CN116063397A - 一类靶向her2蛋白的多肽及其在制备多肽偶联药物中的应用 - Google Patents
一类靶向her2蛋白的多肽及其在制备多肽偶联药物中的应用 Download PDFInfo
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Abstract
本发明公开了一类靶向HER2蛋白的多肽及其在制备多肽偶联药物中的应用。该HER2靶向多肽的序列为:Asn‑Pro‑Asn‑Trp‑Gly‑Arg‑Ser‑Trp‑Tyr‑Asn‑Gln‑Arg‑Phe‑Lys‑Xaa‑Arg‑Ile‑Lys‑Pro‑Arg‑Lys‑Gly‑Tyr‑Thr‑Arg‑NH2。其中,Xaa表示1至7个氨基酸残基长度的序列,其中包括至少一个或更多的半胱氨酸残基。本发明提供的多肽具有HER2靶向性,以其作为小分子抗肿瘤药物的载体制备多肽偶联药物,能够定向地将抗肿瘤药物递送至HER2阳性肿瘤,进行特异性靶向治疗。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种特异性靶向HER2蛋白的多肽和由该肽衍生的且能与HER2结合的多肽偶联药物,本发明还公开了其制备方法以及该类化合物在制备癌症靶向治疗药物中的应用。
背景技术
恶性肿瘤是一种严重危害人类健康的重大疾病,特征主要包括肿瘤细胞的无限增殖、逃避机体的生长抑制、抵抗细胞程序性死亡、诱导血管生成、促进侵袭和转移、免疫逃逸等。
恶性肿瘤的常规治疗手段主要包括手术治疗、放射性疗法和化学药物治疗。随着生命科技的发展,肿瘤靶向治疗手段开始出现并日趋成熟。癌症靶向治疗的前提是找准治疗靶点。人表皮生长因子受体2(HER2),又称erbB-2,是17q12 号染色体上ERBB2基因编码的酪氨酸蛋白激酶受体。HER2在多种人类癌症中过表达,包括乳腺癌、胃癌、食道癌、卵巢癌和子宫内膜癌。特别是在乳腺癌中,这种过表达的发生率几乎达到20%。HER2过表达与更高的肿瘤侵袭性、更高的复发风险、更快的进展和较差的预后相关,目前已有多种针对HER2的临床药物被开发用于癌症治疗。
靶向多肽分子量小,阻滞渗透性强,且易于大量合成。此外,多肽可通过反复进行结构的修饰改造以改变其亲和力、电荷、亲疏水性、稳定性及溶解性。在肿瘤靶向治疗中,靶向肽显示了较强的优越性,是抗体的一种有效替代物。在应用方面,靶向肽可以用于构建多肽偶联药物,从而向表达靶蛋白的肿瘤细胞内递送抗肿瘤药物,发挥细胞杀伤作用。
发明内容
本发明的目的在于提供一种特异性靶向HER2蛋白的多肽、和由该肽所衍生的且能与HER2结合的多肽偶联药物。所述多肽具有选择性高,特异性强,分子量小,简便易得,无免疫原性,安全可靠等特点。所述多肽偶联药物,可显著增加肿瘤药物的治疗效果。
本发明第一方面提供一种靶向HER2蛋白的多肽,其氨基酸序列通式为:
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Xaa-Arg-I le-Lys-Pro-Arg-Lys-GLy-Tyr-Thr-Arg-NH2,
上述肽链中Xaa表示1至7个氨基酸残基长度的序列,其中包括至少一个或更多的半胱氨酸残基,
优选地,Xaa为3或5个氨基酸长度的序列,
更优选地,Xaa为Gly-Cys-Gly或Gly-Cys-Gly-Cys-Gly,
部分靶向HER2蛋白的多肽序列如下所示:
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Gly-Cys-G ly-Arg-Ile-Lys-Pro-Arg-Lys-Gly-Tyr-Thr-Arg-NH2(SEQ.ID NO:1),
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Gly-Cys-G ly-Cys-Gly-Arg-Ile-Lys-Pro-Arg-Lys-Gly-Tyr-Thr-Arg-NH2(SEQ.ID NO:2),
