CN111018951A - 一种靶向三阴性乳腺癌细胞的多肽及其应用 - Google Patents
一种靶向三阴性乳腺癌细胞的多肽及其应用 Download PDFInfo
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- CN111018951A CN111018951A CN201911282699.4A CN201911282699A CN111018951A CN 111018951 A CN111018951 A CN 111018951A CN 201911282699 A CN201911282699 A CN 201911282699A CN 111018951 A CN111018951 A CN 111018951A
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Abstract
本发明公开了一种能够特异性靶向三阴性乳腺癌细胞的多肽以及该多肽的应用。该多肽具有如SEQ ID No.1~SEQ ID No.5任一项所示的氨基酸序列。本发明实施例所提供的多肽与三阴性乳腺癌细胞具有高特异性和亲和力,而与其它类型的乳腺癌细胞的结合能力较为微弱,展现出了对三阴性乳腺癌细胞的高特异性选择,可以以此用于三阴乳腺癌的靶向治疗或成像诊断。
Description
技术领域
本发明涉及药物化学领域,尤其是涉及一种靶向三阴性乳腺癌细胞的多肽及其应用。
背景技术
乳腺癌是世界上发病率排第二的癌症,也是女性中发病率最高的癌症类型。我国乳腺癌发病率自上世纪90年代起显著增加,且发病年龄低于欧美国家,发病率城市高于农村。据我国肿瘤登记点数据显示,我国女性乳腺癌发病率从2003年的37.1/10万人增长至2013年46.6/10万人。到2021年,这一数字预计将超过100/10万人,全国乳腺癌患者总人数预计将达到250万人。与此同时,乳腺癌死亡率也由上世纪70年代的2.95/10万人上升至2013年的11.3/10万人。按照不同的分子分型,乳腺癌可被划分为:雌激素/孕激素阳性型(ER/PR+)、HER2高表达型(HER2+)和三阴(性)型。三阴性乳腺癌是一种高侵袭性、高异质性的乳腺癌亚型,其免疫组化表现为雌激素受体、孕激素受体、人表皮生长因子受体2表达阴性。虽然三阴性乳腺癌发病率只占女性乳腺癌总发病率的12-20%,但其发病年龄小、侵袭性高、预后极差、存活率低。晚期患者5年生存率不足15%。对于ER/PR+型乳腺癌,目前可采用内分泌法进行治疗;对于HER2+型,目前可采用HER2单抗药物或HER2抑制剂进行治疗,如帕妥珠单抗、曲妥珠单抗、拉帕替尼、阿法替尼等。但对于三阴性乳腺癌,缺乏针对性的临床治疗方法。传统内分泌治疗及HER-2靶向治疗对三阴性乳腺癌效果不佳。全身化疗仍然是目前的主要治疗手段。但是针对三阴性乳腺癌的全身化疗效果不如其他类型的乳腺癌,而且全身化疗药物通常具有较强的毒副作用,对人体各脏器损伤较大。目前对三阴性乳腺癌细胞的研究还不完全,缺乏特异性靶点,这严重阻碍了针对三阴性乳腺癌细胞的靶向药物的研发。
噬菌体展示技术是一种能够将所需性质的多肽从大量变异体的集落中提取出来的体外筛选技术。自从Smith首次提出该方法以来,噬菌体展示技术已经发展成为一种发现新特性及改变已有多肽性质的强大工具。噬菌体展示技术在发现靶标分子对应的新的结合多肽上极为有效。其基本原理是:首先,将随机序列的核苷酸序列插入噬菌体衣壳蛋白基因中,从而使噬菌体可以展示该核苷酸所编码的多肽。接着,通过该噬菌体库,对靶标分子进行筛选,使能够与该靶标分子进行特异性结合的噬菌体进行富集,从而得到对应的特异性结合多肽。噬菌体展示技术在为各种类型的靶标分子筛选特异性结合物的过程中,显示出了非常强大的应用潜力和重要作用。基于此,有必要寻找能够特异性靶向三阴性乳腺癌细胞的多肽。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此,本发明提出一种能够特异性靶向三阴性乳腺癌细胞的多肽以及该多肽的应用。
