CN117106035A - 一种肿瘤靶向多肽、多肽偶联药物及制备与应用 - Google Patents
一种肿瘤靶向多肽、多肽偶联药物及制备与应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,尤其涉及一种肿瘤靶向多肽、多肽偶联药物及制备与应用,所述肿瘤靶向多肽的氨基酸序列如SEQ ID NO:1所示。本发明的多肽偶联药物对人结肠癌HT29裸鼠皮下移植瘤具有较强的增殖抑制作用,抗肿瘤作用明显;作为靶头的靶向多肽保留了受体亲和力,其分子量远小于抗体,不易引起免疫反应,完全由化学方法合成,效率更高,降低了制备成本。本发明的多肽偶联药物提高了偶联药物对肿瘤细胞的靶向性,降低对正常组织的毒副作用,是一类新的可供选择的靶向偶联药物。
Description
技术领域
本发明属于生物医药技术领域,尤其涉及一种肿瘤靶向多肽、多肽偶联药物及制备与应用。
背景技术
肿瘤的治疗包括手术切除、放疗、药物治疗,其中药物治疗包括化疗和靶向治疗。临床用于化疗的药物由于缺乏靶向性,在杀伤肿瘤细胞的同时也会杀伤正常组织细胞,毒副作用明显,给患者造成了极大的痛苦,使得化疗药物的临床应用受到很大限制。靶向治疗包括小分子靶向药物、抗体靶向药物、靶向配体药物偶联物等。其中,小分子靶向药物主要包括伊马替尼、埃罗替尼等,但这类药物的半衰期较短,并且容易引起耐药性。抗体靶向药物主要靶向肿瘤细胞所表明的膜受体,如EGFR、HER2/neu、VEGFR等,但单独使用时疗效常常不佳,也容易引起肿瘤的抗药性等。为了有效清除肿瘤细胞,并克服耐药性,靶向配体与抗肿瘤药物偶联物的研发备受关注。其中,靶向配体包括抗体、多肽、小分子化合物、核酸寡核苷酸适配子等。偶联药物进入体内后,靶头可以特异性识别受体表达的肿瘤细胞,利用细胞内吞作用使抗肿瘤药物进入肿瘤细胞内发生作用,从而杀死肿瘤细胞,弥补了抗体药物疗效偏低、抗肿瘤药物毒副作用大的缺陷。
目前,抗体药物偶联物(Antibody Drug Conjugate,ADC)是偶联药物的研发热点。全球已有10余款ADC药物上市,国内也有70余款ADC药物处于不同的研发阶段。但ADC药物的研发存在一些难点,包括(1)抗体分子量大,组织穿透能力差,免疫原性强,用药量大;(2)通过肝脏代谢,体内滞留时间长,毒副作用大,治疗窗较窄;(3)仅偶联高毒化合物;(4)抗体偶联小分子毒性药物的平均数量不一,混合组分和制备工艺复杂,成本较高。因此,寻找一种既保留受体亲和力,又具有较低分子量的配体作为偶联药物的靶头,对于降低偶联药物的免疫原性、提高偶联药物的肿瘤穿透能力,并降低生产成本,具有十分重要的现实意义。
发明内容
本发明针对上述现有技术存在的不足,提供一种肿瘤靶向多肽、多肽偶联药物及制备与应用,具体的技术方案如下:
本发明的第一个目的在于提供一种肿瘤靶向多肽,所述多肽的氨基酸序列SEQ IDNO:1为:
Cys-Gly-Val-Asp-Asn-Lys-Phe-Asn-Lys-Glu-Met-Leu-lle-Ala-Met-Glu-Glu-lle-Gly-Ser-Asp-Asp-Trp-Leu-Ser-Leu-lle-Phe-Ala-Gln-Glu-Gln-Gly-Trp-Asn-Leu-Asn-Pro-Leu-Pro-Ser-Gln-Ser-Ala-Asn-Leu-Leu-Ala-Glu-Ala-Lys-Lys-Leu-Asn-Asp-Ala-Gln-Ala-Pro-Lys。
