CN106632613B - 与柯萨奇病毒腺病毒受体相关的亲和肽 - Google Patents
与柯萨奇病毒腺病毒受体相关的亲和肽 Download PDFInfo
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Abstract
本发明发现了一系列与柯萨奇病毒腺病毒受体相关的亲和多肽YQC‑1和YQC‑2,这些多肽对柯萨奇病毒腺病毒受体特异性结合的性质将有可能实现特定恶性肿瘤的近红外成像,可用于细胞粘附抑制、肿瘤诊断或示踪的药物的制备、靶向型化疗以及用于药物辅料或连接物,从而达到实时无损在位监测早期恶性肿瘤的目的。本发明涉及与肿瘤诊断相关的药物领域,具体涉及多条多肽、其亲和试验以及这些多肽为有效成分的药物组合物以及它们在制备诊断药物中应用。
Description
技术领域
本发明属于生物工程制药技术领域和蛋白质多肽类药物及生物医学工程领域,具体涉及针对柯萨奇病毒腺病毒受体具有高亲和力多肽及其应用,例如用于癌症诊断和治疗中。
背景技术
目前,癌症已成为危害我国居民健康的最大的罪魁祸首,严重威胁着人类的健康。临床上用于***的方法有外科手术法、化学药物治疗、放射性治疗。其中,化学治疗法是目前肿瘤治疗最广泛使用的方法,在失去手术机会的晚期肿瘤患者中,化疗为其主要治疗手段;在合并有高危因素的手术患者术后,术后辅助化疗也已被证实可以降低术后肿瘤复发率;在乳腺癌等多种肿瘤中,术前新辅助化疗的地位也日益得到重视。
CAR是柯萨奇B组病毒(Coxsackievirus B,CBV)和腺病毒(Adenovirus,Ad)与靶细胞结合的共同受体。1997年,Bergelson等首次分离出能编码CVB与Adv共同受体的cDNA克隆定位于人类染色体21q21-cen上,它编码一种含365个氨基酸的多肽,属于免疫球蛋白超家族。CAR分布广泛,且不同种属、组织的分布不同。在小鼠中,CAR分布于心、肝、脑、肾、肺等,且在肝脏中表达量最高。CAR分布广泛,且不同种属、组织的分布不同。在小鼠中,CAR分布于心、肝、脑、肾、肺、大肠等,在肝脏中表达量最高。在人体,许多组织器官能检测到CAR的mRNA,包括心、肝、脑、肾、肺、肠、胰以及睾丸等CAR在心脏、胰腺及动脉血管新生内膜的表达量非常丰富。值得注意的是,CAR在某些肿瘤及细胞系,如肝癌细胞系、***细胞系、黑色素瘤等高度表达但在神经胶质瘤,***癌,肾癌,膀胱癌,人卵巢癌细胞系等中存在着CAR表达的下降、丢失。
作为参与柯萨奇病毒等的感染的蛋白质,已知柯萨奇病毒-腺病毒受体(COXSACKIEVIRUS AND ADENOVIRUS RECEPTOR;CXADR)。另外,关于该蛋白质,被报告了在肝癌和皮肤基底细胞癌中表达亢进。另一方面,在胆管癌中确认了CXADR的纯合子缺失,启示了CXADR作为癌抑制基因发挥功能。这样,虽然有关于CXADR与癌的关联的报告,但是现状是CXADR是贡献于癌的发病、恶性化等,还是对癌发挥抑制作用尚未确定。因此,关于针对CXADR的抗体是否具有抗癌活性也尚不明。