本发明所采取的技术方案是:
本发明的第一方面,提供一种多肽,该多肽具有如下SEQ ID No.1~SEQ ID No.5任一项所示的氨基酸序列;
其中,SEQ ID No.1所示氨基酸序列为AAHRVGGFNYHM;
SEQ ID No.2所示氨基酸序列为SSHYHSRSPTNP;
SEQ ID No.3所示氨基酸序列为GSAAGTISPSLL;
SEQ ID No.4所示氨基酸序列为HSLSSPQRVGHT;
SEQ ID No.5所示氨基酸序列为SMPQLYPLSPWQ。
本发明实施例的有益效果是:
本发明实施例所提供的多肽与三阴性乳腺癌细胞具有高特异性和亲和力,与其它类型的乳腺癌细胞的结合能力较为微弱,展现出了对三阴性乳腺癌细胞的高特异性选择,可以以此用于三阴性乳腺癌的靶向治疗或成像诊断。
本发明的第二方面,提供一种偶联物,该偶联物包括上述的多肽和偶联部分。该偶联物可以与三阴性乳腺癌细胞特异性结合,呈现出较高的特异性选择性,可以以此用于三阴性乳腺癌的靶向治疗或成像诊断。
根据本发明的实施例,偶联部分选自成像剂、治疗剂中的至少一种。
根据本发明的实施例,成像剂为各类影像学技术的造影剂中的至少一种,诸如计算机断层扫描(CT)、核磁共振(MRI)、超声、放射性核素扫描、正电子发射断层扫描(PET)等影像学技术的造影剂。
根据本发明的实施例,成像剂为光学标记中的至少一种,诸如荧光标记物、化学发光标记物、生物发光标记物等。
根据本发明的实施例,成像剂选自放射性核素、放射性核素标记物、分子影像剂、荧光素、量子点。
根据本发明的实施例,治疗剂选自化学药物、生物药物、光动力药物、光热治疗药物等。
根据本发明的实施例,治疗剂可以是细胞毒素、细胞因子、抗体、酶、凝集素、光敏剂、有机光热治疗分子等。
本发明的第三方面,提供一种核酸分子,该核酸分子编码前述的多肽或偶联物。
本发明的第四方面,提供一种重组载体,该重组载体包括前述的核酸分子。该重组质粒用于三阴性乳腺癌的靶向治疗或成像诊断。
根据本发明的实施例,该重组载体可以是重组质粒或噬菌体。
根据本发明的实施例,该重组载体为重组质粒,该重组质粒在质粒载体的多克隆位点插入上述核酸分子。
根据本发明的实施例,该重组载体为重组噬菌体。
根据本发明的实施例,该重组噬菌体在其DNA或RNA链上插入前述的核酸分子,随外壳蛋白的表达而表达,从而高效表达前述的多肽或偶联物。
根据本发明的实施例,该重组噬菌体为包含前述核酸分子的M13噬菌体。
本发明的第五方面,提供一种重组细胞,该重组细胞包括前述的核酸分子。
根据本发明的实施例,该重组细胞通过在宿主细胞内转导或转染前述核酸分子得到。
根据本发明的实施例,宿主细胞为革兰氏阴性菌;更具体地,可以是大肠杆菌。
本发明的第六方面,提供一种组合物,该组合物包括前述的多肽、偶联物、核酸分子、重组载体、重组细胞中的任一种。该组合物具体可以是用于三阴性乳腺癌的诊断组合物或治疗组合物。
根据本发明的实施例,组合物为药物组合物,该药物组合物还包括药物递送载体。
根据本发明的实施例,药物递送载体为纳米级载体系统、微米级载体系统中的任一种。
根据本发明的实施例,药物递送载体选自脂质体、聚合物胶束、树枝状化合物、无机纳米颗粒。
