CN1686562A - 一种转铁蛋白与生物还原剂的结合物及其制备方法 - Google Patents

一种转铁蛋白与生物还原剂的结合物及其制备方法 Download PDF

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CN1686562A
CN1686562A CNA2005100386313A CN200510038631A CN1686562A CN 1686562 A CN1686562 A CN 1686562A CN A2005100386313 A CNA2005100386313 A CN A2005100386313A CN 200510038631 A CN200510038631 A CN 200510038631A CN 1686562 A CN1686562 A CN 1686562A
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胡一桥
吴锦慧
罗玲英
支枫
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Nanjing University
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Priority to PCT/CN2006/000582 priority patent/WO2006102854A1/zh
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Abstract

本发明属于生物制药技术领域，具体涉及一种在治疗癌症方面有效的蛋白与生物还原剂的结合物，特别是靶向蛋白和生物还原剂的结合物。靶向蛋白包括转铁蛋白、血浆铜盐蛋白、生长抑素、维生素结合蛋白如：转钴胺蛋白、激素、细胞活素，生物还原剂主要包括双功能的硝基杂环化合物，醌类，杂环氮氧化合物，拓扑II异构酶的抑制剂和DNA靶向药物。结合物可降低药物的毒性和耐受性，因此可制备用于治疗癌症的药物。

