(ADM)，5-氟尿嘧啶(5-Fu)，多西他赛(Docetaxel)中的一种或几种。
优选的，所述化疗药物为阿霉素(ADM)或5-氟尿嘧啶(5-Fu)。
优选的，所述有效剂量为血卟啉衍生物A2占药物组合物的质量分数为0.1-99％。
优选的，所述有效剂量为血卟啉衍生物A2占药物组合物质量分数为10％、20％、30％、50％、70％。
本申请中所述药学上可接受的载体包括赋形剂、稳定剂、抗氧化剂、着色剂、稀释剂、缓释剂等一种或几种功能的辅料，如淀粉、脂类、蜡、糊精、蔗糖、乳糖、微晶纤维素、明胶、柠檬酸、无机盐类、羟丙基甲基纤维素、羟乙基纤维素等。
优选的，所述药物组合物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂中任意一种。
本发明另一目的是提供血卟啉衍生物A2在制备抗肝癌药物的增敏剂或者逆转耐受剂中的应用。
本发明还提供血卟啉衍生物A2与肝癌化疗药物的联合应用，所述血卟啉衍生物A2用于逆转耐受或增敏肝癌化疗药物；在肝癌化疗药物作用肝癌细胞的应用中增加肝癌化疗药物对肝癌细胞的抑制作用，增强了肿瘤细胞对药物的敏感性。所述化疗药物为阿霉素(ADM)，5-氟尿嘧啶(5-Fu)，多西他赛(Docetaxel)中的一种或几种。
优选的，所述血卟啉衍生物A2用于逆转耐受或增敏肝癌化疗药物阿霉素(ADM)或5-氟尿嘧啶(5-Fu)。
本发明提供血卟啉衍生物A2及其在药理学上容许的盐在制备抗肝癌药物的增敏剂或者逆转耐受剂中的应用。
优选的，所述在药理学上容许的盐包括血卟啉衍生物A2与无机酸、有机酸、碱金属、碱土金属或碱性氨基酸中任一种成的盐；所述无机酸为盐酸、硝酸、硫酸、磷酸、氢溴酸中的任一种，所述有机酸为马来酸、富马酸、酒石酸、乳酸、柠檬酸、乙酸、甲磺酸、对甲苯磺酸，己二酸，棕榈酸，单宁酸中的任一种，所述碱金属为锂，钠、钾中的任一种；所述碱土金属为钙、镁中的任一种；所述碱性氨基酸为赖氨酸。
本发明的有益效果在于：
1)考虑到：VER静脉应用的有效浓度所至毒性限制；体外实验和靶血管灌注、胸腹腔、局部注射对恶性实体肿瘤有良好的逆转效果；血卟啉在肿瘤组织中选择性潴留的特性；我们在国内外首次发明了血卟啉与维拉帕米片段合成新的化合物即血卟啉衍生物A2并验证了本全新的化合物联合化疗药物抗肿瘤作用的研究。
2)本发明提供了具有血卟啉衍生物A2对恶性实体肿瘤在逆转肝癌化疗药物耐受及增敏的用途；
3)从血卟啉与维拉帕米功能基团制备得到一种对恶性实体肿瘤在逆转肝癌化疗药物耐受及增敏的衍生物，在治疗恶性肿瘤具有广阔的应用前景；
4)本发明的方法易掌握、发明的衍生物能够产业化生产，并且本发明所涉及的血卟啉衍生物为全新结构可应用于抗肿瘤领域。
附图说明
图1：血卟啉衍生物A2在肝癌SMMC-7721细胞中的非毒性范围；
图2：血卟啉衍生物A2在肝癌HepG2细胞中的非毒性范围；
图3：CCK8法检测阿霉素+血卟啉衍生物A2作用于肝癌SMMC-7721细胞药物敏感性结果；
图4：CCK8法检测阿霉素+血卟啉衍生物A2作用于肝癌HepG2细胞药物敏感性结果。
具体实施方式
下面结合实施例对本发明的技术方案做出更为具体的说明，除非另有说明，本文中所使用的术语均具有本领域技术人员常规理解的含义。本文中使用的“A2”仅作为对本申请使用的血卟啉衍生物的命名，并不用于限制该血卟啉衍生物。
实施例1：
血卟啉衍生物A2的合成