本发明第二方面提供了靶向HER2蛋白的多肽的制备方法,本发明采用微波促进Fmoc/tBu正交保护固相合成策略高效快速地合成得到特异性靶向HER2的肽链,
本发明第三方面提供了靶向HER2蛋白的多肽在制备多肽偶联药物中的应用,优选在制备靶向HER2蛋白的多肽偶联药物中的应用
本方明第四方面提供一类多肽偶联药物,其包括所述靶向HER2蛋白的多肽、细胞毒性药物和连接子,所述连接子是指将上述靶向HER2蛋白的多肽与所选细胞毒性药物连接的结构。
优选的,连接子与所述靶向HER2的多肽中的半胱氨酸残基连接。
进一步的优选,连接子结构选自以下任意一种:
进一步地,所述细胞毒性药物为肿瘤化疗药物,优选吉西他滨、阿霉素、紫杉醇、喜树碱,进一步优选喜树碱。
本发明多肽偶联药物是利用靶向HER2蛋白的多肽对过表达HER2的癌细胞的靶向作用,将肿瘤化疗药物递送至肿瘤从而发挥靶向抗癌作用,因此,所述的肿瘤化疗药物可以为临床已知的或已报到的任意一种肿瘤化疗药物。
进一步地,所述多肽偶联药物具有如式A所示结构:
式A
本发明第五方面提供所述多肽偶联药物在制备癌症靶向治疗药物中的应用,
进一步地,所述癌症包括HER2阳性的肿瘤,优选HER2阳性的乳腺癌、卵巢癌、肺癌、胃癌、前列腺癌、膀胱癌。
优选地,所述癌症为HER2阳性的乳腺癌。
与现有的技术相比,本发明有以下优点:
本发明涉及的肽可特异性靶向HER2阳性细胞,选择性高,且本发明涉及的肽可用化学合成的方法制备得到,纯度高,分子量小,特异性强,无免疫原性,安全可靠。
本发明的多肽偶联药物,在一个药物分子中,引入细胞毒性药物喜树碱,增加了肿瘤药物的治疗效果。
附图说明
图1SPR测定多肽与HER2蛋白的亲和力
图2多肽与HER2阳性或阴性细胞的结合。(A)SEQ.ID NO.1;(B)SEQ.ID NO. 2
图3多肽在SK-BR-3荷瘤裸鼠内的体内分布
图4多肽偶联药物的体内抗肿瘤活性评估
具体实施方式
在本说明书中采用以下缩写:
NMP:N-甲基吡咯烷酮;DIPEA:N,N'-二异丙基乙胺;DMF:二甲基甲酰胺; DMSO:二甲亚砜;DCM:二氯甲烷;Fmoc:N-9-芴甲氧羰基;DIC:N,N’-二异丙基碳二亚胺;DMAP:4-二甲氨基吡啶;HBTU:苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯;HOBT:1-羟基-苯并三氮唑;HPLC:高效液相色谱;ESI-MS:电喷雾质谱;Gly:甘氨酸;Ser:丝氨酸;Ala:丙氨酸;Thr:苏氨酸;Val:缬氨酸;Ile:异亮氨酸;Leu:亮氨酸;Tyr:酪氨酸;Phe:苯丙氨酸;His:组氨酸;Pro:脯氨酸;Asp:天门冬氨酸;Met:蛋氨酸;Glu:谷氨酸;Trp:色氨酸;Lys:赖氨酸;Arg:精氨酸;Asn:天冬酰胺;Gln:谷氨酰胺。本发明是通过下列实施例来进行说明的,但这些实施例不做任何限制本发明的解释。
实施例1
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Gly-Cys-Gly-Arg-Ile-Lys-Pro-Arg-Lys-Gly-Tyr-Thr-Arg-NH2(SEQ.ID NO:1)的微波促进固相合成
(1)树脂的溶胀
称取Fmoc-Rink amide-MBHA Resin 50mg(取代量0.4mmol/g),经7mL DCM 溶胀30min,抽滤去DCM,再用10mL NMP溶胀30min,最后分别用NMP,DCM, NMP 7mL冲洗干净。
(2)微波促进Fmoc保护基的脱除
将溶胀好的树脂放入反应器中,加入7mL含0.1M HOBT的25%哌啶/NMP(V/V)溶液,在微波反应器中反应1min,微波功率为15W,反应温度控制在50℃以内,使用空气压缩机压缩空气冷却,反应结束后滤去溶液;再加入7mL含0.1M HOBT的25%哌啶/NMP(V/V)溶液在微波反应器中再反应4min,微波功率为25 W,反应温度控制在50℃,使用空气压缩机压缩空气冷却。反应结束后滤去溶液,用NMP洗涤干净。得到脱去初始连接的Fmoc保护基的树脂。
