CN105255862B - 一种用于制备抑制肿瘤生长药物的寡聚核酸及其应用 - Google Patents

一种用于制备抑制肿瘤生长药物的寡聚核酸及其应用 Download PDF

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CN105255862B
CN105255862B CN201410844012.2A CN201410844012A CN105255862B CN 105255862 B CN105255862 B CN 105255862B CN 201410844012 A CN201410844012 A CN 201410844012A CN 105255862 B CN105255862 B CN 105255862B
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王雪根
叶青
孙益军
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Jiangsu Kaiji biological technology Limited by Share Ltd
Nanjing New Industrial Investment Group Co., Ltd.
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NANJING NMG-ADDS Co Ltd
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Abstract

本发明提供了一种用于制备抑制肿瘤生长药物的寡聚核酸及其应用，该寡聚核酸分为三类，核心序列分别为RGGGAHTTYCS、TTYSGGAAWT和TTTCSCGCS，其中，R为G或A；H为A或C或T；Y为C或T；S为C或G；W为A或T。上述寡聚核酸还包括其反义链和修饰型。经本发明的寡聚核酸对体内外肿瘤生长有抑制作用，有望用于制备抑制肿瘤生长的药物，专一性高，抑制率高。

Description

一种用于制备抑制肿瘤生长药物的寡聚核酸及其应用
技术领域
本发明属于生物医药领域，具体涉及一种用于制备抑制肿瘤生长药物的寡聚核酸及其应用。
背景技术
寡聚核酸可分为反义核酸、小干扰RNA、适配体、微小RNA、DECOY核酸等，按作用靶点与机制的不同，发挥其各自生物学功能。作为治疗药物的寡聚核酸已在美国获批上市，同时进行临床研究的也有数十个品种，随着生物技术、药物筛选与制备等技术的进步，越来越多的有特定功能的寡聚核酸被发现，并被开发和应用于治疗、预防和诊断各种疾病。
发明内容
发明目的：本发明的目的在于提供一种用于制备抑制肿瘤生长药物的寡聚核酸及其应用，通过对系列寡聚核酸Oligo dsDNA的筛选和抑癌活性评价试验，发现了序列1～序列10的寡聚核酸对体内外肿瘤生长有抑制作用。
技术方案：为实现上述技术目的，本发明提供一种用于制备抑制肿瘤生长药物的寡聚核酸，其特征在于，所述寡聚核酸为下述序列1～10中的任意一种：
序列1：5`-CTTGAGGGGAATTTCCCAG-3`
序列2：5`-GAGAGGGGACTTTCCGAGAG-3’
序列3：5`-CCTTGAAGGGATTTCCCTCC-3`
序列4：5’-GCCATTTCCGGGAATTGCTA-3’
序列5：5’-AGTTCTGGGAATTCC-3’
序列6：5’-AGTCATTTCCGGGAAATGACT-3’
序列7：5’-TGACTATTTCCCGCGACTT-3’
序列8：5’-TTGACTATTTCCCGCCACTT-3’
序列9：5’-ATCTATTTCGCGCCCTTATG-3’
序列10：5’-TTAAGTTTCGCGCCCTTTCTC-3’。
所述的寡聚核酸还可以为上述序列1～10的反义链。
作为另一种实施方案，所述的寡聚核酸为上述的寡聚核酸的修饰型。
具体地，所述的修饰型为特别位点硫代化修饰；或两端各3个核苷酸硫代化修饰；或全硫代修饰。
优选地，对应各个序列的修饰的位点如下：
序列1(正)：5’-CTTGAGGGGAATTTCCCAG-3’
序列2(正)：5’-GAGAGGGGACTTTCCGAGAG-3’
序列3(正)：5’-CCTTGAAGGGATTTCCCTCC-3’
序列4(正)：5’-GCCATTTCCGGGAATTGCTA-3’
序列5(正)：5’-AGTTCTGGGAATTCC-3’
序列6(正)：5’-AGTCATTTCCGGGAAATGACT-3’
序列7(正)：5’-TGACTATTTCCCGCGACTT-3’
序列8(正)：5’-TTGACTATTTCCCGCCACTT-3’
序列9(正)：5’-ATCTATTTCGCGCCCTTATG-3’
序列10(正)：5’-TTAAGTTTCGCGCCCTTTCTC-3’
其中，正表示即仅列出正义链，反义链略。
本发明同时提出了上述寡聚核酸在制备用于抑制肿瘤生长的药物中的应用。
具体地，包括如下步骤：将所述的寡聚核酸经HPLC纯化，灭菌水配制成浓度1～2mg/mL后，将该寡聚核素与其反义链进行等摩尔数混合、水浴加温至80～85℃10～15分钟，自然冷却至室温，退火结合成双链用于制备抑制肿瘤生长的药物。
其中，所述的肿瘤为肺癌、乳腺癌和胰腺癌中的任意一种。
有益效果：本发明提供的寡聚核酸对体内外肿瘤生长有抑制作用，有望用于制备抑制肿瘤生长的药物，专一性高，抑制率高。
附图说明
图1为序列5(KT17)对人乳腺癌细胞MDA-MB-231裸鼠异种移植肿瘤生长体积变化的示意图；
图2为序列5(KT17)对人乳腺癌细胞MDA-MB-231裸鼠异种移植肿瘤生长的抑制作用的示意图；