本发明的第七方面,提供一种试剂盒,该试剂盒包括前述的多肽、偶联物中的任一种。该多肽或偶联物具有对三阴性乳腺癌细胞的靶向特异性,以此制备的试剂盒能够用于特异性识别、标记三阴性乳腺癌细胞或用于三阴性乳腺癌的诊断、治疗。
本发明的第八方面,提供前述的多肽、偶联物、核酸分子、重组载体、重组细胞、组合物在制备用于诊断、预防、治疗三阴性乳腺癌的试剂中的用途。
附图说明
图1是本发明的一个实施例中40个随机选取的噬菌体单菌落与三阴性乳腺癌细胞MDA-MB-231的酶联免疫反应结果。
图2是本发明的又一实施例的多肽与三阴性乳腺癌细胞的亲和力荧光分析结果,其中,2~7分别表示量子点(csc+qd)、量子点标记的多肽1(csc+c1+qd)、量子点标记的多肽2(csc+c2+qd)、量子点标记的多肽3(csc+c3+qd)、量子点标记的多肽4(csc+c4+qd)、量子点标记的多肽5(csc+c5+qd)与三阴性乳腺癌细胞MDA-MB-231结合后的荧光结果,1为对照组三阴性乳腺癌细胞MDA-MB-231的荧光结果。
图3是本发明的又一实施例的多肽5与三阴性乳腺癌细胞MDA-MB-231膜蛋白的SPR结果。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
实施例1
多肽的筛选合成
采用Negative-/Positive+的方法利用噬菌体肽库对细胞进行筛选。其中,负筛细胞选用包括MDA-MB-453、MCF-7等在内的多种不同分型的乳腺癌细胞,用以排除能与这些负筛细胞相结合的多肽;正筛细胞选用三阴性乳腺癌细胞MDA-MB-231,用以选取能与其特异性结合的多肽。筛选过程共三轮。筛选步骤如下:
1)MCF-7、MDA-MB-453、SK-BR3、BT-474、T47D作为负筛细胞,三阴性乳腺癌细胞MDA-MB-231作为正筛细胞分别培养在含有10%FBS的RPMI-1640培养基中。
2)负筛细胞用0.5%BSA的封闭液封闭1h后,将噬菌体随机十二肽库(Ph.D.-12噬菌体展示肽库试剂盒,New England Bio-LABS,美国)以1×1011PFU的滴度加入其中,37℃孵育1h(负筛);
3)3000rpm离心3min,收集上清,转移至经封闭处理的正筛细胞中,37℃孵育1h(正筛);
4)孵育完成后,3000rpm离心3min,取沉淀;
5)用TBST溶液清洗3次后,3000rpm离心3min,取沉淀;
6)加入1mL洗脱液,12000rpm离心,将上清转移到新的离心管中,加入150μL中和液,此即第一轮淘选得到的噬菌体;
7)将淘选得到的噬菌体在E.coli ER2378宿主菌进行扩增并滴定计数;
8)扩增后的噬菌体取1×1011PFU,重复步骤1)~7)两次。
9)3轮负筛正筛后的噬菌体经E.coli ER2378宿主菌扩增涂板,随机挑选40个独立的噬菌体菌斑,利用E.coli ER2378宿主菌扩增后,以三阴性乳腺癌细胞MDA-MB-231为底物进行酶联免疫反应测试亲和力。
10)选择其中亲和力最高的一系列噬菌体,提取噬菌体DNA,测序。
11)根据测得的DNA序列,分析靶向多肽的氨基酸序列。利用固相多肽合成技术合成对应的多肽。
12)以三阴性乳腺癌细胞MDA-MB-231为底物,再次利用酶联免疫反应验证合成的多肽与底物的亲和力,得到具有如SEQ ID No.1~SEQ ID No.5所示氨基酸序列的多肽。
其中,步骤9)通过酶联免疫反应测试三轮筛选得到的噬菌体对三阴性乳腺癌细胞MDA-MB-231的亲和力的具体步骤如下:
a.在96孔板中接种三阴性乳腺癌细胞MDA-MB-231,待细胞生长至适宜密度,对细胞进行固定,每孔加入100μL 4%多聚甲醛溶液,室温固定15min,再用PBS溶液洗板三次;
b.每孔加入200μL 1%BSA-PBS-T封闭液,于37℃封闭2h。封闭完成后用PBS溶液洗板三次;
c.每孔加入封闭液稀释的噬菌体,于室温孵育90min,孵育完成后用PBST溶液洗板三次,再用PBS溶液洗板三次;
d.加入100μL封闭液稀释的辣根过氧化氢酶标记的鼠M13噬菌体抗体,于室温孵育90min,孵育完成后用PBS溶液洗板三次;
e.每孔加入100μL ELISA显色液,于暗处显色15min后,用2mol/L的硫酸终止反应,PBS溶液洗板三次;
f.用酶标仪在492nm波长下读取溶液吸光度数值。
图1是本发明的一个实施例中40个随机选取的噬菌体单菌落与三阴性乳腺癌细胞MDA-MB-231的酶联免疫反应结果。对照组(Ctrl)为第一轮洗脱得到的未结合噬菌体。从图中可以看出,部分噬菌体与对照组相比具有更强的亲和力,从中选出亲和力最高的一系列噬菌体进行步骤10)。
实施例2
亲和力和结合强度实验
本实施例利用流式细胞仪及表面等离子共振技术(SPR)分析实施例1中筛选得到的5条多肽(SEQ ID No.1~SEQ ID No.5的多肽分别以多肽1~5进行表示)与三阴性乳腺癌细胞MDA-MB-231的亲和力及结合常数,具体步骤如下:
a.五条多肽分别用量子点标记后,与三阴性乳腺癌细胞MDA-MB-231共同孵育,利用流式细胞仪分析荧光强度,以判断五条多肽与三阴性乳腺癌细胞的亲和力强弱。
b.提取三阴性乳腺癌细胞MDA-MB-231膜蛋白。
c.利用EDC/NHS将三阴性乳腺癌细胞MDA-MB-231膜蛋白偶联至SPR芯片上。
d.将靶向多肽配制成不同浓度,并依次流过SPR芯片表面,并分析结合常数。
图2是本发明的又一实施例的多肽与三阴性乳腺癌细胞的亲和力荧光分析结果,其中,2~7分别表示量子点(csc+qd)、量子点标记的多肽1(csc+c1+qd)、量子点标记的多肽2(csc+c2+qd)、量子点标记的多肽3(csc+c3+qd)、量子点标记的多肽4(csc+c4+qd)、量子点标记的多肽5(csc+c5+qd)与三阴性乳腺癌细胞MDA-MB-231结合后的荧光结果,1为对照组三阴性乳腺癌细胞MDA-MB-231的荧光结果。从图中可以看出,多肽1~5均能有效与三阴性乳腺癌细胞MDA-MB-231结合,具有较好的靶向特异性。其中,多肽5与三阴性乳腺癌细胞MDA-MB-231的结合强度最高。
图3是本发明的又一实施例的多肽5与三阴性乳腺癌细胞MDA-MB-231膜蛋白的SPR结果。多肽5与三阴性乳腺癌细胞MDA-MB-231的结合强度为10-8M数量级,表明该多肽与三阴性乳腺癌细胞的结合强度极高,具有极好的亲和力。
实施例3
靶向三阴性乳腺癌细胞的荧光探针
一种特异性靶向三阴性乳腺癌细胞的荧光探针,包括实施例1中氨基酸序列如SEQID No.5所示的多肽以及偶联在该肽链上的荧光基团FITC。
对该荧光探针的靶向特异性进行检测,具体步骤如下:
1)合成连接FITC荧光基团的多肽;
2)于24孔板中分别接种三阴性乳腺癌细胞MDA-MB-231和作为对照组的SK-BR3细胞,待细胞生长至适宜密度;
3)吸去培养基,用PBS洗涤三次,每次3min,每孔加入500μL 4%的多聚甲醛溶液,室温固定20min,吸去固定液,用PBS溶液清洗三次,每次3min;
4)多肽按1:500稀释,添加到相应的孔板内,37℃孵育1h,PBS清洗三次,每次5min;
5)每孔加入100μL的DAPI染液,室温孵育15min,吸走DAPI,PBS清洗3次,每次5min;