Description

一种转铁蛋白与生物还原剂的结合物及其制备方法
一、技术领域
本发明属于生物制药技术领域，具体涉及一种在治疗癌症方面有效的蛋白与生物还原剂的结合物，特别是靶向蛋白和生物还原剂的结合物。
二、背景技术
目前，在肿瘤的治疗过程中遇到的两个最大的问题就是药物耐受和药物的毒性。解决药物耐受和药物毒性的一种方法就是将药物靶向的给予肿瘤细胞，许多研究者致力于研究利用抗体及其他手段达到靶向的目的，这些虽然取得了一些成果但是又引来了一系列新的问题。比如：抗体通常会结合于正常组织，甚至会引起严重的过敏反应，而利用微粒体靶向性又差。
转铁蛋白(Transferrin)是一种β1球蛋白，分子量约为77kD，约占血浆蛋白总量的0.3％～0.5％。其主要作用是运载细胞外的铁，可通过细胞膜上特异的转铁蛋白受体介导的内吞作用，将铁等外源物质转入细胞内。虽然在50年前转铁蛋白就已被发现，最近研究才发现：由于肿瘤生长旺盛，需要铁的量增多，因而肿瘤细胞表面转铁蛋白受体表达大大超过了正常细胞。
生物还原药物被还原酶代谢活化后，产生细胞毒代谢产物。此过程在富含DT-黄递酶和乏氧的实体肿瘤中比在正常组织中更易进行，因此也就更加增强了它对肿瘤的选择性杀伤作用。
本发明利用肿瘤细胞的这种性质，将转铁蛋白与生物还原剂相结合，达到肿瘤靶向治疗的目的。
现在利用转铁蛋白与化疗药物结合的研究已经有了很大的进展，如在专利US5108987，US5000935，US4895714，US4886780，US2004157767中提到，转铁蛋白与阿霉素，道诺霉素，甲氨喋呤，长春新碱，6-巯基嘌呤，阿糖孢苷，环磷酰胺，放射性碘的结合物其靶向性均有不同程度的提高，同时降低药物的毒性。
三、发明内容
本发明的目的是为了解决肿瘤治疗过程中药物的毒性和耐受性。研制出一种蛋白与生物还原剂的结合物，特别是靶向蛋白和生物还原剂的结合物。靶向蛋白包括转铁蛋白、血浆铜盐蛋白、生长抑素、维生素结合蛋白如：转钴胺蛋白、激素、细胞活素，生物还原剂主要包括，双功能的硝基杂环化合物(CB1954，RSU1069，RB6145，CB1954，SN23862)，醌类(丝裂霉素C，吲哚醌E09，马蔺子素，Methyl DZQ，diaziquone，streptonigrin，porfiromycin和RH1)，杂环氮氧化合物(Tirapazamine)，拓扑II异构酶的抑制剂AQ4N和DNA靶向药物(NLCPQ-1、NLCQ-1、THNLA-1)等。结合物之间的连接方式有：
(1)共价结合：可通过戊二醛、二硫键、苯甲酰腙、N-羟基丁二酰亚胺等手段进行结合。
(2)配位结合：可通过氢键、电荷、络合等非共价键手段结合。
本发明主要包括转铁蛋白与生物还原剂的结合。无论应用什么样的结合方法，结合物必须保持其活性，能够杀死肿瘤细胞，而对正常细胞损伤有限。为了达到这些要求，本发明中以丝裂霉素为例，结合物的制备方法大致如下：
将戊二酐加入到含有丝裂霉素的四氢叶酸中，混合物在氮气保护得条件下加热，40℃～60℃，10～15小时。在反应完成以后蒸馏。残渣溶于甲醇中，并以甲醇为流动相，通过Sephadex L-20色谱柱，柱层析。馏分蒸干得到G-MMC(戊二醛脂化的丝裂霉素)。将G-MMC溶于乙腈中，加入N-羟基琥珀酰亚胺(HOSu)和DDC，混合物在N2保护的条件下0℃～4℃搅拌40～50小时。然后加入冰水，过滤，滤过物用氯仿抽提三次，蒸干氯仿，得到MMC-G-OSu，用丁酸正己醇酯重结晶，得到紫色粉末。
将转铁蛋白溶于含有NaCl的磷酸钠缓冲液中，加入MMC-G-OSu的二甲基甲酰胺溶液，0℃～4℃下搅拌15～20小时，反应液在0℃～4℃下透析，即得到Tf-G-MMC。
结合物用聚丙烯酰胺凝胶电泳可以除去聚合物，Tf-G-MMC溶于磷酸缓冲液中，363nm处测定紫外吸收，与标准MMC比较可知结合物的含量。
本发明较现有技术相比其优势在于：
(1)利用转铁蛋白等与生物还原剂相结合，得到的结合物具有双重靶向性能：a、靶向肿瘤表面转铁蛋白受体，b、靶向乏氧性实体瘤。从而达到降低药物毒性的目的。
(2)利用转铁蛋白等的内吞作用，使抗肿瘤药物能够进入细胞，从而降低肿瘤细胞对药物的耐受性，提高疗效。
因此本发明可用于制备抗肿瘤药物。
四、具体实施方式
将51.3mg戊二酐加入到10ml含有50mg的四氢叶酸中，混合物在氮气保护的条件下加热至60℃，10小时。在反应完成以后蒸馏。残渣溶于2ml甲醇中，并以甲醇为流动相，通过Sephadex L-20(2.5×97cm)色谱柱中，柱层析。馏分蒸干得到G-MMC(戊二醛脂化的丝裂霉素)。将56.0mgG-MMC溶于3.4ml乙腈中，加入N-羟基琥珀酰亚胺(HOSu)21.6mg和DDC155.6mg，混合物在N2保护的条件下4℃搅拌48小时。然后加入7ml冰水，过滤，滤过物用10ml氯仿抽提三次，蒸干氯仿，得到MMC-G-OSu，用丁酸正己醇酯重结晶，得到紫色粉末。
将30mg转铁蛋白溶于含有3ml0.1M的NaCl磷酸钠缓冲液中(pH＝7.5)，加入0.3mlMMC-G-OSu的二甲基甲酰胺溶液，4℃下搅拌16小时，反应液在4℃下透析，即得到Tf-G-MMC。
Tf-G-MMC结合物经聚丙烯酰胺凝胶电泳，溶于pH为7.4的磷酸缓冲液中，363nm处测定紫外吸收，与标准MMC比较得出结合物中MMC的含量。结合物中MMC的含量随着MMC-G-OSu加入量的增加而增加，当摩尔比MMC-G-OSu/TF为43时，结合物中MMC的质量分数为9.49％。
●结合物对肿瘤细胞选择性实验
选用癌细胞株，如SMMC-7721、和正常细胞如人肝细胞L-02，采用常规方法进行体外细胞培养，用于对转铁蛋白载体对肿瘤靶向性进行评价。细胞生长在培养瓶中，培养液为1640或MEM/EBSS NEAA等(pH7.4，含胎牛血清10％，L-谷氨酰胺2mM，Hepes 10mM，青霉素，链霉素)，在37℃，含5％CO2培养箱中全湿度培养。
选用对数生长期的细胞作为受试细胞，制成细胞悬液，每孔一定量，铺于96孔板中，加入不同浓度的游离药物、结合物。空白为对照，无细胞孔作背景，重复4孔以上，置在37℃，含5％ CO2培养箱中全湿度培养，不同时间取样，离心，弃上清液，用培养液洗涤，继续培养一定时间，弃上清液，加每孔各加5mg/ml的MTT20ul，再培养4小时，加二甲亚砜，用酶标仪测定OD值，
Figure A20051003863100061
结果表明：与游离状态比较，结合物能够提高正常细胞的IC50；降低肿瘤细胞的IC50。
●对肿瘤细胞穿透性能实验
利用单层Caco-2细胞模型，对转铁蛋白对肿瘤细胞的穿透性进行评价。
细胞常规培养条件下，以8×104个/mL的接种密度接种于Millicell***式培养皿中，培养21天后可用于药物跨膜转运实验。用光镜、电镜、细胞密度测定等方法检查细胞的形态学特点及生长特点，测定碱性磷酸酶活性、跨膜电阻、荧光素钠透过量以验细胞单层的极化现象和致密程度。
利用单层Caco-2细胞，测定双侧的药物浓度，可对结合物的透过性能进行评价。
结果表明：与游离状态比较，结合物对Caco-2细胞的单向透过能力增强。