(3)微波促进Fmoc-Arg(Pbf)-Rink amide-MBHA Resin的合成
将Fmoc-Arg(Pbf)-OH(0.04mmol),HBTU(0.04mmol),HOBT(0.04mmol)和DIPEA(0.08mmol)溶于10mL NMP中,再将此溶液加入上面的树脂中,在微波反应器中反应7min,微波功率为25W,反应温度控制在50℃,使用空气压缩机压缩空气冷却。反应结束后滤除反应液,用DCM和NMP各7mL洗涤树脂 3次。
(4)偶合效率的检测
用茚三酮法或者溴酚兰法定性检测树脂的偶合效率,显色反应为阴性即可进入下一个偶合循环。
茚三酮法:取少量树脂颗粒用乙醇洗涤,放入透明小瓶中加入5%茚三酮乙醇、KCN吡啶溶液(2mL 0.001M KCN稀释于98mL吡啶中)、80%苯酚乙醇溶液各2滴,于100℃加热5分钟,如果树脂显蓝色即为阳性。
溴酚兰法:取少量树脂颗粒用二甲酰乙酰胺洗涤,放入透明小瓶中加入3滴 1%的溴酚蓝二甲基乙酰胺溶液,常温下振摇3min,如果树脂显蓝色即为阳性。
(5)肽链的延长
按照多肽的序列,重复上述脱保护和偶合的步骤依次连接上相应的氨基酸,偶合微波促进反应时间5~20min不等。得到连有(SEQ.ID NO:1)多肽序列的树脂。
(6)树脂上多肽的裂解
将上述得到的连有(SEQ.ID NO:1)多肽序列的树脂放入反应瓶中,各加入裂解剂Reagent K(TFA/苯甲硫醚/水/苯酚/EDT,82.5:5:5:5:2.5,V/V)10mL,先在0℃下振摇30min,再在常温下反应3h。反应结束后抽滤,加少量TFA 和DCM洗涤三次,合并滤液。将滤液加入大量的冰乙醚中析出白色絮状沉淀,冷冻离心得到目标多肽的粗品。
将上述多肽粗品溶于2mL水中,直接进制备液相色谱纯化,色谱条件为: C18反相柱(320mm×28mm,5μm);流动相A:0.1%TFA/水(V/V),流动相B: 0.1%TFA/乙腈(V/V);流动相梯度:流动相B 40%~90%,20min;流速为6mL/min 检测波长为214nm。收集的溶液冻干得纯品25mg。理论相对分子质量为3325.8。 ESI-MS m/z:found[M+3H]3+1110.6,[M+4H]4+833.1;calcu[M+3H]3+1109.6, [M+4H]4+832.5。
实施例2
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Gly-Cys-Gly-Cys-Gly-Arg-Ile-Lys-Pro-Arg-Lys-Gly-Tyr-Thr-Arg-NH2(SEQ.ID NO:2)的微波促进固相合成
按照实施例1中披露的方法制备SEQ.ID NO:2所示多肽。理论相对分子质量为3484.7。ESI-MS m/z:found[M+3H]3+1163.4,[M+4H]4+872.4;calcu [M+3H]3+1162.6,[M+4H]4+872.2。
实施例3
表面等离子共振(SPR)方法检测SEQ.ID NO:1、SEQ.ID NO:2分别对HER2蛋白的结合作用。
将人重组蛋白HER2偶联至CM 5芯片上,将分析物稀释成浓度梯度(500,250, 125,62.5,31.25nM),使用合适的再生条件(如Glycine,pH 2.5),流速设为30μL/min,每个循环进样时间设置为90s,解离时间也为90s。按照 Biacore仪器程序流程,进行多循环动力学测试,最终通过Biacore T200 Evaluation Software分析拟合结合-解离曲线,计算亲和力相关参数。
结果如图1所示,SEQ.ID NO:1肽与HER2的平衡解离常数KD为151nM,SEQ. ID NO:2肽与HER2的平衡解离常数KD为385nM,说明本发明的肽对HER2有强结合作用,可以作为靶向HER2的多肽使用。
实施例4
免疫荧光方法检测SEQ.ID NO:1、SEQ.ID NO:2与HER2阳性的SK-BR-3或HER2 阴性的MDA-MB-231细胞的结合作用
