CN113956344A - 一种新型治疗肝癌的fgf类似物及其应用 - Google Patents
一种新型治疗肝癌的fgf类似物及其应用 Download PDFInfo
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Abstract
本发明公开了一种新型治疗肝癌的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428个氨基酸组成的分泌蛋白,本发明通过细胞学实验和动物实验证明,制备的新型FGF21类似物可以抑制肝癌细胞系的增殖、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肝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肝癌的FGF类似物及其应用,特别涉及人FGF21类似物在制备用于治疗肝癌药物中的应用,属于医药技术领域。
背景技术
肝癌为我国常见恶性肿瘤之一,高发于东南沿海地区。我国肝癌病人的中位年龄为40~50岁,男性比女性多见。近年来其发病率有增高趋势。我国肝癌年死亡率占肿瘤死亡率的第二位,在消化系统恶性肿瘤中列第三位,仅次于胃和食管癌。乙型、丙型肝炎、肝硬化,肝细胞坏死伴有肝细胞的再生过程中易于发生恶变。
目前,肝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,肝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、安全的治疗肝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肝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,针对肝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
本发明经过大量的研究发现,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可以显著抑制肝癌的发生发展以及转移。基于此,本发明提供了FGF21类似物在制备预防、缓解和/或治疗肝癌的药物方面的新用途。
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所示任一。
本发明提供了编码所述FGF21蛋白类似物的基因。
本发明提供了携带所述基因的载体和/或微生物细胞。
本发明提供了所述基因在筛选具有治疗肝癌的药物中的应用。
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。
本发明提供了一种药物或药物组合物,所述药物或药物组合物含有所述FGF21类似物。
在一种实施方式中,所述药物或药物组合物还包括人体可接受的修饰、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。
在一种实施方式中,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
疗癌症的药物或药物组合物中的应用。
在一种实施方式中,所述癌症包括但不限于肝癌、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、透明细胞肾癌、黑素瘤、多发性骨髓瘤。
在一种实施方式中,所述预防、缓解和/或治疗肝癌包括但不限于(a)~(d):
(a)降低肝癌症因子的表达水平;
(b)降低肿瘤质量、减少肿瘤体积;
(c)抑制肿瘤细胞的转移;
(d)抑制肿瘤的生成、生长和增殖。
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,所述药物或药物组合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。
本发明的有益效果:
(1)本发明获得FGF21融合蛋白能够作用与肝癌的治疗中,可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。
(2)本发明将含有FGF21类似的药品通过注射的方式注射入体内,可有效降低肝癌症因子的表达水平、缓解肝癌的发生和发展、抑制肝癌的生成和转移,对于肝癌的治疗具有极其重大的意义。
附图说明
图1为FGF21对人肝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对四氯化碳诱导的小鼠肝癌的影响;其中,A为甲胎蛋白含量;B为肝癌切片。
具体实施方式
实验动物及饲养:裸鼠及C57BL/6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:肝癌细胞系HepG2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。肝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
将融合FGF21蛋白(氨基酸序列如SEQ ID NO.1~3所示),根据大肠杆菌密码子偏好性,设计出对应的核苷酸序列,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种基因送至公司合成,将3个基因连接至pET30a(+)载体的NdeI与BamHI酶切位点间,将酶连产物分别转化至大肠杆菌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
将步骤1得到的含有正确序列的重组质粒分别转化至表达菌株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。并对菌体进行破碎、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SEQID NO.3所示。
实施例2:FGF21对人肝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。
将人肝癌细胞HepG2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250mm3,最终体积仅为对照组的20%,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45%和53%(如图1所示)。
实施例3:FGF21对四氯化碳诱导的小鼠肝癌的影响
按照实施例1的方法制备氨基酸序列如SEQ ID NO.1所示的FGF21蛋白。
小鼠在出生后第14天,腹腔注射二乙基亚硝胺(DEN)2mg/kg,并在给药2周后,腹腔注射20%四氯化碳(CCI4)5mL/kg,每周2次共16周。诱导16周后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6周。
结果如图2A所示,图2A显示了FGF21治疗组和对照组的甲胎蛋白水平,甲胎蛋白含量是肝癌的特征性标志物,表明FGF21显著降低肝癌标志物含量,图2B显示了肿瘤的病理切片,进一步说明FGF21对肝癌的抑制效果。
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肝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 ID NO.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> 一种新型治疗肝癌的FGF类似物及其应用
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ggcgctttgt acggctctct gcattttgat ccagaggcct gcagcttccg cgagctgttg 600
ctagaggacg gctataacgt gtatcagagc gaagcgcatg gtctacctct gcacctgccg 660
ggaaacaaaa gcccgcatcg tgatccggcg ccgagaggcc ctgcgcgttt cctgccactg 720
ccgggcttgc cgccggcact gccggagccg ccaggtatcc tggcgccgca gccgctggaa 780
accgactcaa tggatccgtt tggtttggtc accggcctgg aagctgtgcg tagcccgtcg 840
ttcgagaagt aa 852
<210> 6
<211> 633
<212> DNA
<213> 人工序列
<400> 6
atggattccg acgaaactgg tttcgaacat agcggtttat gggtgagtgt tctggctggt 60
cttcttttgg gtgcctgcca agcgcacccg attccggact cctccccgct gctccaattt 120
ggcggtcagg ttcgccagcg ttatctgtac accgacgacg cacagcagac cgaagctcac 180
ttggagatcc gcgaagatgg caccgttggt ggtgctgcgg atcagagccc ggagagcctg 240
ctgcagttga aggcgctgaa gccgggcgtg atccaaattc tgggtgtcaa aacctctcgt 300
ttcctgtgtc agcgtccgga cggcgctttg tacggctctc tgcattttga tccagaggcc 360
tgcagcttcc gcgagctgtt gctagaggac ggctataacg tgtatcagag cgaagcgcat 420
ggtctacctc tgcacctgcc gggaaacaaa agcccgcatc gtgatccggc gccgagaggc 480
cctgcgcgtt tcctgccact gccgggcttg ccgccggcac tgccggagcc gccaggtatc 540
ctggcgccgc agccgctgga aaccgactca atggatccgt ttggtttggt caccggcctg 600
gaagctgtgc gtagcccgtc gttcgagaag taa 633
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所示任一。
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.权利要求2所述基因在筛选具有治疗肝癌的药物中的应用。
5.一种药物或药物组合物,其特征在于,含有权利要求1所述FGF21类似物。
6.根据权利要求5所述的药物或药物组合物,其特征在于,所述药物或药物组合物还包括人体可接受的修饰、药用载体和/或辅料。
7.权利要求1所述FGF21类似物在制备预防、缓解和/或治疗癌症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,所述癌症包括但不限于肝癌、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、透明细胞肾癌、黑素瘤、多发性骨髓瘤。
9.根据权利要求8所述的应用,其特征在于,所述预防、缓解和/或治疗肝癌包括但不限于(a)~(d):
(a)降低肝癌症因子的表达水平;
(b)降低肿瘤质量、减少肿瘤体积;
(c)抑制肿瘤细胞的转移;
(d)抑制肿瘤的生成、生长和增殖。
10.根据权利要求9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。
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