CN113577284A - Sstr2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用及多肽偶联药物 - Google Patents
Sstr2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用及多肽偶联药物 Download PDFInfo
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- CN113577284A CN113577284A CN202110855643.4A CN202110855643A CN113577284A CN 113577284 A CN113577284 A CN 113577284A CN 202110855643 A CN202110855643 A CN 202110855643A CN 113577284 A CN113577284 A CN 113577284A
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Abstract
本发明属于生物医药技术领域,具体涉及SSTR2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用及多肽偶联药物,其中,所述SSTR2蛋白作为抗鼻咽癌药物的靶点,所述鼻咽癌由EB病毒所诱发的;所述多肽偶联药物包括与SSTR2蛋白特异性结合的多肽以及与所述多肽相偶联的抗肿瘤剂,所述多肽由氨基酸序列SEQ ID NO:1所限定。本发明所提供的以SSTR2蛋白为靶点的多肽偶联药物,可有效针对由EB病毒所诱发的鼻咽癌,提高多肽偶联药物的治疗疗效。
Description
技术领域
本发明属于生物医药技术领域,具体涉及SSTR2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用及多肽偶联药物。
背景技术
鼻咽癌主要发生于我国南方五省,即广东、广西、湖南、福建和江西,占当地头颈部恶性肿瘤的首位,东南亚国家也是高发区。在上述地区的鼻咽癌发病率为20-30/10万,15-20/10万女性。鼻咽癌是发生于鼻咽部的恶性肿瘤,由于位置隐蔽,早期症状不典型,约70%患者确诊时已是中晚期。对于鼻咽癌的治疗,目前主要手段仍然是手术、放疗和化疗手段。然而,鼻咽癌大多对放射治疗具有中度敏感性,且放疗和化疗副作用巨大,因此靶向治疗是治疗鼻咽癌的发展方向。
肿瘤靶向治疗是针对肿瘤特异性表达的功能分子,设计开发靶向性的药物包括单克隆抗体、多肽和/或其偶联小分子的复合体等。该类靶向性分子可以特异性抑制肿瘤细胞的生长、转移及化疗耐药等,而对正常的组织细胞破坏作用较小。因此,靶向治疗可以极大的延长患者的生存时间及生存质量。然而,现阶段针对鼻咽癌可用的靶向治疗靶点有限,可用的靶向药匮乏,因此提供一种新型的肿瘤治疗靶点是目前亟需解决的问题。
EB(Epstein–Barr)病毒(virus)是Epstein和Barr于1964年首次成功地将Burkitt非洲儿童淋巴瘤细胞通过体外悬浮培养而建株,并在建株细胞涂片中用电镜观察到疱疹病毒颗粒,认为该病毒是多种恶性肿瘤(如鼻咽癌)的病因之一,它主要感染人类口咽部的上皮细胞和B淋巴细胞。在中国南方鼻咽癌患病人群中大多都检测到有EB病毒基因组存在。
EBV在淋巴细胞中长期潜伏,通过环状DNA离开细胞质,并能整合到细胞染色体中。EBV在潜伏感染过程中表达多种潜伏基因。EBV潜伏基因与癌基因的相互作用导致宿主细胞周期紊乱,包括促进G1/S相变和抑制细胞凋亡,从而促进EBV相关肿瘤的发生发展。EBV驱动细胞周期进展和肿瘤发生的分子机制涉及多种基因和信号通路。
生长抑素通过五个独立的生长抑素细胞细胞表面受体亚型起作用,生长抑素受体(somatostatin receptor,SSTR)是G蛋白偶联受体家族的成员,共有五个亚型,分别为SSTR1、SSTR2、SSTR3、SSTR4和SSTR5,其特征是七个螺旋跨膜结构域,形成三个细胞内和细胞外环,其中大多数差异发生在细胞外N末端和细胞内羧基末端(C末端)结构域中。但是在现有技术中少见基于生长抑素对制备抗鼻咽癌的靶向药物的相关报道,特别是用于治疗基于EBV所引发的鼻咽癌的靶向药物的相关报道。
发明内容
为了克服上述现有技术的缺陷,本发明所要解决的技术问题是:提供一种基于SSTR2蛋白的鼻咽癌药物治疗靶点;
以及进一步提供一种由可与SSTR2蛋白特异性结合的多肽和抗肿瘤剂所组成的多肽偶联药物。
为了解决上述技术问题,本发明采用的技术方案为:
提供一种SSTR2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用,所述SSTR2蛋白作为抗鼻咽癌药物的靶点,所述鼻咽癌由EB病毒所诱发的。