其中,Cys表示半胱氨酸(C),Gly表示甘氨酸(G),Val表示缬氨酸(V),Asp表示天冬氨酸(D),Asn表示天冬酰胺(N),Lys表示赖氨酸(K),Phe表示苯丙氨酸(F),Glu表示谷氨酸(E),Met表示甲硫氨酸(M),Leu表示亮氨酸(L),lle表示异亮氨酸(I),Ala表示丙氨酸(A),Ser表示丝氨酸(S),Trp表示色氨酸(W),Gln表示谷氨酰胺(Q),Pro表示脯氨酸(P)。
本发明提供的肿瘤靶向多肽具有靶向性和穿透性,以本发明靶向多肽与抗肿瘤药物相偶联,能够定向地把抗肿瘤药物穿透癌细胞的细胞膜,并完成药物的释放,进行肿瘤的特异性靶向治疗,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,提高抗肿瘤药物的治疗疗效。本发明的靶向多肽作为偶联药物的靶头,既保留了受体亲和力,又具有较低分子量,降低偶联药物的免疫原性,提高偶联药物的肿瘤穿透能力,并降低生产成本。
本发明第二方面提供所述肿瘤靶向多肽的制备方法,包括如下步骤:
(1)采用固相多肽合成法,在N ,N’-二异丙基乙胺(DIEA)存在的条件下由9-芴甲氧羰基保护氨基的赖氨酸(Fmoc-Lys(Boc)-OH)和Rink Amide-MBHA树脂反应得到Fmoc-Lys(Boc)-Rink Amide-MBHA树脂;
(2)步骤(1)制得的Fmoc-Lys(Boc)-Rink Amide-MBHA树脂经过哌啶/N ,N’-二甲基甲酰胺(DMF)溶液除去Fmoc保护基团后,以O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)为缩合试剂,按照肽序列从C端向N端逐步偶联氨基酸得到全保护肽树脂;
(3)按照质量体积比为1g:5~10mL的比例向步骤(2)得到的全保护肽树脂中添加裂解液切肽,采用乙醚沉降、离心,弃去上层清液后,加乙醚混匀下层沉降物进行洗涤,重复进行离心分离后,弃去上清液,置于真空干燥箱内干燥,从而得到粗肽;
(4)步骤(3)得到的粗肽通过制备液相纯化,冷冻干燥后得到肿瘤靶向多肽。
进一步地,所述步骤(1)中,所述Rink Amide-MBHA树脂、DIEA和Fmoc-Lys(Boc)-OH的摩尔比为1:2~6:4~8。
进一步地,所述步骤(1)中,所述Rink Amide-MBHA树脂取代度为0 .337mmol/g。
进一步地,所述步骤(2)中,所述哌啶/N ,N’-二甲基甲酰胺溶液中哌啶的体积浓度为20%~40%。
进一步地,所述步骤(2)中,所述Fmoc-Lys(Boc)-Rink Amide-MBHA树脂、缩合试剂HBTU、所述缩合试剂与需偶联的9-芴甲氧羰基保护氨基(Fmoc-氨基酸)的摩尔比为1:2~6:4~8,偶联时间为30min~3h。
进一步地,所述步骤(3)中,所述裂解液由体积比为三氟乙酸(TFA):1,2-乙二硫醇(EDI):三异丙基硅烷(TIS):纯化水(H2O)=92~94:2~4:2~4:2~4组成。
进一步地,所述步骤(3)中,所述裂解液在室温裂解30~60min,乙醚沉降后,在转速8000~10000rpm下,离心10~15min;沉降物进行洗涤时,每g沉淀物的乙醚的用量为50~60ml,洗涤后在转速8000~10000rpm下,离心10~15min;所述真空干燥箱的真空度为-0.1MPa,室温条件下干燥24~36h。
