CN113577304B - 一种针对乳腺癌her2靶点的多肽偶联药物的开发及应用 - Google Patents
一种针对乳腺癌her2靶点的多肽偶联药物的开发及应用 Download PDFInfo
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- CN113577304B CN113577304B CN202110844408.7A CN202110844408A CN113577304B CN 113577304 B CN113577304 B CN 113577304B CN 202110844408 A CN202110844408 A CN 202110844408A CN 113577304 B CN113577304 B CN 113577304B
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Abstract
本发明公开了生物医药技术领域的一种针对乳腺癌HER2靶点的多肽偶联药物的开发及应用,包括HER2蛋白作为药物靶点的多肽TYELD在制备产品中的应用,多肽TYELD序列如SEQ ID NO:1所示,以及通过提取细胞总RNA、反转录、实时定量PCR步骤,检测乳腺癌细胞系SKBR‑3和MCF7是否高表达HER2,经实验验证HER2基因在乳腺癌细胞系SKBR‑3上高表达,而在乳腺癌细胞系MCF7中没有表达,表明HER2可以作为一个潜在的药物靶点,并以此为靶点,开发出创新型的多肽偶联药物(peptide‑drug conjugate,PDC)。
Description
技术领域
本发明涉及生物医药技术领域,具体是一种针对乳腺癌HER2靶点的多肽偶联药物的开发及应用。
背景技术
人表皮生长因子受体-2(human epidermal growth factorreceptor 2,HER-2)是一种跨膜受体,在15%~25%的乳腺癌中过表达。HER-2过表达与不良生物学特性和临床结局相关,是乳腺癌的有效治疗靶点。
HER2如何引发乳腺癌?在正常细胞中,HER2在不同细胞过程中和维持HER2蛋白表达水平的稳定中有重要作用,然而由于某些原因导致的过表达HER2基因或者过表达的HER2蛋白,会导致肿瘤的形成及迁移,HER2形成二聚体后,影响细胞的过程,包括抑制细胞自噬以促进细胞迁移,EGFR受体的首选是与HER2形成二聚体,能激活细胞增殖的RAS/Raf/MAPK信号通路及细胞存活的PI3K/Akt通路,所有过表达的HER2会破坏细胞过程的动态平衡,导致肿瘤不受控制的生长。
目前市面上有四种抗HER2药物,包括单克隆抗体,小分子酪氨酸激酶抑制剂(TKIs),抗体偶联药物(Antibody–DrugConjugates,ADC)及其他抗HER2药。单克隆抗体包括曲妥单抗,帕妥珠单抗等,其分子机制通过与HER2受体结合,阻止HER2二聚体的形成,或者进行免疫应答,抑制HER2的分解,最后破坏下游信号通路;小分子酪氨酸激酶抑制剂包括Lapatinib拉帕替尼,Afatinib阿法替尼及Neratinib来那替尼,其通过与HER2胞外酪氨酸激酶结合,以抑制酪氨酸激酶的磷酸化,从而抑制下游信号通路的活性;单抗药物包括赫赛丁等,其作用机制与HER2胞外结构结合形成复合体后,诱发细胞内吞后使药物发挥作用。然而HER-2抗体(如曲妥珠单抗)不可避免的耐药性和心脏毒性问题在一定程度上限制了其广泛应用。
然而目前市场上还没有针对HER2的多肽偶联药物(peptide-drug conjugate,PDC)上市,多肽偶联药物是采用特定的连接子将靶向性的多肽和具有生物活性的抗癌剂连接起来,利用多肽的靶向性,从而降低抗癌剂对正常细胞的杀伤作用,进而增强抗肿瘤药效,PDC具有靶向性强、特异性高和毒副作用低等特点,同时相对于ADC,工艺简单,成本低廉,可极大的降低病人的经济负担,因此是当下生物医药研究的热点之一。
因此,本发明提供了一种针对乳腺癌HER2靶点的多肽偶联药物的开发及应用,以解决上述背景技术中提出的问题。
发明内容
本发明的目的在于提供一种针对乳腺癌HER2靶点的多肽偶联药物的开发及应用,以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:
一种针对乳腺癌HER2靶点的多肽偶联药物的开发及应用,包括HER2蛋白作为药物靶点的多肽TYELD在制备产品中的应用,所述多肽TYELD序列如SEQ ID NO:1所示,以及通过提取细胞总RNA、反转录、实时定量PCR步骤,检测乳腺癌细胞系SKBR-3和MCF7是否高表达HER2。
作为本发明进一步的方案:所述多肽TYELD的功能如下:
1)提高抗乳腺癌药物的溶解度;
2)增强抗乳腺癌药物的靶向性;
3)降低抗乳腺癌药物的毒副作用;
4)减少抗乳腺癌药物的剂量;
5)提高抗乳腺癌药物的疗效。
作为本发明再进一步的方案:所述的抗乳腺癌药物包括但不限于:通过生物信息技术模拟和经过相关细胞、动物实验筛选的具有靶向性的多肽、以及该多肽与抗肿瘤剂偶联形成的复合体、烷化剂或具有烷化作用的药剂、抗代谢物、抗生素、双膦酸盐、生物碱类、长春花生物碱类以及其它抗肿瘤剂。
作为本发明再进一步的方案:所述烷化剂或具有烷化作用的药剂包括但不限于:环磷酰胺(CTX)、苯丁酸氮芥(CHL)、顺铂(CisP)、奥沙利铂、白消安、美法仑、卡氮芥(BCNU)、三乙撑蜜胺(TEM);
所述抗代谢物包括但不限于:甲氨蝶呤(MTX)、依托泊苷(VP16)、6-巯基嘌呤(6MP)、6-硫鸟嘌呤(6TG)、阿糖胞苷(AraC)、5-氟尿嘧啶(5-FU)、卡培他滨、达卡巴嗪(dacarbazine,DTIC);
所述抗生素包括但不限于:烯二炔抗生素,所述烯二炔抗生素包括但不限于卡奇霉素(calicheamicin);达内霉素(dynemicin),所述达内霉素包括但不限于达内霉素A;
所述双膦酸盐包括但不限于氯屈膦酸盐(clodronate)、埃斯培拉霉素(esperamicin)、新制癌菌素发色团(neocarzinostatin chromophore)和相关色蛋白烯二炔抗生素发色团、阿克拉霉素(aclacinomysin)、放线菌素、安曲霉素(authramycin)、偶氮丝氨酸、博莱霉素(bleomycin)、放线菌素C(cactinomycin)、卡拉霉素(carabicin)、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(包括但不限于吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯啉基-多柔比星和脱氧多柔比星)、表柔比星、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(包括但不限于丝裂霉素C)、霉酚酸(mycophenolicacid)、诺拉霉(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链脲霉素、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他汀(zinostatin)、佐柔比星(zorubicin);
所述生物碱类包括但不限于美登素(maytansine)及其衍生物(包括但不限于DM1、DM4);
所述长春花生物碱类包括但不限于长春新碱(VCR)、长春花碱;
所述其它抗肿瘤剂包括但不限于如紫杉醇及紫杉醇衍生物、喜树碱及其喜树碱衍生物、秋水仙碱、细胞抑制剂、糖皮质激素类(包括但不限于地塞米松(DEX))和皮质类固醇类(包括泼尼松)、核苷酶抑制剂(包括羟基脲)、氨基酸消耗酶(包括天冬酰胺酶)、甲酰四氢叶酸、亚叶酸、雷替曲塞以及和类似其它叶酸衍生物的各种抗肿瘤剂。
作为本发明再进一步的方案:HER2基因的引物序列如下:
HER2-F | 5‘-CCAGGACCTGCTGAACTGGT-3‘ |
HER2-R | 5‘-GTACGAGCCGCACATCC-3’ |
作为本发明再进一步的方案:细胞总RNA(total RNA)提取步骤如下:
S1:RNA清洗缓冲液II在使用前必须用乙醇(96-100%)稀释,并在室温下保存;
S2:用500μL的GTC缓冲液在离心管中裂解细胞;
S3:将裂解液移入gDNA去除管中,再置于2mL收集管,室温下14000g离心3分钟,将收集管中的裂解液转移到一个新的1.5mL管中;
S4:将样品加入HiBindTM RNA微型管中,将微型管置于2mL收集管中,室温下10000g离心30-60秒,弃去收集管及液体;
S5:将微型管置于新的2mL收集管中,加入300μL RNA清洗缓冲液I,室温下10000g离心30-60秒,弃去管中液体;