图3为为序列5(KT17)对人乳腺癌细胞MDA-MB-231裸鼠异种移植肿瘤生长体积变化的照片；
图4为核酸序列8(KT59)对人胰腺癌细胞CFPAC-1裸鼠异种移植肿瘤生长体积变化的示意图；
图5为核酸序列1(KT32)对人肺癌细胞NCI-H1975裸鼠异种移植肿瘤生长的抑制作用的示意图。
具体实施方式
本发明提供的寡聚核酸主要分三类，共计10个序列，具体如下：
第一类：主要由核心序列RGGGAHTTYCS所组成的Oligo dsDNA包括：
序列1(正)：5’-CTTGAGGGGAATTTCCCAG-3’
序列2(正)：5’-GAGAGGGGACTTTCCGAGAG-3’
序列3(正)：5’-CCTTGAAGGGATTTCCCTCC-3’
第二类：主要由核心序列TTYSGGAAWT所组成的Oligo dsDNA，包括：
序列4(正)：5’-GCCATTTCCGGGAATTGCTA-3’
序列5(正)：5’-AGTTCTGGGAATTCC-3’
序列6(正)：5’-AGTCATTTCCGGGAAATGACT-3’
第三类：主要由核心序列TTTCSCGCS所组成的Oligo dsDNA，包括：
序列7(正)：5’-TGACTATTTCCCGCGACTT-3’
序列8(正)：5’-TTGACTATTTCCCGCCACTT-3’
序列9(正)：5’-ATCTATTTCGCGCCCTTATG-3’
序列10(正)：5’-TTAAGTTTCGCGCCCTTTCTC-3’
其中，正即仅列出正义链，反义链略；修饰类型中，一类为部位位点硫代化修饰，下划线处为修饰位点，另一类为两端各3个核苷酸硫代化修饰或全硫代修饰，R＝G/A；H＝A/C/T；Y＝C/T；S＝C/G；W＝A/T。
下面通过具体的实施例说明上述寡聚核酸对肿瘤的抑制作用。
实施例1 寡聚核酸体外对肿瘤细胞生长的抑制作用。
合成的序列1～序列10及其反义链的寡聚核酸，同时经过不同的结构修饰，包括三种，特定位点的硫代(如上所述)、两端3个碱基硫代和全硫代三组，经HPLC纯化，纯度90％以上，灭菌水配制成浓度1mg/mL后，正反义链等摩尔数混合、水浴加温至85℃10分钟，自然冷却至室温，退火结合成双链备用。
体外按常规方法分别培养乳腺癌细胞株MDA-MB-231、肺癌细胞株NCI-H1975、胰腺癌细胞株CFPAC-1，待细胞生长到105-106个/mL时，细胞消化收集、计数、配制成浓度为3～5×104个/mL的细胞悬液，于96孔细胞培养板中每孔加入100μL细胞悬液(每孔3～5×103个细胞)；将96孔细胞培养板置于37℃，5％CO2培养箱中培养24小时；用完全培养基稀释各组寡聚核酸至所需浓度，每孔加入100μL相应的含寡聚核酸的培养基，同时设立阴性对照组和阳性对照组，其中，阴性对照组为生理盐水，阳性对照组为紫杉醇，转染方法参照Lipofectimine的产品说明书；96孔细胞培养板置于37℃，5％CO2培养箱中培养72小时；每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4小时；弃去培养基，每孔加入150μL DMSO溶解，摇床10分钟轻轻地混匀；酶标仪λ＝490nm读取每孔的OD值，计算抑制率。
各组抑制率的计算方法：
体外筛选结果表明，序列1～10的三类修饰组均对肿瘤细胞生长有一定的抑制作用，其中序列1～10的特定位点硫代代修饰组(硫代位点见序列表有下划线处)在体外对不同肿瘤细胞有较好的生长抑制作用。其试验结果如表1所示：
表1
部份复筛实验结果如表2和表3所示：
表2
表3
实施例2 寡聚核酸在动物体对人异植肿瘤生长的抑制作用。
将序列1、序列5、序列8的核酸样品(特定位点修饰组)分别配制成阳离子脂质体制剂，对照药物选用紫杉醇(阳性对照组)，生理盐水对照组(阴性对照组)、、低、中、高剂量组共5组。受试动物为12～15g，4～5周的雌性BALB/c裸小鼠等。收集培养的肿瘤细胞悬液，接种于裸小鼠右侧腋窝皮下，接种7～9天后，肿瘤生长至50～75mm3时将动物随机分组，每组8只。同时，各组裸鼠开始给药，给药次数1次/日，14-18天，给药方式为尾静脉注射，使用测量瘤径的方法，动态观察受试样品的抗肿瘤效应。给药14-18天后随即处死裸鼠，手术剥取瘤块称重，拍照。
肿瘤体积(tumor volume，TV)的计算公式为：
TV＝1/2×a×b2
其中a、b分别表示长宽。
根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：
RTV＝Vt/V0，
其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。
抗肿瘤活性的评价指标：相对肿瘤增殖率T/C(％)，计算公式如下：
TRTV：治疗组RTV；CRTV：模型组RTV
均值用X±SD表示，组间分析用t检验进行统计学处理，应用SPSS(StaffsticalPackage for the Social Science)17.0对结果进行统计分析。
上述体内药效试验结果表明，核酸序列5(KT17)对乳腺癌细胞MDA-MB-231的体内抑制率高中低剂量组分别达到：47.13％、66.42％和41.81％。(如图1～3所示)核酸序列8(KT59)对胰腺癌CFPAC-1的体内抑制率高中低剂量组分别达到：64.36％、57.89％和44.15％，抑瘤率较高并有一定的量效关系。(如图4所示)核酸序列1(KT32)对肺癌细胞NCI-H1975的体内抑制率高、低剂量组分别达到：56.35％和49.44％(如图5所示)。
综上所述，本发明提供的序列对肿瘤生长有明显抑制作用，可作为候选药物进一步开发。