将HER2阳性的SK-BR-3细胞或HER2阴性的MDA-MB-231细胞按照3000-5000 个/皿的密度接种于共聚焦小皿中。培养24h后,吸干净皿内的培养基,然后分别加入含有异硫氰酸荧光素(FITC)标记的10μM的SEQ.ID NO.1或SEQ.ID NO.2肽,细胞核用hochest试剂染色,HER2的表达用PE标记的抗HER2抗体指示。避光冰浴孵育30min,PBS清洗,加入200μL PBS,使用激光共聚焦显微镜观测荧光信号。
从图2中可以看出,SEQ.ID NO:1和SEQ.ID NO:2肽均可以与HER2阳性的 SK-BR-3细胞结合,而与HER2阴性的MDA-MB-231细胞几乎没有结合,说明本发明的肽对HER2阳性肿瘤细胞是选择性特异性结合的,可以作为特异性靶向HER2 的多肽使用。
实施例5
SEQ.ID NO:1、SEQ.ID NO:2肽体内靶向能力评估
取SK-BR-3细胞,调整细胞悬液浓度为5×106个/mL,在每只裸鼠腋下接种 200μL细胞悬液。待肿瘤长至120mm3左右,将荷瘤裸鼠随机分为对照组和实验组,对照组尾静脉注射FITC染料(10μM,200μL),实验组尾静脉注射FITC 标记的多肽(10μM,200μL),注射90min以后,将所有小鼠处死并解剖,收集心、肝、脑、肾、脾、肺和肿瘤,使用IVIS Spectrum成像系统观测并拍照。
由图3可以看出,与生理盐水组相比,SEQ.ID NO:1、SEQ.ID NO:2组均在肿瘤组织中观察到了最强的荧光信号,而FITC组荧光信号富集于肾脏和肝脏,说明SEQ.ID NO:1、SEQ.ID NO:2肽可以靶向富集于肿瘤部位。
实施例6
Conjugate 1的合成
称取实施例1中所得SEQ.ID NO:1肽,用甲醇/水混合溶剂溶解,加入化合物 4-乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪[1,2-b]喹啉-4-基(2-(吡啶-2-基二硫烷基)乙基)碳酸酯,室温搅拌过夜,利用LC-MS 检测反应进程。反应液经过滤后直接进制备液相色谱纯化,色谱条件为:C18反相柱(320mm×28mm,5μm);流动相A:0.1%TFA/水(V/V),流动相B:0.1%TFA/ 乙腈(V/V);流动相梯度:流动相B 40%~90%,20min;流速为6mL/min检测波长为214nm。纯化得到多肽药物偶联物Conjugate 1,理论相对分子质量为 3773.8。ESI-MS m/z:found[M+4H]4+944.9,[M+5H]5+755.8;calcu[M+4H]4+944.5, [M+5H]5+755.8结构如下所示:
实施例7
Conjugate 2的合成
称取实施例1中所得SEQ.ID NO:1肽,用甲醇/水混合溶剂溶解,加入化合物 4-乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪[1,2-b]喹啉-4-基3-(吡啶-2-基二硫烷基)丙酸酯,室温搅拌过夜,利用LC-MS检测反应进程。反应液经过滤后直接进制备液相色谱纯化,色谱条件为:C18反相柱(320 mm×28mm,5μm);流动相A:0.1%TFA/水(V/V),流动相B:0.1%TFA/乙腈(V/V);流动相梯度:流动相B 40%~90%,20min;流速为6mL/min检测波长为214nm。纯化得到多肽药物偶联物Conjugate 2,理论相对分子质量为3760.3。ESI-MS m/z: found[M+4H]4+941.3,[M+5H]5+753.3;calcu[M+4H]4+941.1,[M+5H]5+753.1结构如下所示:
实施例8
Conjugate 3的合成