本发明的第三个目的在于提供所述肿瘤靶向多肽在制备多肽偶联药物中的应用。
本发明的第四个目的在于提供一种多肽偶联药物,包括所述肿瘤靶向多肽、肿瘤化疗药物和连接子,所述连接子将所述肿瘤靶向多肽与所述肿瘤化疗药物相连接。
进一步地,所述连接子包括不可裂解类和可裂解类,其中,不可裂解的连接子包括碳链连接子、酰胺键连接子、醚键连接子;可裂解连接子包括腙键连接子、烯醚键连接子、缩醛/缩酮连接子、二硫键连接子、肽基连接子如Gly-Phe-Leu-Gly、Val-Cit(Cit-Citrulline)、Phe-Lys等。
进一步地,所述肿瘤化疗药物为美登素衍生物DM1。
进一步地,所述多肽偶联药物的分子结构式如式I所示:
式I
其中,肿瘤化疗药物为美登素衍生物DM1,R-SH表示;连接子为S键。
本发明第五方面提供上述多肽偶联药物的制备方法,包括如下步骤:
以2,2'-二硫二吡啶与上述肿瘤靶向多肽为原料,在DMSO溶剂存在条件下,室温条件下搅拌反应24~48h,反应结束后通过制备型高效液相色谱分离纯化,浓缩后冻干得到Linker-肿瘤靶向多肽偶联物;
将DM1与制得的Linker-肿瘤靶向多肽偶联物室温下搅拌反应24~36小时得反应液,将反应液采用制备型高效液相色谱分离纯化,然后浓缩后冻干得到多肽偶联药物。
进一步地,所述2,2'-二硫二吡啶与肿瘤靶向多肽的摩尔比为1~4:1。
进一步地,所述DM1与Linker-肿瘤靶向多肽偶联物的摩尔比1~4:1。
本发明第六方面提供所述多肽偶联药物在制备用于预防或/和治疗肿瘤药物中的应用。
进一步地,所述肿瘤是结肠癌。
本发明的有益效果为:
本发明的多肽偶联药物对人结肠癌HT29裸鼠皮下移植瘤具有较强的增殖抑制作用,抗肿瘤作用明显;作为靶头的靶向多肽保留了受体亲和力,其分子量远小于抗体,不易引起免疫反应,完全由化学方法合成,效率更高,降低了制备成本。本发明的多肽偶联药物提高了偶联药物对肿瘤细胞的靶向性,降低对正常组织的毒副作用,是一类新的可供选择的靶向偶联药物。
附图说明
图1为本发明DM1-多肽偶联药物的TOF图谱;
图2为本发明DM1-多肽偶联药物对人结肠癌HT-29裸鼠皮下移植瘤的生长抑制作用示意图。
具体实施方式
以下结合实例对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
实施例:
一种美登素(DM1)-多肽偶联药物的制备方法,包括如下步骤:
1.肿瘤靶向多肽的合成
(1)采用固相多肽合成法,在0.6M N ,N’-二异丙基乙胺(DIEA)存在的条件下由9-芴甲氧羰基保护氨基的赖氨酸(Fmoc-Lys(Boc)-OH)和取代度为0.337mmol/g的RinkAmide-MBHA树脂进行反应,其中Rink Amide-MBHA Resin树脂的添加量为2.225g, Fmoc-Lys(Boc)-OH的添加量为1.406g;
(2)步骤(1)制得的Fmoc-Lys-Rink Amide-MBHA树脂经过哌啶体积浓度为20%的哌啶/N ,N’-二甲基甲酰胺(DMF)溶液除去Fmoc保护基团后,以O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)为缩合试剂,按照肽序列从C端向N端逐步偶联氨基酸得到全保护肽树脂,其中Fmoc-Lys-Rink Amide-MBHA树脂、缩合试剂HBTU和Fmoc-氨基酸的摩尔比为1:4:4,偶联时间为40min;
