CN113912699A - 一种新型治疗乳腺癌的fgf类似物及其应用 - Google Patents
一种新型治疗乳腺癌的fgf类似物及其应用 Download PDFInfo
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- CN113912699A CN113912699A CN202111197493.9A CN202111197493A CN113912699A CN 113912699 A CN113912699 A CN 113912699A CN 202111197493 A CN202111197493 A CN 202111197493A CN 113912699 A CN113912699 A CN 113912699A
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Abstract
本发明公开了一种新型治疗乳腺癌的FGF类似物及其应用,属于医药技术领域。本发明提供的FGF21蛋白是一个由约210个氨基酸组成的分泌蛋白,本发明首次发现FGF21具有治疗乳腺癌的效果,通过细胞学实验和动物实验证明,FGF21可以抑制乳腺癌细胞系的增殖、侵袭、迁移;能够在小鼠模型中显著降低肿瘤病灶的大小。由FGF21作为活性物质制备的乳腺癌的治疗药物具有安全性好,药效持续时间长,同时保护器官无损并且改善脂质代谢紊乱的效果。
Description
技术领域
本发明涉及一种新型治疗乳腺癌的FGF类似物及其应用,特别涉及人FGF21类似物在制备用于治疗乳腺癌药物中的应用,属于医药技术领域。
背景技术
乳腺癌是临床上常见的恶性肿瘤之一,据2018年国际癌症研究机构(IARC)调查的最新数据显示,乳腺癌在全球女性癌症中的发病率为24.2%,位居女性癌症的首位,其中52.9%发生在发展中国家。
目前,乳腺癌的治疗主要以外科根治手术为主,化疗、放疗、中医药治疗及生物治疗作为其辅助性治疗手段。首次诊断的病人中大约有三分之二接受了根治术,其中超过一半的患者出现复发或远处转移。对晚期癌肿或有广泛转移的癌肿,不能进行根治性手术,内科综合治疗常成为主要治疗手段,在可手术的患者中,乳腺癌术后仍有较高的复发率。而常用的治疗药物通常为广谱类化学药物,具有较多的副作用。因此,开发一种安全的、同时具有抑制肿瘤生长和复发且器官保护效应的、无相关明显副作用的、安全的治疗乳腺癌药物是目前研发的理想目标。
近年来,大量临床调查结果显示乳腺癌癌的发生发展与代谢异常存在十分紧密的联系。大量研究发现代谢通路包括糖酵解、三羧酸循环、脂肪酸代谢、谷氨酰胺代谢等在肿瘤细胞中均发生了重编程变化,肿瘤细胞可通过对各种代谢途径间的协调,提供增殖所必须的脂肪酸、核苷酸等,从而使生物大分子的合成过程更适合于肿瘤细胞的快速增殖。尤其需要指出的是,代谢异常并不仅仅是肿瘤发生发展的结果,还可能直接参与肿瘤的始发过程。目前,从代谢的角度开发抗肿瘤药物,已在诸多的肿瘤中获得了成功的应用,比如,最近的研究发现某些编码代谢酶类的基因本身就是癌基因,如延胡索酸羧化酶的突变与肾癌的发生、发展;琥珀酸羧化酶的突变与嗜铬细胞瘤的发生发展;异柠檬酸脱氢酶的突变产生代谢物小分子2HG一直HNF4α的表达从而诱导胆管癌等。基于以上分析表明靶向肿瘤细胞代谢可能是杀死肿瘤细胞的有效途径之一。然而,目前开发的药物都是一些小分子抑制剂,靶向性较弱,副作用较多,而生物蛋白类药物吸收快,靶向性强。因此,针对乳腺癌开发新型靶向生物蛋白类制剂是目前肿瘤研究的热点。
发明内容
发明人通过对原始序列进行改造,构建得到融合FGF21蛋白,结果显示,作为参与糖脂代谢网络多个环节的重要成员的人成纤维细胞生长因子21通过融合之后,可以显著抑制乳腺癌的发生发展以及转移。
本发明提供了FGF21类似物,所述FGF21蛋白类似物氨基酸序列如SEQ ID NO.1~3任一所示。
本发明提供了编码所述FGF21蛋白类似物的基因,所述基因的序列分别如SEQIDNO.4~6所示。
本发明提供了携带所述基因的载体和/或微生物细胞。
本发明提供了含有所述FGF21类似物的药物或药物组合物。
在一种实施方式中,所述药物中还含有人体可接受的修饰、药用载体和/或辅料。
在一种实施方式中,所述修饰包括PEG修饰、FC修饰以及其他各种融合修饰;所述药用辅料包括溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂。