进一步提供一种多肽偶联药物,包括与SSTR2蛋白特异性结合的多肽以及与所述多肽相偶联的抗肿瘤剂,所述多肽由氨基酸序列SEQ ID NO:1所限定。
本发明的有益效果在于:SSTR家族中,SSTR2亚型在由EB病毒所诱发的鼻咽癌细胞表面高表达,而其他亚型不表达或低表达,表明SSTR2亚型蛋白具有作为用于治疗由EB病毒所诱发的鼻咽癌的靶向药物的治疗靶点的潜力。并且,本发明进一步提供一种用于与SSTR2蛋白特异性结合的多肽,通过将所述多肽与抗肿瘤药物相偶联,可有效提高抗肿瘤药物的溶解度、增强抗肿瘤药物的靶向性;同时由于多肽是与SSTR2蛋白是特异性结合的,即抗肿瘤药物可在病变部位高浓度地积蓄和释放,可有效降低抗肿瘤药物对非病变部位的毒副作用,以及减少患者的给药剂量和提高抗肿瘤药物的治疗疗效。
附图说明
图1所示为本发明在检测例1中的TYEST-阿霉素在C666-1和CNE2细胞上的细胞毒性测试;
图2所示为本发明在检测例2中EB病毒在C666-1和CNE2细胞中的存在性测试;
图3所示为本发明在检测例3中SSTR家族在C666-1和CNE2细胞中的表达量测试。
具体实施方式
为详细说明本发明的技术内容、所实现目的及效果,以下结合实施方式并配合附图予以说明。
SSTR2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用,所述SSTR2蛋白作为抗鼻咽癌药物的靶点,所述鼻咽癌由EB病毒所诱发的。
其中,所述SSTR2蛋白由氨基酸序列SEQ ID NO:2所表示。
由EB病毒所诱发的鼻咽癌细胞可高表达SSTR2蛋白,而低表达或不表达SSTR家族的其他亚型,因此表明SSTR2蛋白具有作为靶向药物的治疗靶点的潜力。
一种多肽偶联药物,包括与SSTR2蛋白特异性结合的多肽以及与所述多肽相偶联的抗肿瘤剂,所述多肽由氨基酸序列SEQ ID NO:1所限定。
需要说明的是,所述多肽可通过特定的连接子与药物相偶联,也可以直接与药物相偶联。其中,特定的连接子是由药物的性质所决定的,举例而言,在一种实施方式中,多肽通过其天冬酰胺上的氨基与阿霉素的羧基形成酰胺键相偶联。
进一步的,所述抗肿瘤剂为烷化剂或具有烷化作用的药剂;
优选的,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)中的一种。
进一步的,所述抗肿瘤剂为抗代谢药物;
优选的,所述抗代谢药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)中的一种。
进一步的,所述抗肿瘤剂为烯二炔类抗生素;
优选的,所述烯二炔类抗生素包括但不限于奇霉素(calicheamicin)、达内霉素(dynemicin)中的一种。
其中,所述达内霉素包括但不限于达内霉素A。
进一步的,所述抗肿瘤剂为双膦酸盐;
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、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)中的一种。
其中,所述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。
进一步的,所述抗肿瘤剂为美登素或其衍生物中的一种。
其中,所述美登素的衍生物包括但不限于DM1和DM4。
进一步的,所述抗肿瘤剂为长春花生物碱类药物。
优选的,所述长春花生物碱类药物包括但不限于长春新碱(VCR)和长春花碱。
进一步的,所述抗肿瘤剂为紫杉醇及其衍生物、喜树碱及其衍生物、秋水仙碱、细胞抑制剂、糖皮质激素类、皮质类固醇类、核苷酶抑制剂、氨基酸消耗酶、甲酰四氢叶酸、亚叶酸、雷替曲塞中的一种。
其中,所述抗肿瘤剂还包括与甲酰四氢叶酸、亚叶酸、雷替曲塞相类似的其他叶酸衍生物。
其中,所述糖皮质激素类包括但不限于地塞米松(DEX);
所述皮质类固醇类包括但不限于泼尼松;
所述核苷酶抑制剂包括但不限于羟基脲;
所述氨基酸消耗酶包括但不限于天冬酰胺酶。
进一步的,所述多肽通过生物信息技术模拟以及经过细胞、动物实验筛选所获得。
具体而言,所述多肽,可通过生物信息技术将多肽的编码序列结合到特定的载体上,并转染至表达细胞内进行细胞表达,并通过动物实验筛选获得;可选的,所述多肽也可以基于蛋白质合成技术在细胞外直接合成,并通过动物实验筛选获得。
需要说明的是,在全文中,TYEST指代由氨基酸序列SEQ ID NO:1所限定的多肽。
实施例1
TYEST-阿霉素的构建。
具体构建步骤如下:
S1、采用Fmoc固相合成法合成多肽TYEST,参照序列为SEQ ID NO:1;
S2、将TYEST和阿霉素以1:2配比进行偶联,具体连接方式为TYEST上的天冬酰胺的氨基与阿霉素的羧基之间反应形成酰胺键;