S6:将微型管置于新的2mL收集管中,加入400μL RNA清洗缓冲液I,重复如上步骤清洗;
S7:再用500μL RNA清洗缓冲液II按如上步骤清洗两次;
S8:将微型管在室温下12000g离心2分钟,使管中完全干燥;
S9:转移到一个干净的1.5mL离心管,用30-50μL DEPC处理的水洗脱RNA,在室温下静置2分钟,10000g离心1分钟,即可得到total RNA。
作为本发明再进一步的方案:反转录步骤如下:
S11:将试剂组份置于冰上融解,融解后轻柔混匀,短暂离心后置于冰上保存;
S21:按照下表准备逆转录反应液,补水至终体积为20μl:
S31:反转录反应程序设置表:
温度 | 时间 |
25℃ | 5min |
42℃ | 15min* |
85℃ | 5min |
4℃ | hold |
S41:逆转录产物无需纯化即可直接用于下一步实验。
作为本发明再进一步的方案:实时定量PCR步骤如下:
S111:解冻并轻柔混匀试剂盒中的5×BlazeTaq qPCRMix,并进行短暂离心;
S211:按照下表内容,在4℃(冰上)或者室温准备qPCR反应液:
试剂 | 体积 |
5×BlazeTaqqPCRMix | 4μl |
PCRforwardprimer(2μM) | 2μl |
PCRreverseprimer(2μM) | 2μl |
Template | 2μl |
ddH2O | 10μl |
总体积 | 20μl |
S311:轻柔混匀qPCR预混液并短暂离心,按照反应体系说明将预混液加入PCR反应管或者反应板中,短暂离心确保预混反应液填充满PCR反应管底部;
S411:根据下表设置二步法PCR程序,并设定熔解曲线分析反应程序,然后开始qPCR反应:
试剂 | 体积 |
5×BlazeTaqqPCRMix | 4μl |
PCRforwardprimer(2μM) | 2μl |
PCRreverseprimer(2μM) | 2μl |
Template | 2μl |
ddH2O | 10μl |
总体积 | 20μl |
熔解曲线反应程序:
步骤 | 温度范围 | 升温速率 | 恒定温度/持续时间 | 检测与否 |
1 | 72-95℃ | 2.05℃/sec | 95℃/15sec | 否 |
2 | 95-60℃ | -1.71℃/sec | 60℃/60sec | 否 |
3 | 60-95℃ | 0.05℃/sec | 95℃/15sec | 是 |
作为本发明再进一步的方案:在乳腺癌细胞系SKBR-3和MCF7上进行多肽偶联药物TYELD-喜树碱抗肿瘤药效测定的实验方法如下:
S1111:向培养板加入50μl不同浓度的待测物质,每个浓度做4个复孔,具体如下:TYELD-喜树碱在乳腺癌细胞系SKBR-3上的浓度设置如下:10-11、10-10、10-9、10-8、5×10-8、10-7、10-6、10-5mol/L;TYELD-喜树碱在乳腺癌细胞系MCF7上的浓度设置如下:10-9、10-8、5×10-8、10-7、5×10-7、10-6、10-5mol/L;
S2111:在96孔板中配制50μl的细胞悬液,细胞数量8*103/孔;
S3111:显微镜下观察细胞是否铺均匀,确保均匀后,将96孔培养板放在细胞培养箱最下层,离水最近的那层,培养72h;
S4111:72h后,配制不含血清的培养基和CCK8的混合液,按每孔90μl培养基+10μlCCK8计算,配制混合液;
S5111:真空泵移除旧的培养基,用8联排枪加入上述混合液100μl/孔;
S6111:将上述96孔培养板在培养箱内孵育1-2小时;
S7111:用酶标仪在450nm处测定吸光度;
S8111:数据处理:细胞存活率=[(As-Ab)/(Ac-Ab)]×100%,As:实验孔,Ac:对照孔,Ab:空白孔。
As:实验孔(含有细胞的培养基、CCK-8、待测物质)Ac:对照孔(含有细胞的培养基、CCK-8、没有待测物质)Ab:空白孔(不含细胞和待测物质的培养基、CCK-8)
有益效果
与现有技术相比,本发明的有益效果是:
通过提取细胞总RNA、反转录、实时定量PCR步骤验证HER2基因在乳腺癌细胞系SKBR-3上高表达,而在乳腺癌细胞系MCF7中没有表达,表明HER2可以作为一个潜在的药物靶点,并以此为靶点通过药物设计、细胞毒性实验等步骤,开发出市场上鲜有的、创新型、靶向型的多肽偶联药物。
附图说明