(3)按照质量体积比为1g: 10mL的比例向步骤(2)得到的全保护肽树脂中添加裂解液切肽,裂解液组成为三氟乙酸(TFA):1,2-乙二硫醇(EDI):三异丙基硅烷(TIS):纯化水(H2O)=94:2:2:2(体积比),室温裂解50min后过滤取滤液,采用50mL乙醚沉降,沉降后进行离心分离(8000rpm离心10min),弃去上层清液后加50mL乙醚混匀下层沉降物进行洗涤,重复进行离心分离操作(8000rpm离心10min),离心结束后弃去上清液,置于真空干燥箱内,真空度为-0.1MPa,室温条件下干燥24h,得到粗肽3.75g;
(4)步骤(3)得到的粗品溶于乙腈:水(v:v=1:1)中,以C18制备柱进行纯化,检测波长:214nm,流动相A:乙腈(含0.1%三氟乙酸),流动相B:水(含0.1%三氟乙酸);MS确定所得纯品分子量,经冷冻干燥得到目标亲合体多肽1.81g。
2.L-多肽偶联物的合成:
将2,2'-二硫二吡啶(61mg, 0.278 mmol, 1.02 eq),与步骤1所得的1.81g肿瘤靶向多肽溶于30 mL DMSO中,在室温条件下反应26小时,反应结束后,将反应液用乙腈进行稀释处理,以C18制备柱进行纯化,检测波长:214nm,流动相A:乙腈(含0.1%三氟乙酸),流动相B:水(含0.1%三氟乙酸);MS确定所得纯品分子量,HPLC确定样品纯度,经冷冻干燥得到L-多肽偶联物956mg,收率52%;
3.DM1-多肽偶联药物的合成:
将美登素(27.1 mg,0.037 mmol,1.25 eq)、L-多肽偶联物 (200 mg,0.030mmol)溶于10 mL DMSO中,室温搅拌反应,HPLC显示反应约8小时完成;将反应液直接进行制备液相纯化,将含有产物的馏分合并,浓缩后冻干得到106 mg固体目标偶联物,收率48%。
对得到的目标偶联物进行TOF检测,TOF图谱如图1所示,可以清楚找到4e+,5e+,6e+,7e+分子离子峰,说明本实施例成功合成了DM1-多肽偶联药物。
DM1-多肽偶联药物(BX-215)对人结肠癌HT-29裸鼠皮下移植瘤的生长抑制作用的检测实验:
人结肠癌HT29细胞以含10% FBS、1%青-链霉素的DMEM高糖培养基扩增培养,接种前细胞密度调整为1×107cells/mL,在无菌条件下于裸鼠右侧腋下靠背部接种200 μL细胞悬液。用游标卡尺测量移植瘤直径,待肿瘤生长至平均体积约为100~150 mm3左右将动物分为3组。分别为溶剂对照组(Control)、紫杉醇(PTX)组(20 mg/kg)、BX-215(10 mg/kg)组。每周尾静脉注射给药2次,连续给药3周,给药结束后取出小鼠体内的肿瘤,对比测量不同组的肿瘤,实验测试结果如表1、表2和图2所示。
表1 BX-215对人结肠癌HT29裸鼠皮下移植瘤的生长抑制作用比较
注:与Control组相比,** P<0.01
表2 BX-215对人结肠癌HT29荷瘤鼠瘤重的影响
注:与Control组相比,** P<0.01
从表1、表2数据及图2可以看出,实验终点时(D21),与Control组相比,BX-215和PTX组裸鼠体重均无显著性变化;BX-215和PTX组裸鼠TV和RTV均明显降低(P<0.01),T/C均低于40%,IR大于60%。提示,BX-215治疗有效。