Claims (7)

1.一种用于制备抑制肿瘤生长药物的寡聚核酸，其特征在于，所述寡聚核酸为：
序列1： 5`-CTTGAGGGGAATTTCCCAG-3`。
2.根据权利要求1所述的寡聚核酸，其特征在于，所述的寡聚核酸为权利要求1中的序列1的反义链。
3.根据权利要求1或2所述的寡聚核酸，其特征在于，所述的寡聚核酸为权利要求1或2所述的寡聚核酸的修饰型。
4.根据权利要求3所述的寡聚核酸，其特征在于，所述的修饰型为特别位点硫代化修饰；或两端各3个核苷酸硫代化修饰；或全硫代修饰。
5.权利要求1~4任一项所述的寡聚核酸在制备用于抑制肿瘤生长的药物中的应用。
6.根据权利要求5所述的应用，其特征在于，包括如下步骤：将所述的寡聚核酸经HPLC纯化，灭菌水配制成浓度1~2 mg/mL后，将该寡聚核素与其反义链进行等摩尔数混合、水浴加温至80~85℃10~15分钟，自然冷却至室温，退火结合成双链用于制备抑制肿瘤生长的药物。
7.根据权利要求5所述的应用，其特征在于，所述的肿瘤为肺癌、乳腺癌和胰腺癌中的任意一种。
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