CAR在肿瘤中的作用一直被认为是肿瘤抑制因素。一些人类的恶性肿瘤,包括膀胱癌、***癌及恶性神经胶质瘤中,CAR的表达水平随肿瘤恶性程度的发展而下调。对缺乏CAR表达的***和神经胶质肿瘤细胞系进行CAR转染可导致细胞增殖活性和肿瘤形成能力的下降。在神经胶质瘤的体内外研究中,CAR均起到了肿瘤抑制功能,这为CAR在恶性的神经胶质瘤中表达下调提供了合理的解释CAR表达在其他的肿瘤中也有相似的下调现象,包括卵巢癌,恶性黑色素细胞瘤、头颈部肿瘤,肌肉骨骼***肿瘤,不成熟的软骨母细胞瘤,人横纹肌肉瘤。目前抗体是证明对柯萨奇病毒腺病毒受体具有高亲和力的蛋白(详见专利:抗CXADR抗体,申请号201380024727.7)。
本发明公开了能高度亲和柯萨奇病毒腺病毒受体的多肽,这些多肽能高效结合柯萨奇病毒腺病毒受体,从而靶向高表达该受体的肿瘤细胞,最终达到标记肿瘤细胞的效果。这些多肽可制备成诊断癌症的药物。
发明内容
本发明的目的在于提供能够与柯萨奇病毒腺病毒受体相关的靶向多肽,使其能够对柯萨奇病毒腺病毒受体高表达的肿瘤进行在体诊断,可用于制备新型的靶向药物载体。
本发明的目的还在于提供包含或部分包含YQC-1、YQC-2序列多肽或蛋白的分子作用方式,其结合柯萨奇病毒腺病毒受体,诱导细胞粘附降低。
本发明的另一个目的在于提供一种含有YQC-1、YQC-2的抗体作为体内外检测柯萨奇病毒腺病毒受体的有效成分。
本发明所述的YQC-1、YQC-2肽是由腺病毒亲和基团结构优化得到,其具有天然氨基酸序列,免疫原性小,生物活性好。
为了检测本发明多肽的药理活性,体外实验通过荧光染料罗丹明B对多肽进行标记,体内实验通过近红外染料ICG-Der-02对多肽进行标记,以检测其对肿瘤的体内外靶向性。在体外细胞亲和力实验和摄取实验中,本发明的YQC-1、YQC-2肽展现出了其良好的对肿瘤细胞柯萨奇病毒腺病毒受体的靶向能力。在体外细胞毒性实验中,本发明的YQC-1、YQC-2肽未表现出对细胞的毒性。
详细发明内容如下:
一、标记体外实验荧光染料
本发明应用于体外细胞实验的荧光染料为罗丹明B(Rhodamine B),简称RhB,分别与本发明YQC-1、YQC-2肽通过酰胺键连接,简称分别为YQC-1-RhB与YQC-2-RhB,连接方法具体为取1mg罗丹明B(详见参考文献:Cao,J.,et al.,Fast clearing RGD-based near-infrared fluorescent probes for in vivo tumor diagnosis.Contrast Media MolImaging,2012.7(4):p.390-402)溶于1ml PBS(pH为7.4)中,加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,N-羟基琥珀酰亚胺(EDC/NHS)(摩尔比Rhodamine B∶EDC∶NHS=1∶1.5∶1.5),避光反应4h,活化。分别称取1mmol YQC-1、YQC-2肽溶入含有荧光染料罗丹明B的1ml PBS缓冲液(pH7.4)中,室温避光搅拌过夜。反应结束后,反应液浓缩后通过葡聚糖凝胶G-25柱,PBS缓冲液(pH7.4)作洗脱液,得到纯化的YQC-1-RhB及YQC-2-RhB,-20℃储存备用。
二、体外细胞亲和力实验
将培养好的人肝癌HepG2和人脑胶质瘤U87MG细胞从12孔板上洗脱后重悬于PBS溶液,分别与罗丹明B标记的YQC-1、YQC-2肽(10umol/L)共孵育2小时,并通过流式细胞术检测其平均荧光强度,荧光强度越强证明对细胞的亲和力越强。当探针与细胞上的受体亲和力强时,流式细胞仪检测出的细胞平均荧光强度值高。体外亲和力实验结果显示浓度相同的标记了RhB的YQC-1、YQC-2肽的探针分别与柯萨奇腺病毒受体高表达的HepG2细胞孵育后,在HepG2细胞中YQC-1肽探针平均荧光强度为68,YQC-2肽探针平均荧光强度为344,空白染料平均荧光强度为5,结果表明这些探针在与HepG2细胞亲和力强弱对比中,本发明YQC-2的强度最大。而对柯萨奇腺病毒受体低表达的U87细胞,YQC-1和YQC-2多肽探针平均荧光强度都很低。说明其特异性很强。