Claims (9)

1、一种包括靶向载体和生物还原剂的结合物，其特征是靶向载体为转铁蛋白，生长素释放抑制因子，表皮生长因子，叶酸和转钴胺蛋白；生物还原剂是双功能的硝基杂环化合物，醌类，杂环氮氧化合物，拓扑II异构酶的抑制剂和DNA靶向药物，其中相似的结合物包括二聚体，三聚体和多聚体。
2、根据权利要求1所述的结合物，其特征是双功能的硝基杂环化合物是CB1954，RSU1069，RB6145，CB1954，SN23862。
3、根据权利要求1所述的结合物，其特征是醌类化合物是丝裂霉素C，吲哚醌E09，马蔺子素，Methyl DZQ，diaziquone，streptonigrin，porfiromycin和RH1。
4、根据权利要求1所述的结合物，其特征是杂环氮氧化合物是Tirapazamine。
5、根据权利要求1所述的结合物，其特征是拓扑II异构酶的抑制剂是AQ4N。
6、根据权利要求1所述的结合物，其特征是DNA靶向药物是NLCPQ-1、NLCQ-1、THNLA-1。
7、一种权利要求1所述的结合物的制备方法，其特征在于：a)滴加药物分子于连接剂中，b)将药物和连接剂的连接物加入到蛋白中产生预定药物和蛋白比例的结合物。
8、根据权利要求7所述的方法，其特征是连接剂包括戊二醛，苯甲酰棕和N-羟基丁二酰亚胺。
9、一种权利要求1所述的结合物在制备***药物中的应用。
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CN101015698B (zh) * 2007-03-02 2010-04-07 北京大学 稀土转铁蛋白络合物作为药物载体的药物
CN108864291A (zh) * 2011-11-23 2018-11-23 拜奥文斯瑞有限公司 重组蛋白及其治疗用途

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WO2014055253A1 (en) * 2012-10-04 2014-04-10 The General Hospital Corporation Methods of synthesizing and using peg-like fluorochromes
WO2014062856A1 (en) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods

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US5108987A (en) * 1982-02-25 1992-04-28 Faulk Ward P Conjugates of proteins with anti-tumor agents
GB8519457D0 (en) * 1985-08-02 1985-09-11 Faulk Ward Page Tumour imaging agents
WO2002094271A1 (en) * 2001-05-15 2002-11-28 Faulk Pharmaceuticals, Inc. Targeted delivery of bioaffecting compounds for the treatment of cancer

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CN101015698B (zh) * 2007-03-02 2010-04-07 北京大学 稀土转铁蛋白络合物作为药物载体的药物
CN108864291A (zh) * 2011-11-23 2018-11-23 拜奥文斯瑞有限公司 重组蛋白及其治疗用途

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