将0.5mmol血卟啉溶于30mL DMF中，放在磁力搅拌器上搅拌，随后加入2mmol 3,4-二甲氧基苯乙胺和0.5mmol苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)，室温搅拌3小时，使用薄板层析(TLC)检测反应进程。待反应结束后，向反应体系内加入100mL水搅拌均匀，再将反应容器放于冰上析出固体。抽滤析出的固体并将该固体干燥，得到粗产物。将粗产物溶于乙酸乙酯中，加入相当于粗产物质量三倍量的200-300目硅胶，真空旋蒸掉乙酸乙酯，然后干法上样，以二氯甲烷：甲醇体积比50:1为洗脱剂在硅胶柱层析中纯化，得到棕色的血卟啉衍生物A2固体，产率为38％。
本实施例制备的血卟啉衍生物A2的氢谱和质谱结果如下所示：
1H NMR(400MHz,DMSO-d6)δ8.52–8.46(m,2H),8.27(d,J＝11.0Hz,2H),8.16(s,1H),7.86(t,J＝4.8Hz,1H),6.85–6.77(m,4H),6.74–6.66(m,2H),4.85(dd,J＝16.5,5.2Hz,2H),4.71(ddtd,J＝7.3,6.3,5.1,1.0Hz,1H),4.45(qd,J＝6.7,5.4Hz,1H),3.82–3.77(m,12H),3.45(td,J＝5.3,4.8Hz,2H),3.14(q,J＝5.3Hz,5H),3.01–2.92(m,2H),2.71(tt,J＝5.3,1.0Hz,4H),2.55(dd,J＝16.4,0.4Hz,2H),2.50–2.39(m,4H),2.09(s,3H),1.98(d,J＝1.0Hz,3H),1.94(s,3H),1.28–1.16(m,6H).MS(ESI):m/z 925.5[M+H]+.
实施例2
CCK8试剂盒检测血卟啉衍生物A2和化疗药物抑制肝癌细胞增值活性
实验材料：血卟啉衍生物A2由血卟啉和维拉帕米的部分片段依据实施例1合成并加以提纯，纯度不低于95％。人肝癌SMMC-7721、HepG2由安徽省肿瘤医院表观遗传学实验室提供。血卟啉，3,4-二甲氧基苯乙胺，卡特缩合剂，BOP，DIC，5-氨基-2-(3,4-二甲氧基苯基)-2-异丙基戊腈，阿霉素(ADM)，5-氟尿嘧啶(5-Fu)，奥沙利铂(Oxaliplatin)，多西他赛(Docetaxel)购自拜尔迪公司，纯度均大于99％。CCK8试剂盒购自biosharp Life sciences公司。
实验方法：
1.细胞复苏
1)从液氮罐中取出冻存管，直接投入37℃温水中，并不时摇动令其尽快融化。
2)从37℃水浴中取出冻存管，用吸管吸出细胞悬液1ML，注入离心管并加入2mL培养液，混合后低速离心，弃去上清，再重复用培养液洗一次。
3)将培养液适当稀释后，接种于培养瓶，放在37℃培养箱静置培养，次日更换培养液，继续培养。培养到一定密度时进行传代。
2.细胞传代培养
将人肝癌SMMC-7721、HepG2细胞株培养于含有10％胎牛血清的高糖DMEM培养基中。每天观察细胞生长的情况，当细胞在培养瓶中生长到约90％汇合度(贴壁细胞)时，按照1:3到1:5的比例传代，约每隔2-4天传代一次。方法如下：
1)用1×磷酸盐缓冲液洗涤细胞三次。
2)加入1-2ml 0.25％胰蛋白酶消化液消化，置于37℃培养箱中数分钟。待到细胞分离。
3)用含10％胎牛血清的合适培养基终止消化。将细胞分装于新的培养瓶中，继续培养。
3.细胞冻存
1)取培养至对数生长期的细胞，胰蛋白酶消化，收集于离心管中并计数，离心。