本发明提供了所述FGF21类似物在制备预防、缓解和/或治疗乳腺癌、前列腺癌、乳腺癌、食管癌、结肠直肠腺癌、宫颈癌、子宫内膜癌、卵巢癌、胰腺癌、胆囊癌、肝癌、透明细胞肾癌、黑素瘤、多发性骨髓瘤中的一种或多种疾病的药物或药物组合物中的应用。
在一种实施方式中,所述预防、缓解和/或治疗乳腺癌包括减小肿瘤的体积、抑制肿瘤的生长和增殖、肿瘤质量的降低、抑制肿瘤细胞的生成和转移。
在一种实施方式中,所述FGF21类似物的有效剂量为0.1-100mg/kg。
在一种实施方式中,所述药物的给药途径包括皮内注射、皮下注射、静脉注射、肌肉注射、腹腔注射、静脉滴注、动脉注射、体腔内注射和/或口服。
本发明提供了FGF21基因在筛选具有治疗乳腺癌的药物中的应用。
在一种实施方式中,所述FGF21基因作为药物靶标。
在一种实施方式中,所述FGF21基因的核苷酸序列如SEQ ID NO.4~6任一所示。
在一种实施方式中,所述应用是用于筛选FGF21蛋白的小分子激活剂。
与现有技术相比,本发明具有以下有益效果:
(1)本发明发现FGF21基因的新功能,能够显著降低肿瘤病灶的大小,因而可作为各种剂型药物的有效成分,对于乳腺癌的治疗具有极其重大的意义。
(2)本发明通过注射FGF21蛋白,可缓解乳腺癌的发生和发展,抑制乳腺癌的生成和转移。
附图说明
图1为FGF21对人乳腺癌移植瘤生长速度的影响;其中,A为肿瘤体积的变化;B为肿瘤质量的变化;
图2为FGF21对MMTV-PYVT自发性小鼠乳腺癌的影响;其中,A为乳腺肿瘤数目;B为乳腺肿瘤重量。
具体实施方式
实验动物及饲养:裸鼠及MMTV-PYVT小鼠购于江苏集萃药康生物科技有限公司。饲养于江南大无锡医学院动物中心,每12小时交替照明,温度20±2℃。
细胞培养:乳腺癌细胞系MDA-MB-231由中国科学院生物化学与细胞生物学研究所提供。
DMEM、0.05%Trypsin,购于博士德公司;胎牛血清购于四季青公司。其他药品为国产分析纯。乳腺癌细胞系贴壁生长于含10%胎牛血清的DMEM培养液中,于37℃,5%CO2湿化培养箱中培养,隔天传代一次。
下述实施例中对小鼠注射1mg/kg、5mg/kg和10mg/kg的FGF21蛋白,分别对应的人体剂量为0.1mg/kg、0.5mg/kg和1mg/kg。
实施例1:重组蛋白的构建、表达及纯化
(1)FGF21蛋白表达载体的构建
根据计算机模拟替换及大肠杆菌密码子偏好性,设计出新型FGF21基因,其核苷酸序列分别如序列表中FGF21-1(核苷酸序列如SEQIDNO.4所示)、FGF21-2(核苷酸序列如SEQIDNO.5所示)、FGF21-3(核苷酸序列如SEQIDNO.6所示)所示。将这3种基因送至上海捷瑞生物公司合成,同时在各基因两端设计NdeI与BamHI两酶切位点。分别用NdeI与BamHI将3种合成的含有各自目的基因片段的载体和pET30a(+)双酶切,酶切完毕后,胶回收各自需要的目标片段。使用T4DNA连接酶将4种目的片段分别与原核表达载体pET30a(+)连接,连接反应体系为10μL,混匀,4℃连接过夜,然后各自转化至大肠杆菌DH5α中。挑取阳性克隆,经过酶切鉴定后,即分别构建得到3种重组质粒pET30a-FGF21-1、pET30a-FGF21-2和pET30a-FGF21-3。
(2)蛋白的表达及纯化
将含有正确序列的重组质粒pET30a-FGF21-1、pET30a-FGF21-2和pET30a-FGF21-3转化至表达菌株Rosseta(DE3)感受态细胞中。转化后的单菌落分别接种至20mL含Kan(50μg/mL)的LB培养基中,37℃培养8h,以体积比为1:100接种于另一20mL含Kan(50μg/mL)的LB培养基中,37℃培养,当A600在0.35左右时,加入IPTG至终浓度为0.25mmol/L进行诱导,诱导温度为30℃,5h后收获菌体,用Lysisbuffer(20mmol/LTris,150mmol/LNaCl,pH8.0)重悬菌体,破碎菌体后离心,分别取上清和沉淀进行12wt%SDS-PAGE电泳分析。结果显示FGF21-1、FGF21-2和FGF21-3蛋白在大肠杆菌中表达量显著增加,目标蛋白大部分以包涵体形式存在。对菌体进行破碎、并纯化蛋白得到纯化后的FGF21-1、FGF21-2和FGF21-3,其对应的氨基酸序列分别如SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示。
实施例2:FGF21对人乳腺癌移植瘤生长速度的影响