图1为本发明实中在乳腺癌细胞系上进行HER2基因表达的检测;
图2为本发明实中在乳腺癌细胞系SKBR-3和MCF7上进行靶向多肽偶联药物TYELD-喜树碱细胞毒性检测。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
请参阅图1~2,本发明实施例中,一种针对乳腺癌HER2靶点的多肽偶联药物的开发及应用,包括HER2蛋白作为药物靶点的多肽TYELD在制备产品中的应用,多肽TYELD序列如SEQ ID NO:1所示,以及通过提取细胞总RNA、反转录、实时定量PCR步骤,检测乳腺癌细胞系SKBR-3和MCF7是否高表达HER2。
作为本发明进一步的实施方案:多肽TYELD的功能如下:
1)提高抗乳腺癌药物的溶解度;
2)增强抗乳腺癌药物的靶向性;
3)降低抗乳腺癌药物的毒副作用;
4)减少抗乳腺癌药物的剂量;
5)提高抗乳腺癌药物的疗效。
作为本发明再进一步的实施方案:的抗乳腺癌药物包括但不限于:通过生物信息技术模拟和经过相关细胞、动物实验筛选的具有靶向性的多肽、以及该多肽与抗肿瘤剂偶联形成的复合体、烷化剂或具有烷化作用的药剂、抗代谢物、抗生素、双膦酸盐、生物碱类、长春花生物碱类以及其它抗肿瘤剂。
作为本发明再进一步的实施方案:烷化剂或具有烷化作用的药剂包括但不限于:环磷酰胺(CTX)、苯丁酸氮芥(CHL)、顺铂(CisP)、奥沙利铂、白消安、美法仑、卡氮芥(BCNU)、三乙撑蜜胺(TEM);
抗代谢物包括但不限于:甲氨蝶呤(MTX)、依托泊苷(VP16)、6-巯基嘌呤(6MP)、6-硫鸟嘌呤(6TG)、阿糖胞苷(AraC)、5-氟尿嘧啶(5-FU)、卡培他滨、达卡巴嗪(dacarbazine,DTIC);
抗生素包括但不限于:烯二炔抗生素,烯二炔抗生素包括但不限于卡奇霉素(calicheamicin);达内霉素(dynemicin),达内霉素包括但不限于达内霉素A;
双膦酸盐包括但不限于氯屈膦酸盐(clodronate)、埃斯培拉霉素(esperamicin)、新制癌菌素发色团(neocarzinostatin chromophore)和相关色蛋白烯二炔抗生素发色团、阿克拉霉素(aclacinomysin)、放线菌素、安曲霉素(authramycin)、偶氮丝氨酸、博莱霉素(bleomycin)、放线菌素C(cactinomycin)、卡拉霉素(carabicin)、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、道诺霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(包括但不限于吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯啉基-多柔比星和脱氧多柔比星)、表柔比星、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(包括但不限于丝裂霉素C)、霉酚酸(mycophenolicacid)、诺拉霉(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链脲霉素、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他汀(zinostatin)、佐柔比星(zorubicin);
生物碱类包括但不限于美登素(maytansine)及其衍生物(包括但不限于DM1、DM4);
长春花生物碱类包括但不限于长春新碱(VCR)、长春花碱;
其它抗肿瘤剂包括但不限于如紫杉醇及紫杉醇衍生物、喜树碱及其喜树碱衍生物、秋水仙碱、细胞抑制剂、糖皮质激素类(包括但不限于地塞米松(DEX))和皮质类固醇类(包括泼尼松)、核苷酶抑制剂(包括羟基脲)、氨基酸消耗酶(包括天冬酰胺酶)、甲酰四氢叶酸、亚叶酸、雷替曲塞以及和类似其它叶酸衍生物的各种抗肿瘤剂。
作为本发明再进一步的实施方案:HER2基因的引物序列如下:
HER2-F | 5‘-CCAGGACCTGCTGAACTGGT-3‘ |
HER2-R | 5‘-GTACGAGCCGCACATCC-3’ |
作为本发明再进一步的实施方案:细胞总RNA(total RNA)提取步骤如下:
S1:RNA清洗缓冲液II在使用前必须用乙醇(96-100%)稀释,并在室温下保存,使
用前:
在涉及到RNA的实验中,一定要带上乳胶手套,以最大限度地减少RNA酶的污染。使用提供的试剂时,只使用干净的去RNase的一次性塑料EP管尖端。
GTC缓冲液在较冷的环境温度下会形成晶体,可以加热瓶体使盐重新融解。
2-巯基乙醇(β-巯基乙醇)用于RNases变性,在使用前必须添加到GTC缓冲液中。每1mL GTC缓冲液加入20μL 2-巯基乙醇,混合物在室温下可以保存一周;
S2:用500μL的GTC缓冲液在离心管中裂解细胞,在使用前,每1mL GTC缓冲液加入20μL 2-巯基乙醇。
对于单层培养细胞(成纤维细胞、内皮细胞等),将细胞直接在培养皿中裂解,步骤如下:吸干净培养基,10cm皿中加入500μL GTC缓冲液,覆盖整个容器表面,以确保完全溶解。将裂解液转移到1.5mL的干净试管中,利用旋涡振荡器均化裂解液30秒;
S3:将裂解液移入gDNA去除管中,再置于2mL收集管,室温下14000g离心3分钟,将收集管中的裂解液转移到一个新的1.5mL管中;
S4:将样品加入HiBindTM RNA微型管中,将微型管置于2mL收集管中,室温下10000g离心30-60秒,弃去收集管及液体;
S5:将微型管置于新的2mL收集管中,加入300μL RNA清洗缓冲液I,室温下10000g离心30-60秒,弃去管中液体;
S6:将微型管置于新的2mL收集管中,加入400μL RNA清洗缓冲液I,重复如上步骤清洗;
S7:再用500μL RNA清洗缓冲液II按如上步骤清洗两次;
S8:将微型管在室温下12000g离心2分钟,使管中完全干燥;
S9:转移到一个干净的1.5mL离心管,用30-50μL DEPC处理的水洗脱RNA,在室温下静置2分钟,10000g离心1分钟,即可得到total RNA。
作为本发明再进一步的实施方案:反转录步骤如下:
S11:将试剂组份置于冰上融解,融解后轻柔混匀,短暂离心后置于冰上保存;
S21:按照下表准备逆转录反应液,补水至终体积为20μl:
反应液组份 | 体积 | 质量或20μl终浓度 |
SureScriptRTaseMix(20X) | 1μl | 1x |
SureScriptRTReactionBuffer(5X) | 4μl | 1x |
TotalRNA或者polyARNA | 1μg或者10ng | |
ddH2O | 补水至20μl |
S31:反转录反应程序设置表:
温度 | 时间 |
25℃ | 5min |
42℃ | 15min* |
85℃ | 5min |
4℃ | hold |
S41:逆转录产物无需纯化即可直接用于下一步实验。
作为本发明再进一步的实施方案:实时定量PCR步骤如下:
S111:解冻并轻柔混匀试剂盒中的5×BlazeTaq qPCRMix,并进行短暂离心;
S211:按照下表内容,在4℃(冰上)或者室温准备qPCR反应液:
S311:轻柔混匀qPCR预混液并短暂离心,按照反应体系说明将预混液加入PCR反应管或者反应板中,短暂离心确保预混反应液填充满PCR反应管底部;
S411:根据下表设置二步法PCR程序,并设定熔解曲线分析反应程序,然后开始qPCR反应:
试剂 | 体积 |
5×BlazeTaqqPCRMix | 4μl |
PCRforwardprimer(2μM) | 2μl |
PCRreverseprimer(2μM) | 2μl |
Template | 2μl |
ddH2O | 10μl |
总体积 | 20μl |
熔解曲线反应程序:
步骤 | 温度范围 | 升温速率 | 恒定温度/持续时间 | 检测与否 |
1 | 72-95℃ | 2.05℃/sec | 95℃/15sec | 否 |
2 | 95-60℃ | -1.71℃/sec | 60℃/60sec | 否 |
3 | 60-95℃ | 0.05℃/sec | 95℃/15sec | 是 |
作为本发明再进一步的实施方案:在乳腺癌细胞系SKBR-3和MCF7上进行多肽偶联药物TYELD-喜树碱抗肿瘤药效测定的实验方法如下:
S1111:向培养板加入50μl不同浓度的待测物质,每个浓度做4个复孔,具体如下:TYELD-喜树碱在乳腺癌细胞系SKBR-3上的浓度设置如下:10-11、10-10、10-9、10-8、5×10-8、10-7、10-6、10-5mol/L;TYELD-喜树碱在乳腺癌细胞系MCF7上的浓度设置如下:10-9、10-8、5×10-8、10-7、5×10-7、10-6、10-5mol/L;