6)用镊子从24孔板中夹起盖玻片,在载玻片上滴加10μL抗荧光淬灭封片剂,将铺有细胞的盖玻片倒扣在载玻片上,自然风干后于共聚焦显微镜观察荧光强度、拍照。
结果显示,对照组SK-BR3细胞除DAPI的蓝色荧光外,未见有其他荧光,表示连有荧光基团FITC的多肽没有结合到SK-BR3细胞上;而实验组三阴性乳腺癌细胞MDA-MB-231可以观察到有明亮的绿色荧光,表示连有荧光基团FITC的多肽结合到了三阴性乳腺癌细胞MDA-MB-231上。该结果表明本实施例所提供的荧光探针可以与三阴性乳腺癌细胞发生特异性结合。
实施例4
提供一种靶向三阴性乳腺癌细胞的治疗药物组合物。该药物组合物包括PEG-PLGA高分子纳米颗粒药物载体,负载在该药物载体上的化疗药物紫杉醇,以及与该载体共价偶联的多肽,该多肽具有如SEQ ID No.1~SEQ ID No.5任一项所示的氨基酸序列。本实施例所提供的药物组合物可以特异性靶向三阴性乳腺癌细胞,患者施用后,能够有效杀伤三阴性乳腺癌细胞,从而对三阴性乳腺癌起到高效的治疗作用。
通过以上实施例可见,本发明提供的多肽具有靶向三阴性乳腺癌细胞的特性,因而在实际应用中,可以将本发明的多肽作为靶向多肽,与能杀伤癌细胞的制剂结合,用于肿瘤的靶向治疗;或与影像学诊断试剂结合,用于靶向肿瘤的分子成像与诊断。
上面结合附图对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所述技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。
SEQUENCE LISTING
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Claims (10)
1.一种多肽,其特征在于,具有如SEQ ID No.1~SEQ ID No.5任一项所示的氨基酸序列;
其中,SEQ ID No.1所示氨基酸序列为AAHRVGGFNYHM;
SEQ ID No.2所示氨基酸序列为SSHYHSRSPTNP;
SEQ ID No.3所示氨基酸序列为GSAAGTISPSLL;
SEQ ID No.4所示氨基酸序列为HSLSSPQRVGHT;
SEQ ID No.5所示氨基酸序列为SMPQLYPLSPWQ。
2.一种偶联物,其特征在于,包括权利要求1所述的多肽和偶联部分。
3.根据权利要求2所述的偶联物,其特征在于,所述偶联部分选自成像剂、治疗剂。
4.一种核酸分子,其特征在于,编码权利要求1所述的多肽,或编码权利要求2至3任一项所述的偶联物。
5.一种重组载体,其特征在于,包括权利要求4所述的核酸分子。
6.一种重组细胞,其特征在于,包括权利要求4所述的核酸分子。
7.一种组合物,其特征在于,包括权利要求1所述的多肽,或包括权利要求2至3任一项所述的偶联物,或包括权利要求4所述的核酸分子,或包括权利要求5所述的重组载体,或包括权利要求6所述的重组细胞。
8.根据权利要求7所述的组合物,其特征在于,所述组合物还包括药物递送载体。
9.一种试剂盒,其特征在于,包括权利要求1所述的多肽,或包括权利要求2至3任一项所述的偶联物。
10.权利要求1所述的多肽,或权利要求2至3任一项所述的偶联物,或权利要求4所述的核酸分子,或权利要求5所述的重组载体,或权利要求6所述的重组细胞,或权利要求7至8任一项所述的组合物在制备用于诊断、预防、治疗三阴性乳腺癌的试剂中的用途。
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