S3、将偶联完成的TYEST-阿霉素通过LC-MS纯化,以获得具有生物学活性的TYEST-阿霉素偶联药物。
需要说明的是,在以下检测例中,定量实验均设置为三次重复实验,结果取平均值;
在以下检测例中,鼻咽癌细胞系C666-1和CNE2均购自北纳生物(BNCC);
在以下检测例中,内参β-actin、反转录试剂盒和实时定量PCR试剂盒均购自Genecopoeia公司,总RNA提取试剂盒购自Omega;
其中,涉及检测EB病毒的引物名称及序列如表1所示。
表1
引物名称 | 引物序列 |
LMP1 F | CCACTTGGAGCCCTTTGTMTACTC |
LMP1 R | TGCCTGTCCGTGCAAATTC |
LMP2A F | TGACTCATCTCAACACATATACGAAGAA |
LMP2A R | GGTAGGGCGCAACAATTACAG |
EBNA1 F | CAGTAGACCTGGGAGCAGATTCA |
EBNA1 R | TGGCCCCTCGTCAGACAT |
EBNA2 F | GCGCCAATCTGTCTACATAGAAGA |
EBNA2 R | AGTGCTGGGTTACTGGCTAAGC |
EBER F | AGGACCTACGCTGCCCTAGAG |
EBER R | AACCACAGACACCGTCCTCAC |
BART8 F | GGGTCACAATCTATGGGGT |
BART8 R | CAGTGCGTGTCGTGGAGT |
BART14F | TACCCTACGCTGCCG |
BART14R | TGCGTGTCGTGGAGTC |
BHRF1 F | GGAGATACTGTTAGCCCTG |
BHRF1 R | GTGTGTTATAAATCTGTTCCAAG |
涉及检测SSTR家族中5中亚型的引物名称及序列如表2所示。
表2
检测例1
将实施例1所获得的TYEST-阿霉素分别在鼻咽癌细胞系C666-1和CNE2中进行IC50测定。
实验方法如下:
设置两组实验,两组实验的待测细胞分别为C666-1和CNE2,待测物质为TYEST-阿霉素,每组实验均设置三组平行实验,具体包括实验组、对照组和空白组;
其中,实验组包括含有特定细胞的培养基、CCK-8和待测物质,记为As;
对照组包括含有特定细胞的培养基、CCK-8,不包括待测物质,记为Ac;
空白组包括不含有特定细胞的培养基、CCK-8,不包括待测物质,记为Ab。
其中,所述培养基为不含有血清的培养基,具体包括但不限于1640或DMEM。
具体的试验方法如下:
1、向培养板中加入50μL不同浓度的待测物质,每个浓度做4个复孔;
其中,浓度分别为10-10、10-9、10-8、10-7、10-6、10-5、10-4、10-3mol/L;
2、在37℃,5%CO2浓度下,分别取一定量的C666-1和CNE2细胞,在96孔板中配置50μL的细胞悬液,细胞数量为8×103/孔;
3、显微镜观察细胞铺匀程度,确保铺匀后,将96孔培养板放在细胞培养箱中离水最接近的一层中,培养72h;
4、72h后,配置培养基和CCK-8混合液,按每孔90μL培养基+10μL CCK-8计算,配制混合液;
5、利用真空泵移除旧的培养基,用8联排枪将上述混合液加入96孔板中,每孔100μL混合液;
6、将步骤5中96孔板置于培养箱中孵育1~2h;
7、用酶标仪在450nm处测试每个孔的吸光度值,获得每个孔的吸光度值数据;
8、对吸光度值数据进行处理,处理公式为:细胞存活率(cell viability)=[(As-Ab)/(Ac-Ab)]×100%,数据处理结果如图1所示。
检测例2
鼻咽癌细胞系C666-1和CNE2内EB病毒存在性检测。
试验方法为:
1、细胞总RNA提取步骤,具体步骤如下:
1.1、用500μL的GTC缓冲液在离心管中裂解细胞(细胞数量小于1×107个,C666-1或CNE2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,在10cm培养皿中加入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。
1.2、将裂解液移入gDNA-free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。加入0.5体积(250μL)无水乙醇到裂解液中,用吸管搅拌均匀。
1.3、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。
1.4、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。