2)弃去胰蛋白酶和旧的培养液，加入配置好的冻存液，冻存液中细胞的最终浓度为0.5-1×107/ml。用吸管轻轻吹打使细胞均匀，然后分装入无菌冻存管中，每管加1-1.5ml。
将冻存管放入冻存盒中置于-80℃，5小时后移入液氮罐中保存。
4.CCK8实验检测细胞药物敏感性
先进行血卟啉衍生物A2对肝癌SMMC-7721、HepG2细胞的安全性实验，用于确定血卟啉衍生物A2的安全范围，以便后续实验。
将肝癌SMMC-7721、HepG2细胞按照5000/孔的密度接种到96孔板中，细胞贴壁后除去培养基，用PBS冲洗细胞两次。用补充有10％FBS和不同浓度的血卟啉衍生物A2的新鲜培养基，每孔100μL，在37℃，5％CO2条件下培养24小时。血卟啉衍生物A2使用50,20,10,5,2.5,1.25μmol/L共6种浓度梯度。温育后将每孔中液体弃去，在96孔板中每孔再加入CCK8溶液10μL和90μL的不含血清的培养基，并将96板再温育2小时。然后将96孔板放在酶标仪中450nm处测吸光度值(OD450值)。空白组为不加细胞只加培养基，对照组为不加药细胞组。细胞抑制率＝1-(实验组OD450-空白组OD450)/(对照组OD450-空白组OD450)。
血卟啉衍生物A2在肝癌细胞中的安全范围结果如图1所示，从图上可以看出，血卟啉衍生物A2在低于等于20μM时(SMMC7721细胞)以及低于等于15μM(HepG2细胞)时对肝癌细胞是无毒的，因此在检测细胞药物敏感性实验中选择血卟啉衍生物A2浓度为15μM进行实验，以排除血卟啉衍生物A2自身对实验结果的干扰。
将肝癌SMMC-7721、HepG2细胞按照5000/孔的密度接种到96孔板中，细胞贴壁后除去培养基，用PBS冲洗细胞两次。用补充有10％FBS和不同浓度的药液的新鲜培养基37℃，5％CO2条件下培养24小时，每孔100μL。上述药液为阿霉素(ADM)，5-氟尿嘧啶(5-Fu)，奥沙利铂(Oxaliplatin)，多西他赛(Docetaxel)四种，每种均使用20,10,5,2.5,1.25μmol/L共5种浓度梯度。温育后将每孔中液体弃去，在96孔板中每孔再加入CCK8溶液10μL和90μL的不含血清的培养基，并将96板再温育2小时。然后将96孔板放在酶标仪中450nm处测吸光度值(OD450值)。空白组为不加细胞只加培养基，对照组为不加药细胞组。
细胞抑制率＝1-(实验组OD450-空白组OD450)/(对照组OD450-空白组OD450)。
以上实验均进行了三次重复，所得结果用SPSS统计分析软件进行分析作图，分析细胞抑制率为50％时所需的药物浓度，结果如表1所示。
表1：化疗药物抑制肝癌细胞增殖的IC50
通过表中单用不同的化疗药物对肝癌细胞作用的IC50值与血卟啉衍生物A2+不同化疗药物后对细胞作用的IC50值的对比可以看出，除奥沙利铂(Oxaliplatin)在两种细胞中显示出增加外，其余化疗药物均显示出不同程度的降低，其中5-氟尿嘧啶(5-Fu)和阿霉素(ADM)在两种肝癌细胞中均显示出降低，多西他赛(Docetaxel)在肝癌细胞Hepg2中显示出降低，提示该血卟啉衍生物A2对肝癌常用化疗药物5-氟尿嘧啶(5-Fu)、阿霉素(ADM)和多西他赛(Docetaxel)有增敏的作用。
以阿霉素(ADM)为例，根据上述实验结果和SPSS统计分析软件进一步分析阿霉素、阿霉素+血卟啉衍生物A2对肝癌细胞的作用，阿霉素+血卟啉衍生物A2对肝癌SMMC-7721药物敏感性结果如图2所示。