三、体外细胞摄取实验
将培养好的人肝癌细胞HepG2和人脑胶质瘤U87MG细胞转移到共聚焦皿中,过夜孵育后分别加入相同浓度的罗丹明B标记的YQC-1和YQC-2肽(40umol/L),37℃孵育4小时后,加入染核试剂12μg/mL Hochest33342染色,最后用激光共聚焦显微镜观察细胞内探针的摄取情况。在柯萨奇腺病毒受体高表达的HepG2和(图2A所示),YQC-1和YQC-2肽探针显示出了很强的荧光强度,而在柯萨奇腺病毒受体低表达的U87细胞(图2B所示),这两种探针的荧光强度不强,这一结果说明YQC-1和YQC-2肽探针对柯萨奇腺病毒受体高表达的细胞有靶向性而对柯萨奇腺病毒受体低表达的细胞靶向性不强。
四、体外细胞毒性实验
U87MG细胞、HepG2细胞与正常肝L02细胞,待长至90%以上时,用0.25%胰蛋白酶液消化后,制备成单细胞悬液(完全生长培养基),以3000个细胞/孔铺96孔板,于37℃,含5%CO2的培养箱中培养,在培养24h后换为1%FBS的低血清培养液,然后加入不同浓度梯度的YQC-1和YQC-2肽,使他们的终浓度为2.5,5,10,20,40,80和100μM。结果显示(图3所示)YQC-1和YQC-2肽对这几种细胞的存活率均在80%以上,说明YQC-1和YQC-2肽对这些细胞基本无毒。
五、活体肿瘤靶向实验
本发明应用于体内动物实验的荧光染料为近红外有机染料ICG-Der-02,分别与YQC-1、YQC-2通过酰胺键连接,简称ICG-Der-02-C1,ICG-Der-02-C2,连接具体方法为取2mgICG-Der-02(详见参考文献)溶于1ml PBS(pH为7.4)中,加入1-乙基-(3-二甲基氨基丙基)碳酰二业胺盐酸盐,N-羟基琥珀酰亚胺(EDC/NHS)(摩尔比ICG-Der-02∶EDC∶NHS=1∶1.5∶1.5),避光反应4h,活化。称取1mmolYQC-1、YQC-2肽溶于含有荧光染料ICG-Der-02的1mlPBS缓冲液(pH=7.4),室温避光搅拌过夜。反应结束后,反应液浓缩后通过葡聚糖凝胶G-25柱,PBS缓冲液(pH=7.4)作洗脱液,得到纯化的ICG-Der-02-C1,ICG-Der-02-C2,-20℃储存备用。在注射后0-24小时,通过近红外成像***在不同的时间点分别对裸鼠进行成像并且对比不同探针之间的不同。对肿瘤部位荧光信号强度的目标特定区域(ROI)分析,进行如下计算:肿瘤/正常组织比值=[肿瘤信号强度-背景信号强度]/[正常组织(肌肉)信号强度-背景信号强度],来定量不同探针在不同肿瘤中的靶向,该值越大说明其靶向性越强。
HepG2荷瘤裸鼠均被尾静脉注射ICG-Der-02标记的YQC-1、YQC-2。在注射后0-12h,通过近红外成像***在不同时间点分别对裸鼠进行成像检测。