1.5、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。
1.6、再用500μL RNA清洗缓冲液II按如上步骤清洗两次。
1.7、将微型管在室温下12000g离心2分钟,使管中完全干燥。
1.8、将微型管转移到一个干净的1.5mL离心管,用30-50μL DEPC处理的水(随试剂盒提供)洗脱RNA,在室温下静置2分钟后,10000g离心1分钟,即可得到total RNA。
2、反转录步骤,具体步骤如下:
2.1、按照表3准备逆转录反应液,补水至终体积为20μl。轻柔混匀准备好的逆转录反应液,短暂离心。
表3
反应液组份 | 体积 | 质量或20μl终浓度 |
SureScript RTase Mix(20X) | 1μL | 1x |
SureScript RT Reaction Buffer(5X) | 4μL | 1x |
Total RNA或者polyA RNA | 1μg或者10ng | |
ddH<sub>2</sub>O | 补水至20μL |
其中,如果使用Total RNA,使用量介于10ng~5μg,如果使用纯化的polyA-RNA,使用量介于1ng~100ng。
22、反转录反应程序设置如表4所示:
表4
温度 | 时间 |
25℃ | 5min |
42℃ | 15min |
85℃ | 5min |
4℃ | hold |
23、逆转录产物无需纯化即可直接用于下一步实验。
其中,对于反应体系25μL的PCR反应,建议使用0.5μL~2μL未稀释的cDNA。对于反应体系为20μL的qPCR反应,建议使用2μL,以1:5~1:20稀释的cDNA。
3、qPCR步骤,具体步骤如下:
31、按照表5内容,在4℃(冰上)或者室温准备qPCR反应液。
表5
试剂 | 体积 |
5×BlazeTaq qPCR Mix | 4μL |
PCR forward primer(2μM) | 2μL |
PCR reverse primer(2μM) | 2μL |
Template | 2μL |
ddH<sub>2</sub>O | 10μL |
总体积 | 20μL |
32、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。
33、根据表6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。
表6
试剂 | 体积 |
5×BlazeTaq qPCR Mix | 4μL |
PCR forward primer(2μM) | 2μL |
PCR reverse primer(2μM) | 2μL |
Template | 2μL |
ddH<sub>2</sub>O | 10μL |
总体积 | 20μL |
熔解曲线反应程序如表7所示:
表7
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 |
通过细胞总RNA提取步骤、反转录步骤和qPCR步骤,分别就C666-1和CNE2细胞中的BHRF1、EBER、LMP1、LMP2A和EBNA1基因进行检测,检测结果如图2所示。
检测例3
基于检测例2所提供的细胞总RNA提取步骤、反转录步骤和qPCR步骤,分别检测C666-1和CNE2中SSTR家族中各亚型的表达量,结果如图3所示。
基于图2表明,BHRF1、LMP1、EBER、LMP2A和EBNA1基因存在于C666-1细胞中,而前述基因均不存在与CNE2细胞中,即表明CNE2细胞中不存在EB病毒,而C666-1细胞中存在EB病毒。
基于图3表明,SSTR2基因在C666-1细胞中高表达,而在CNE2细胞中低表达,且二者之间的差异是具有显著性的,因此SSTR2可作为开发治疗由EB病毒所诱发的鼻咽癌的靶向药物的潜在靶点。
基于图1表明,相较于低表达SSTR2的CNE2细胞,高表达SSTR2的C666-1对TYEST-阿霉素更敏感,且低了一个数量级,因此,由本发明所提供的多肽TYEST可与抗肿瘤剂相结合,作为潜在的鼻咽癌靶向药物。
综上所述,SSTR家族中,SSTR2亚型在由EB病毒所诱发的鼻咽癌细胞表面高表达,而其他亚型不表达或低表达,表明SSTR2亚型蛋白具有作为用于治疗由EB病毒所诱发的鼻咽癌的靶向药物的治疗靶点的潜力。并且,本发明进一步提供一种用于与SSTR2蛋白特异性结合的多肽,通过将所述多肽与抗肿瘤药物相偶联,可有效提高抗肿瘤药物的溶解度、增强抗肿瘤药物的靶向性;同时由于多肽是与SSTR2蛋白是特异性结合的,即抗肿瘤药物可在病变部位高浓度地积蓄和释放,可有效降低抗肿瘤药物对非病变部位的毒副作用,以及减少患者的给药剂量和提高抗肿瘤药物的治疗疗效。