称取实施例1中所得SEQ.ID NO:1肽,用甲醇/水混合溶剂溶解,加入化合物 4-乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪[1,2-b]喹啉-4-基6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酸酯,室温搅拌过夜,利用LC-MS检测反应进程。反应液经过滤后直接进制备液相色谱纯化,色谱条件为: C18反相柱(320mm×28mm,5μm);流动相A:0.1%TFA/水(V/V),流动相B: 0.1%TFA/乙腈(V/V);流动相梯度:流动相B 40%~90%,20min;流速为6mL/min 检测波长为214nm。纯化得到多肽药物偶联物Conjugate 3,理论相对分子质量为3867.4。ESI-MS m/z:found[M+4H]4+968.0,[M+5H]5+774.4;calcu[M+4H]4+967.9,[M+5H]5+774.5结构如下所示:
实施例9
Conjugate 4的合成
称取实施例2中所得SEQ.ID NO:2肽,用甲醇/水混合溶剂溶解,加入化合物4-乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪[1,2-b] 喹啉-4-基(2-(吡啶-2-基二硫烷基)乙基)碳酸酯,室温搅拌过夜,利用LC-MS 检测反应进程。反应液经过滤后直接进制备液相色谱纯化,色谱条件为:C18反相柱(320mm×28mm,5μm);流动相A:0.1%TFA/水(V/V),流动相B:0.1%TFA/ 乙腈(V/V);流动相梯度:流动相B 40%~90%,20min;流速为6mL/min检测波长为214nm。纯化得到多肽药物偶联物Conjugate 4,理论相对分子质量为 4387.0。ESI-MS m/z:found[M+4H]4+1098.3,[M+5H]5+878.9;calcu[M+4H]4+1097.8,[M+5H]5+878.4结构如下所示:
实施例10
Conjugate 5的合成
称取实施例2中所得SEQ.ID NO:2肽,用甲醇/水混合溶剂溶解,加入化合物4-乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪[1,2-b] 喹啉-4-基3-(吡啶-2-基二硫烷基)丙酸酯,室温搅拌过夜,利用LC-MS检测反应进程。反应液经过滤后直接进制备液相色谱纯化,色谱条件为:C18反相柱(320 mm×28mm,5μm);流动相A:0.1%TFA/水(V/V),流动相B:0.1%TFA/乙腈(V/V);流动相梯度:流动相B 40%~90%,20min;流速为6mL/min检测波长为214nm。纯化得到多肽药物偶联物Conjugate 5,理论相对分子质量为4355.0。ESI-MS m/z: found[M+4H]4+1090.4,[M+5H]5+872.4;calcu[M+4H]4+1089.8,[M+5H]5+872.0 结构如下所示:
实施例10
Conjugate 6的合成
称取实施例2中所得SEQ.ID NO:2肽,用甲醇/水混合溶剂溶解,加入化合物4-乙基-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲哚嗪[1,2-b] 喹啉-4-基6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酸酯,室温搅拌过夜,利用LC-MS检测反应进程。反应液经过滤后直接进制备液相色谱纯化,色谱条件为:C18反相柱(320mm×28mm,5μm);流动相A:0.1%TFA/水(V/V),流动相 B:0.1%TFA/乙腈(V/V);流动相梯度:流动相B 40%~90%,20min;流速为 6mL/min检测波长为214nm。纯化得到多肽药物偶联物Conjugate 6,理论相对分子质量为4569.1。ESI-MS m/z:found[M+4H]4+1144.1,[M+5H]5+915.5;calcu [M+4H]4+1143.3,[M+5H]5+914.8结构如下所示:
实施例11
体外抗肿瘤活性研究