S2111:在96孔板中配制50μl的细胞悬液,细胞数量8*103/孔(在37℃,5%CO2的条件下);
S3111:显微镜下观察细胞是否铺均匀,确保均匀后,将96孔培养板放在细胞培养箱最下层,离水最近的那层,培养72h;
S4111:72h后,配制不含血清的培养基和CCK8的混合液,按每孔90μl培养基+10μlCCK8计算,配制混合液;
S5111:真空泵移除旧的培养基,用8联排枪加入上述混合液100μl/孔;
S6111:将上述96孔培养板在培养箱内孵育1-2小时;
S7111:用酶标仪在450nm处测定吸光度;
S8111:数据处理:细胞存活率=[(As-Ab)/(Ac-Ab)]×100%。
本发明的工作原理是:
实施实例1、分别检测乳腺癌细胞系SKBR-3和MCF7是否含高表达HER2;
如图1所示,结果表明,通过提取细胞总RNA、反转录、实时定量PCR步骤,检测出HER2基因在乳腺癌细胞系SKBR-3中高表达,而在乳腺癌细胞系MCF7中没有表达。
实施实例2、分别检测靶向多肽偶联药物TYELD-喜树碱对乳腺癌细胞系SKBR-3和MCF7的细胞毒性情况(IC50)。
我们用筛选出的靶向载体TYELD与细胞毒素小分子喜树碱偶联形成新的药物TYELD-喜树碱,通过培养乳腺癌细胞系SKBR-3和MCF7,并和不同浓度的偶联体TYELD-喜树碱一起孵育72h,通过试剂盒CCK8和酶标仪检测细胞活性。
如图2所示,结果表明,高表达HER2蛋白的乳腺癌细胞系SKBR-3相对于不表达HER2蛋白的乳腺癌细胞系MCF7对多肽偶联药物TYELD-喜树碱更敏感,低一个数量级,而如上所述,HER2蛋白在15%~25%的乳腺癌中过表达。HER-2过表达与不良生物学特性和临床结局相关,是乳腺癌的有效治疗靶点。因此,多肽偶联药物TYELD-喜树碱是HER2阳性乳腺癌潜在的一个创新型靶向药物。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
序列表
<110> 深圳市泰尔康生物医药科技有限公司
<120> 一种针对乳腺癌HER2靶点的多肽偶联药物的开发及应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 12
<212> PRT
<213> 人工合成(Artificially sy)
<400> 1
His Ala Cys Phe Asn Pro Asp Arg Arg Arg Arg Lys
1 5 10
Claims (3)
1.一种TYELD-喜树碱在制备治疗乳腺癌的药物中的应用,其中所述TYELD-喜树碱为多肽TYELD与喜树碱偶联形成,所述多肽TYELD序列如SEQ ID NO:1所示,所述乳腺癌的癌细胞为高表达HER2蛋白的乳腺癌细胞系SKBR-3。
2.根据权利要求1所述的一种TYELD-喜树碱在制备治疗乳腺癌的药物中的应用,其特征在于:HER2基因的引物序列如下:
。
3.根据权利要求1所述的一种TYELD-喜树碱在制备治疗乳腺癌的药物中的应用,其特征在于:在乳腺癌细胞系SKBR-3上进行多肽偶联药物TYELD-喜树碱抗肿瘤药效测定的实验方法如下:
S1111:向培养板加入50μl不同浓度的待测物质,每个浓度做4个复孔,具体如下:
TYELD-喜树碱在乳腺癌细胞系SKBR-3上的浓度设置如下:10-11、10-10、10-9、10-8、5×10-8、10-7、10-6、10-5mol/L;
S2111:在96孔板中配制50μl的细胞悬液,细胞数量8*103/孔;
S3111:显微镜下观察细胞是否铺均匀,确保均匀后,将96孔培养板放在细胞培养箱最下层,离水最近的那层,培养72h;
S4111:72h后,配制不含血清的培养基和CCK8的混合液,按每孔90μl培养基+10μl CCK8计算,配制混合液;
S5111:真空泵移除旧的培养基,用8联排枪加入上述混合液100μl/孔;
S6111:将上述96孔培养板在培养箱内孵育1-2小时;
S7111:用酶标仪在450nm处测定吸光度;
S8111:数据处理:细胞存活率=[(As-Ab)/(Ac-Ab)]×100%,As:实验孔,Ac:对照孔,Ab:空白孔。
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