HepG2肝癌细胞是柯萨奇腺病毒受体高表达细胞,如果一定的时间内探针在裸鼠体内肿瘤部位聚集且能持续一定的时间就说明这种探针能靶向到肿瘤细胞上。如图4所示,分别注射相同量的ICG-Der-02及ICG-Der-02标记的几种探针到HeGp2荷瘤裸鼠后,ICG-Der-02及ICG-Der-02-C1和ICG-Der-02-C2注射2h后荧光分布全身,然后逐渐转移到肾-膀胱代谢,肿瘤部位无明显荧光信号,探针ICG-Der-02-C1和C2注射4h后肿瘤部位荧光信号逐渐增强,随着探针在体内的代谢,探针在肿瘤部位聚集越来越多,其荧光强度在注射6h达到峰值,肿瘤边缘轮廓较清晰,24h后肿瘤部分荧光信号基本消失。用ROI值进一步定量分析探针在肿瘤部位聚集的荧光强度,注射ICG-Der-02-C1和ICG-Der-02-C2探针6h后肿瘤荧光强度与正常组织比值分别为15.23±0.53,8.41±0.24。T/N值越大靶向性越强,这一结果说明探针ICG-Der-02-C1和ICG-Der-02-C2都有较好的靶向性,且可以快速靶向到肿瘤部位,这一结果从动物水平上说明本发明的亲和肽能够靶向到柯萨奇腺病毒受体高表达的细胞。
综上所述,本发明的YQC-1、YQC-2肽能够靶向到柯萨奇腺病毒受体高表达的细胞上,而对柯萨奇腺病毒受体低表达的细胞基本无靶向性,并且YQC-1、YQC-2肽对细胞基本无毒性。由此可见YQC-1、YQC-2肽能够成为对柯萨奇腺病毒受体高表达肿瘤进行体外诊断。
本发明的YQC-1、YQC-2肽可以优选用实施例1和2固相合成的方法制备。
本发明的多肽是柯萨奇腺病毒受体亲和肽。尽管不希望受理论约束,发明人相信本发明多肽的亲和作用是基于其抑制柯萨奇腺病毒受体效应。
药物组合物:可以任何本文所述适应症,包括抑制脑胶质瘤细胞、乳腺癌细胞增殖的治疗有效量,任选地与药学上可接受的添加剂、载体或赋形剂组合,来制备基于YQC-1、YQC-2肽,或其药学上可接受的盐或前药,包括酯的药物组合物。治疗有效量可随着要治疗的感染或病况、其严重性、所应用的治疗方案、所用药剂的药动学性质以及受治疗的患者而改变。
本发明还包括药物制剂,该制剂包含作为活性成分的YQC-1、YQC-2肽或其酯或前药或药学上可接受的载体。上述药学上可接受的载体是指药学领域常规的药物载体,是指一种或几种惰性的、非毒性的固体或液体填充物、稀释剂,助剂等,它们不逆向与活性化合物或病人发生作用。
本发明组合物的剂型可以是片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂、注射液等药剂学上常用的剂型。口服用药片和胶囊含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂。
本发明药物组合物的各种剂型可以按照药学领域中熟知的方法进行制备。
以上活性剂的剂量将因配方而异。
有益效果:
1.发明了一系列新的对柯萨奇病毒腺病毒受体具有高亲和力的多肽,扩大了与柯萨奇病毒腺病毒受体结合分子的种类。
2.这些多肽均为低分子量多肽,合成成本低廉。
3.这些肽均为首次报道,获取渠道方便。
4.本品用ICG-Der-02花菁类近红外荧光染料,其侧链上有一个羧基官能团,适用作生物荧光标记。通过EDC/NHS催化体系可以有效地将将其活化,与多肽分子链末端的氨基共价偶联形成酰胺键,构建ICG-Der-02-peptide分子探针,从而可使多肽带有明显的近红外荧光特性。