以上所述仅为本发明的实施例,并非因此限制本发明的专利范围,凡是利用本发明说明书内容所作的等同变换,或直接或间接运用在相关的技术领域,均同理包括在本发明的专利保护范围内。
序列表
<110> 深圳市泰尔康生物医药科技有限公司
<120> SSTR2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用及多肽偶联药物
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Ile Ile Tyr Thr Phe Ile Leu Gly Phe Leu Val Pro Leu Thr Ile Ile
210 215 220
Cys Leu Cys Tyr Leu Phe Ile Ile Ile Lys Val Lys Ser Ser Gly Ile
225 230 235 240
Arg Val Gly Ser Ser Lys Arg Lys Lys Ser Glu Lys Lys Val Thr Arg
245 250 255
Met Val Ser Ile Val Val Ala Val Phe Ile Phe Cys Trp Leu Pro Phe
260 265 270
Tyr Ile Phe Asn Val Ser Ser Val Ser Met Ala Ile Ser Pro Thr Pro
275 280 285
Ala Leu Lys Gly Met Phe Asp Phe Val Val Val Leu Thr Tyr Ala Asn
290 295 300
Ser Cys Ala Asn Pro Ile Leu Tyr Ala Phe Leu Ser Asp Asn Phe Lys
305 310 315 320
Lys Ser Phe Gln Asn Val Leu Cys Leu Val Lys Val Ser Gly Thr Asp
325 330 335
Asp Gly Glu Arg Ser Asp Ser Lys Gln Asp Lys Ser Arg Leu Asn Glu
340 345 350
Thr Thr Glu Thr Gln Arg Thr Leu Leu Asn Gly Asp Leu Gln Thr Ser
355 360 365
Ile
Claims (10)
1.SSTR2蛋白在制备抗鼻咽癌的多肽偶联药物中的应用,其特征在于,所述SSTR2蛋白作为抗鼻咽癌药物的靶点,所述鼻咽癌由EB病毒所诱发的。
2.一种多肽偶联药物,其特征在于,包括与SSTR2蛋白特异性结合的多肽以及与所述多肽相偶联的抗肿瘤剂,所述多肽由氨基酸序列SEQ ID NO:1所限定。
3.根据权利要求2所述多肽偶联药物,其特征在于,所述抗肿瘤剂为烷化剂或具有烷化作用的药剂;
所述烷化剂或具有烷化作用的药剂为环磷酰胺、苯丁酸氮芥、顺铂、奥沙利铂、白消安、美法仑、卡氮芥、三乙撑蜜胺中的一种。
4.根据权利要求2所述多肽偶联药物,其特征在于,所述抗肿瘤剂为抗代谢药物;
所述抗代谢药物为甲氨蝶呤、依托泊苷、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶、卡培他滨、达卡巴嗪中的一种。
5.根据权利要求2所述多肽偶联药物,其特征在于,所述抗肿瘤剂为烯二炔类抗生素。
6.根据权利要求2所述多肽偶联药物,其特征在于,所述抗肿瘤剂为双膦酸盐;
所述双膦酸盐为氯屈膦酸盐、埃斯培拉霉素、新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团、阿克拉霉素、放线菌素、安曲霉素、偶氮丝氨酸、博莱霉素、放线菌素C、卡拉霉素、洋红霉素、嗜癌霉素、色霉素、放线菌素D、道诺霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素、霉酚酸、诺拉霉、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链脲霉素、杀结核菌素、乌苯美司、净司他汀、佐柔比星中的一种。
7.根据权利要求2所述多肽偶联药物,其特征在于,所述抗肿瘤剂为美登素或其衍生物中的一种。
8.根据权利要求2所述多肽偶联药物,其特征在于,所述抗肿瘤剂为长春花生物碱类药物。
9.根据权利要求2所述多肽偶联药物,其特征在于,所述抗肿瘤剂为紫杉醇及其衍生物、喜树碱及其衍生物、秋水仙碱、细胞抑制剂、糖皮质激素类、皮质类固醇类、核苷酶抑制剂、氨基酸消耗酶、甲酰四氢叶酸、亚叶酸、雷替曲塞中的一种。
10.根据权利要求2至9任一项所述多肽偶联药物,其特征在于,所述多肽通过生物信息技术模拟以及经过细胞、动物实验筛选所获得。
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