为了研究偶联物的体外抗肿瘤活性,选用了HER2阳性的人乳腺腺癌细胞 SK-BR-3、人胃癌细胞NCI-N87、人卵巢腺癌细胞SK-OV-3细胞,HER2阴性的人乳腺癌细胞MDA-MB-231细胞及正常细胞MCF-10A测定偶联物的细胞毒性作用。
取对数生长期的细胞,以104个/孔的密度接种于96孔细胞培养板中,在37℃、 5%CO2条件下培养过夜。将待测化合物和阳性对照配置成不同浓度,然后加至孔中,每个浓度设置3个复孔。孵育48h后,每孔中加入CCK-8溶液10μL,继续孵育2-4h,用酶标仪检测450nm下各孔的吸光度值,计算出不同浓度下细胞的存活率,然后使用Graphpad软件拟合计算IC50。
偶联物的细胞毒性见表1
表1偶联物的细胞毒性a
a所有实验平行三次进行
*P<0.05,**P<0.01,***P<0.001vs CPT;#P<0.05,###P<0.001vs Conjugate 4
实施例12
动物模型上进行多肽偶联药物Conjugate 1和Conjugate 4的抗肿瘤药效测定取SK-BR-3细胞,调整细胞悬液浓度为5×106个/mL,在每只裸鼠腋下接种200 μL细胞悬液。待肿瘤长至120mm3左右,将荷瘤裸鼠随机分为空白对照组、阳性对照组和实验组,每组4只。每三天一次尾静脉注射vehicle、喜树碱(8 μmol/kg)和优选化合物Conjugate 1或Conjugate4(8μmol/kg)。用游标卡尺每两天测量一次肿瘤体积大小,其计算公式为:V=0.5ab2(其中a是最大长度,b是最小长度)。给药两周后,处死所有裸鼠,分离肿瘤组织,测量体积大小并称重。
结果如图4所示,多肽偶联药物Conjugate 1及Conjugate 4对SK-BR-3荷瘤裸鼠模型具有明显的肿瘤生长抑制作用,说明多肽偶联药物Conjugate 1及 Conjugate 4具有明显的抗肿瘤活性。
Claims (10)
1.一类靶向HER2蛋白的多肽,其特征在于,所述HER2靶向多肽的多肽序列为:
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Xaa-Arg-Ile-Lys-Pro-Arg-Lys-Gly-Tyr-Thr-Arg-NH2
其中,Xaa表示1至7个氨基酸残基长度的序列,其中包括至少一个或更多的半胱氨酸残基。
2.根据权利要求1所述的多肽,其特征在于选自以下任意一条序列:
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Gly-Cys-Gly-Arg-Ile-Lys-Pro-Arg-Lys-Gly-Tyr-Thr-Arg-NH2(SEQ.ID NO:1),
Asn-Pro-Asn-Trp-Gly-Arg-Ser-Trp-Tyr-Asn-Gln-Arg-Phe-Lys-Gly-Cys-Gly-Cys-Gly-Arg-Ile-Lys-Pro-Arg-Lys-Gly-Tyr-Thr-Arg-NH2(SEQ.ID NO:2)。
3.权利要求1和权利要求2所述HER2靶向多肽在制备多肽偶联药物中的应用,优选在制备靶向HER2蛋白的多肽偶联药物中的应用。
4.一种多肽偶联药物,其特征在于,包括权利要求1或权利要求2所述靶向HER2的多肽、细胞毒素药物和连接子,所述连接子将权利要求1或权利要求2所述靶向HER2的多肽与所述细胞毒素药物相连接。
5.根据权利要求4所述的多肽偶联药物,其特征在于,连接子与权利要求1或权利要求2所述靶向HER2的多肽中的半胱氨酸残基连接。
7.根据权利要求4所述的多肽偶联药物,其特征在于,所述细胞毒素药物为肿瘤化疗药物,优选包括吉西他滨、阿霉素、紫杉醇、喜树碱,进一步优选地喜树碱。
9.权利要求4-7中任一项多肽偶联药物在制备癌症靶向治疗药物中的应用。
10.根据权利要求9的应用,其特征在于权利要求4-7中任一项多肽偶联药物在制备HER2阳性的癌症靶向治疗药物中的应用,进一步优选在制备HER2阳性的乳腺癌、卵巢癌、肺癌、胃癌、前列腺癌、膀胱癌的药物中的应用。
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