5.这些多肽对柯萨奇病毒腺病毒受体特异结合的性质将有可能实现特定恶性肿瘤的近红外成像,从而达到实时无损在位监测早期恶性肿瘤的目的。柯萨奇病毒腺病毒受体在乳腺癌、肝癌、胶质母细胞瘤、***癌、膀胱癌、骨肉瘤等多种实体肿瘤细胞表面有高水平表达,本文选用了HepG2肝癌细胞与多肽连接有较好的靶向,给药后肿瘤部位即有明显的荧光信号。
附图简要说明:
图1流式细胞仪检测细胞亲和力实验观察罗丹明B标记的探针对不同肿瘤细胞的亲和力(AD为HepG2细胞,BE为U87MG细胞)
图2激光共聚焦细胞摄取实验观察罗丹明B标记的探针对不同肿瘤细胞的摄取(A为HepG2细胞,B为U87MG细胞)
图3体外细胞毒性实验考察YQC-1、YQC-2肽对不同细胞的毒性
图4小动物活体成像技术考察多肽在体内的靶向能力实验
具体实施方式
下面结合实施例对本发明作进一步说明。需要说明的是,下述实施例仅是用于说明,而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
本发明多肽YQC-1的合成过程
1:偶联
先将Fmoc-Arg-Rink amide MBHA resin(芴甲氧羰酰基-精氨酸-rink氨基树脂)0.33/2mmol 6.06g溶胀于二甲基甲酰胺中,10ml/g树脂,接着用20%六氢吡啶/二甲基甲酰胺溶液脱去Fmoc保护基(以下称之为脱帽),用二甲基甲酰胺洗涤脱帽子后的树脂,加入原料Fmoc-Lys(Boc)-OH 2.3g,缩合剂用HBTU 1.44g,反应时间30分钟,kaiser法检测,如检测结果为阴性,说明偶联反应完成,则接下去进行脱帽,时间30分钟,如检测结果仍为阳性,则说明偶联反应未完成或反应不完全,需要延长偶联时间或重新投料偶联,直至偶联反应完成。重复上述操作,依次偶联;Fmoc-Ala-OH;Fmoc-Asp(OtBU)-OH;Fmoc-Leu-OH;Fmoc-Glu(OtBU)-OH;Fmoc-Gln(Trt)-OH;Fmoc-Ile-OH;Fmoc-Leu-OH;Fmoc-Ser(tBU)-OH;Fmoc-Cys(Trt)-OH;Fmoc-Asn(Trt)-OH;Fmoc-Pro-OH;Fmoc-Pro-OH;Fmoc-Pro-OH;Fmoc-Asp(OtBU)-OH,完成所有直链肽合成后,用甲醇洗涤所得到的peptidyl resin,真空干燥箱里充分干燥。
2:树脂与肽的分离裂解
将120ml裂解液(10ml/g peptidyl resin)加入树脂中,25℃条件下,磁力搅拌2.5h后用砂芯漏斗将裂解液与树脂分离,弃去树脂,保留滤液。将滤液缓慢滴加到10eq体积的冰无水***中,滴加完毕后,自然沉降30min。然后用高速离心机离心10min(4000rpm),弃去上清液,保留沉淀,将所得沉淀在干燥箱中干燥8-10h,得到干粉粗品。
3:纯化
取上述干粉粗品1g,用0.1%三氟乙酸/水溶解。经过滤后,上样到C18制备柱,用高效液相进行梯度洗脱,收集目标肽的洗脱液体,检测液体纯度。把合格的样品混合后旋蒸,最后用冻干机冻干,得到Asp-Pro-Pro-Pro-Asn-Cys-Ser-Leu-Ile-Gln-Glu-Leu-Asp-Ala-Lys-Arg,纯度大于98%。
序列为:Asp-Pro-Pro-Pro-Asn-Cys-Ser-Leu-Ile-Gln-Glu-Leu-Asp-Ala-Lys-Arg
质谱图中可以看出Asp-Pro-Pro-Pro-Asn-Cys-Ser-Leu-Ile-Gln-Glu-Leu-Asp-Ala-Lys-Arg分子量是599.35*3-3=1795.05