按照实施例1的方法制备得到氨基酸序列如SEQ ID NO.1所示的FGF21蛋白。
将人乳腺癌细胞MDA-MB-231细胞按照1×106个细胞/只接种6周龄的雄性裸鼠的皮下,待肿瘤长至200mm3随机分为四组:
①生理盐水组:注射等体积生理盐水;②低剂量组:注射1mg/kg FGF21;③中剂量组:注射5mg/kg FGF21;④高剂量组:注射10mg/kg FGF21。
每天注射一次,连续注射15天。每天监测肿瘤体积,三周后处死小鼠,称量肿瘤重量。
结果显示:三种不同剂量的FGF21均能抑制移植瘤体积和最终肿瘤重量,且呈现剂量依赖性。高剂量FGF21(10mg/kg)注射后,可完全抑制肿瘤生长,使肿瘤维持在400mm3,最终体积仅为对照组的26.5%,同样肿瘤质量也下降了约70%,注射1mg/kg和5mg/kg分别能使肿瘤质量下降40%和50%(如图1所示)。
实施例3:FGF21对MMTV-PYVT自发型小鼠乳腺癌的影响
按照实施例1的方法制备得到氨基酸序列如SEQ ID NO.1所示的FGF21蛋白。
出生后鉴定为阳性小鼠后在第6周开始分组为生理盐水组及FGF21注射组,FGF21注射组注射剂量为10mg/kg,生理盐水组注射同样量的生理盐水,每天注射一次,连续注射8周,8周后分别测定生理盐水组和FGF21注射组小鼠的肿瘤数量、肿瘤质量。
结果如图2A所示,注射FGF21后能够使平均肿瘤灶个数由8减少至3.8个,图2B显示了FGF21治疗组和对照组的肿瘤重量,治疗组中肿瘤重量仅为对照组的1/3。
发明人还尝试对SEQ ID NO.2~3所示的FGF21蛋白的融合蛋白在治疗乳腺癌方面的效果进行了研究,结果显示,如SEQ ID NO.2~3任一所示的FGF21融合蛋白与SEQ IDNO.1所示的FGF21蛋白具有相当的效果。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
SEQUENCE LISTING
<110> 江南大学
<120> 一种新型治疗乳腺癌的FGF类似物及其应用
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ccgctccatc tgccgggtaa taagtcccca catcgtgatc cggcgccacg tggtccggcg 1140
cgtttcctgc cgttgccggg tctgccgccg gctctgccgg agccgcctgg catcctggca 1200
ccgcaaccgt tagaaaccga cagcatggat ccgtttggct tggttaccgg tttggaggct 1260
gtgcgctctc cgtccttcga aaaataa 1287
Claims (10)
1.FGF21类似物,其特征在于,所述FGF21蛋白类似物氨基酸序列如SEQ ID NO.1~3任一所示。
2.编码权利要求1所述FGF21蛋白类似物的基因。
3.携带权利要求2所述基因的载体和/或微生物细胞。
4.含有权利要求1所述FGF21类似物的药物或药物组合物。
5.根据权利要求4所述的药物或药物组合物,其特征在于,所述药物中还含有人体可接受的修饰、药用载体和/或辅料。
6.根据权利要求5所述的药物或药物组合物,其特征在于,所述修饰包括PEG修饰、FC修饰以及其他各种融合修饰;所述药用辅料包括溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂。
7.权利要求1所述FGF21类似物在制备预防、缓解和/或治疗乳腺癌、前列腺癌、乳腺癌、食管癌、结肠直肠腺癌、宫颈癌、子宫内膜癌、卵巢癌、胰腺癌、胆囊癌、肝癌、透明细胞肾癌、黑素瘤、多发性骨髓瘤中的一种或多种疾病的药物或药物组合物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述预防、缓解和/或治疗乳腺癌包括减小肿瘤的体积、抑制肿瘤的生长和增殖、降低肿瘤的质量、抑制肿瘤细胞的生成和转移。
9.根据权利要求8所述的应用,其特征在于,所述FGF21类似物的有效剂量为0.1~100mg/kg;所述药物的给药途径包括皮内注射、皮下注射、静脉注射、肌肉注射、腹腔注射、静脉滴注、动脉注射、体腔内注射和/或口服。
10.权利要求2所述基因在筛选具有治疗乳腺癌的药物中的应用。
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