从图2可以看出，阿霉素的IC50值为402.49，阿霉素+血卟啉衍生物A2的IC50值为254.15，即随着阿霉素药物浓度的不断增加，对肿瘤细胞的抑制越明显，肿瘤细胞存活率越低，其中在浓度梯度中，相同浓度条件下阿霉素+血卟啉衍生物A2的抑制作用明显高于阿霉素单用组，并且所得IC50值也显示出相应的优势。
阿霉素+血卟啉衍生物A2对肝癌HepG2药物敏感性结果如图3所示。从图3可以看出，阿霉素的IC50值为412.85，阿霉素+血卟啉衍生物A2的IC50值为336.86，即随着阿霉素药物浓度的不断增加，对肿瘤细胞的抑制越明显，肿瘤细胞存活率越低，其中在浓度梯度中，相同浓度条件下阿霉素+血卟啉衍生物A2的抑制作用明显高于阿霉素单用组，并且所得IC50值也显示出相应的优势。
上述实验表明，针对不同的肝癌细胞株，血卟啉衍生物A2可以不同程度增强肝癌常用化疗药物阿霉素(ADM)，5-氟尿嘧啶(5-Fu)，多西他赛(Docetaxel)对肝癌细胞的敏感性，提示该血卟啉衍生物A2对化疗药物有增敏的作用。
Claims (10)
1.一种用于治疗肝癌的药物组合物，该药物由药学上有效剂量的血卟啉衍生物A2和化疗药物，以及药学上可接受的载体制得；所述血卟啉衍生物A2结构如下：
2.如权利要求2所述的药物组合物，其特征在于，所述化疗药物为阿霉素(ADM)，5-氟尿嘧啶(5-Fu)，多西他赛(Docetaxel)中的一种或几种。
3.如权利要求2所述的药物组合物，其特征在于，所述化疗药物为阿霉素(ADM)或5-氟尿嘧啶(5-Fu)。
4.如权利要求1所述的药物组合物，其特征在于，所述有效剂量为血卟啉衍生物A2占药物组合物的质量分数为0.1-99％。
5.如权利要求4所述的药物组合物，其特征在于，所述有效剂量为血卟啉衍生物A2占药物组合物质量分数为10％、20％、30％、50％、70％。
6.如权利要求2所述的药物组合物，其特征在于，所述药物组合物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂中任意一种。
7.血卟啉衍生物A2在制备抗肝癌药物的增敏剂或者逆转耐受剂中的应用。
8.血卟啉衍生物A2与肝癌化疗药物的联合应用，其特征在于，所述血卟啉衍生物A2用于逆转耐受或增敏化疗药物；所述化疗药物为阿霉素(ADM)，5-氟尿嘧啶(5-Fu)，多西他赛(Docetaxel)中的一种或几种。
9.血卟啉衍生物A2在药理学上容许的盐在制备抗肝癌药物的增敏剂或者逆转耐受剂中的应用。
10.如权利要求9所述的应用，其特征在于，所述在药理学上容许的盐包括血卟啉衍生物A2与无机酸、有机酸、碱金属、碱土金属或碱性氨基酸中任一种成的盐；所述无机酸为盐酸、硝酸、硫酸、磷酸、氢溴酸中的任一种，所述有机酸为马来酸、富马酸、酒石酸、乳酸、柠檬酸、乙酸、甲磺酸、对甲苯磺酸、己二酸、棕榈酸、单宁酸中的任一种，所述碱金属为锂、钠、钾中的任一种；所述碱土金属为钙、镁中的任一种；所述碱性氨基酸为赖氨酸。
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| 徐士超等: "3, 8双-乙酰基次卟啉二甲酯的合成", 《应用化学》, vol. 28, no. 6, pages 657 - 661 * |
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