实验证实,本发明的DM1-多肽偶联药物对人结肠癌HT29裸鼠皮下移植瘤具有较强的增殖抑制作用,抗肿瘤作用明显,作为靶头的亲合体多肽分子量远小于抗体,不易引起免疫反应,完全由化学方法合成,效率更高,降低了制备成本。本发明的DM1-多肽偶联药物提高了偶联药物对肿瘤细胞的靶向性,降低对正常组织的毒副作用,是一类新的可供选择的靶向偶联药物。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种肿瘤靶向多肽,其特征在于,所述多肽的氨基酸序列如SEQ ID NO:1所示。
2.一种如权利要求1所述的肿瘤靶向多肽的制备方法,其特征在于,包括如下步骤:
(1)采用固相多肽合成法,在N ,N’-二异丙基乙胺存在的条件下由9-芴甲氧羰基保护氨基的赖氨酸和Rink Amide-MBHA树脂反应得到Fmoc-Lys(Boc)-Rink Amide-MBHA树脂;
(2)步骤(1)制得的Fmoc-Lys(Boc)-Rink Amide-MBHA树脂经过哌啶/N ,N’-二甲基甲酰胺溶液除去Fmoc保护基团后,以O-苯并三氮唑-四甲基脲六氟磷酸盐为缩合试剂,按照肽序列从C端向N端逐步偶联氨基酸得到全保护肽树脂;
(3)按照质量体积比为1g:5~10mL的比例向步骤(2)得到的全保护肽树脂中添加裂解液切肽,采用乙醚沉降、离心,弃去上层清液后,加乙醚混匀下层沉降物进行洗涤,重复进行离心分离后,弃去上清液,置于真空干燥箱内干燥,得到粗肽;
(4)步骤(3)得到的粗肽通过液相纯化,冷冻干燥后得到肿瘤靶向多肽。
3.根据权利要求2所述的肿瘤靶向多肽的制备方法,其特征在于,所述步骤(1)中,所述Rink Amide-MBHA树脂、N ,N’-二异丙基乙胺和9-芴甲氧羰基保护氨基的赖氨酸的摩尔比为1:2~6:4~8;所述步骤(2)中,所述Fmoc-Lys(Boc)-Rink Amide-MBHA树脂、所述缩合试剂与需偶联的9-芴甲氧羰基保护氨基的氨基酸的摩尔比为1:2~6:4~8,偶联时间为30min~3h;所述步骤(3)中,所述裂解液的组成为三氟乙酸、1,2-乙二硫醇、三异丙基硅烷和纯化水。
4.一种如权利要求1所述的肿瘤靶向多肽在制备多肽偶联药物中的应用。
5.一种多肽偶联药物,其特征在于,包括如权利要求1所述的肿瘤靶向多肽、肿瘤化疗药物和连接子,所述连接子将所述肿瘤靶向多肽与所述肿瘤化疗药物相连接。
6.根据权利要求5所述的多肽偶联药物,其特征在于,所述肿瘤化疗药物为美登素衍生物DM1。
7.根据权利要求6所述的多肽偶联药物,其特征在于,所述多肽偶联药物的分子结构式如式I所示:
式I
其中,肿瘤化疗药物为美登素衍生物DM1,R-SH表示;连接子为S键。
8.一种如权利要求7所述的多肽偶联药物的制备方法,其特征在于,以2,2'-二硫二吡啶与上述肿瘤靶向多肽为原料,在DMSO溶剂存在条件下,室温搅拌反应24~48h,反应结束后通过液相纯化,浓缩后冻干得到Linker-肿瘤靶向多肽偶联物;
将DM1与制得的Linker-肿瘤靶向多肽偶联物室温下搅拌反应24~36小时得到反应液,将反应液采用液相纯化,然后浓缩后冻干得到多肽偶联药物。
9.根据权利要求8所述的多肽偶联药物的制备方法,其特征在于,所述2,2'-二硫二吡啶与肿瘤靶向多肽的摩尔比为1~4:1;所述DM1与Linker-肿瘤靶向多肽偶联物的摩尔比1~4:1。
10.一种如权利要求5-7任一项所述的多肽偶联药物在制备用于预防或/和治疗肿瘤药物中的应用。
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