紫外光谱图中273nm处有肽的吸收峰。
实施例2
本发明多肽YQC-2的合成过程
1:偶联
先将Fmoc-Lys-Rink amide MBHA resin(芴甲氧羰酰基-赖氨酸-rink氨基树脂)0.33/2mmol 6.06g溶胀于二甲基甲酰胺中,10ml/g树脂,接着用20%六氢吡啶/二甲基甲酰胺溶液脱去Fmoc保护基(以下称之为脱帽),用二甲基甲酰胺洗涤脱帽子后的树脂,加入原料Fmoc-Cys(Trt)-OH 2.3g,缩合剂用HBTU 1.44g,反应时间30分钟,kaiser法检测,如检测结果为阴性,说明偶联反应完成,则接下去进行脱帽,时间30分钟,如检测结果仍为阳性,则说明偶联反应未完成或反应不完全,需要延长偶联时间或重新投料偶联,直至偶联反应完成。重复上述操作,依次偶联;Fmoc-Asp(OtBU)-OH;Fmoc-Asn(Trt)-OH;Fmoc-Asp(OtBU)-OH;Fmoc-Ser(tBU)-OH;Fmoc-His(Trt)-OH;Fmoc-Ile-OH;Fmoc-Arg(Pbf)-OH;Fmoc-Cys(Trt)-OH;Fmoc-Asn(Trt)-OH;Fmoc-Pro-OH;Fmoc-Ser(tBU)-OH;Fmoc-Pro-OH;Fmoc-Asp(OtBU)-OH;Fmoc-Pro-OH,完成所有直链肽合成后,用甲醇洗涤所得到的peptidyl resin,真空干燥箱里充分干燥。
2:树脂与肽的分离裂解
将120ml裂解液(10ml/g peptidyl resin)加入树脂中,25℃条件下,磁力搅拌2.5h后用砂芯漏斗将裂解液与树脂分离,弃去树脂,保留滤液。将滤液缓慢滴加到10eq体积的冰无水***中,滴加完毕后,自然沉降30min。然后用高速离心机离心10min(4000rpm),弃去上清液,保留沉淀,将所得沉淀在干燥箱中干燥8-10h,得到干粉粗品。
3:纯化
取上述干粉粗品1g,用0.1%三氟乙酸/水溶解。经过滤后,上样到C18制备柱,用高效液相进行梯度洗脱,收集目标肽的洗脱液体,检测液体纯度。把合格的样品混合后旋蒸,最后用冻干机冻干,得到Pro-Asp-Pro-Ser-Pro-Asn-Cys-Arg-Ile-His-Ser-Asp-Asn-Asp-Cys-Lys,纯度大于98%。
序列为:Pro-Asp-Pro-Ser-Pro-Asn-Cys-Arg-Ile-His-Ser-Asp-Asn-Asp-Cys-Lys
质谱图中可以看出Pro-Asp-Pro-Ser-Pro-Asn-Cys-Arg-Ile-His-Ser-Asp-Asn-Asp-Cys-Lys分子量是599.98*3-3=1796.94
紫外光谱图中273nm处有肽的吸收峰。
Claims (3)
1.对柯萨奇病毒腺病毒受体具有高亲和力的第一条多肽YQC-1,其特征在于,该序列为SEQ ID NO:1;
所述多肽YQC-1是由腺病毒亲和基团结构优化得到。
2.对柯萨奇病毒腺病毒受体具有高亲和力的第二条多肽YQC-2,其特征在于,该序列为SEQ ID NO:2;
所述多肽YQC-2是由腺病毒亲和基团结构优化得到。
3.用于检查与柯萨奇病毒腺病毒受体蛋白相关的疾病的药剂,其特征在于,以权利要求1-2所述的多肽为有效成分。
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