CN113773365A - 生长抑素类似物及其应用 - Google Patents
生长抑素类似物及其应用 Download PDFInfo
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Abstract
本发明提供一种生长抑素类似物及其应用。所述生长抑素类似物的结构如式I)所示:
Description
技术领域
本发明属于生物医药领域,具体地说,涉及一种生长抑素类似物及其应用。
背景技术
神经内分泌肿瘤(NETs)是起源于不同神经内分泌器官的一组异质性肿瘤,包括从具有良好预后的经典类癌到高度恶性的未分化神经内分泌癌的广泛谱系,其中85%来自于消化道,10%源于肺,尚可见于喉、胸腺、肾上腺、卵巢、皮肤、前列腺等部位。研究表明高达94%的NETs细胞表面有生长抑素受体(SSTR)的高表达,甚至一些低分化的肿瘤细胞表面也有SSTR的表达。由于肿瘤的异质性,不同肿瘤细胞表面有不同SSTR亚型(即SSTR1-5)的表达,同一种类的肿瘤也有不同SSTR亚型的表达。前列腺癌和肉瘤细胞表面SSTR1高表达,神经胶质瘤、淋巴瘤、嗜铬细胞瘤和小细胞肺癌细胞SSTR2高表达,大多数非活性垂体瘤中SSTR3高表达,胃肠胰腺神经内分泌瘤、胃癌、室管膜瘤同时有SSTR1和SSTR2的一种或两种高表达。
生长抑素是一种具有广泛生理学功能的内源性调节肽。天然生长抑素对SSTR的五种亚型都有很好的亲和力。目前设计的对天然生长抑素结构进行修饰得到一系列的生长抑素类似物,如经典的生长抑素类似物奥曲肽(Octreotide)和兰乐肽(Lanreotide),已被广泛用于神经内分泌肿瘤、胃肠道肿瘤以及甲状腺癌等SSTR阳性肿瘤的诊断与治疗,但其只对SSTR2阳性的肿瘤有较高的亲和力,对其他亚型阳性的肿瘤特异性不高,容易造成漏诊。因此开发具有广谱性的生长抑素类似物探针对于SSTR阳性肿瘤的诊断和治疗具有重要意义。
发明内容
本发明的目的是提供一种新型的生长抑素类似物及其应用。
为了实现本发明目的,第一方面,本发明提供一种生长抑素类似物,所述生长抑素类似物的结构如式I)所示:
其中,R为双功能螯合基团,R1为放射性核素。
所述双功能螯合基团为-DTPA、-NOTA、-p-SCN-Bn-NOTA、-DOTA或-MPAA-NODA等。
R1可选自18F、64Cu、68Ga等放射性核素中的至少一种。
所述生长抑素类似物的氨基酸序列为Tyr0-cyclo-[D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe]。
从多肽结构来看,KE108结构中保留了对生长抑素受体具有高亲和力的Phe-D-Trp-Lys-Thr基序。其中,D代表氨基酸的构型。
第二方面,本发明提供所述生长抑素类似物的制备方法,包括以下步骤:
A、多肽KE108经过双功能螯合剂修饰,得到标记前体;
B、对标记前体进行放射性核素标记。
其中,所述双功能螯合剂为DTPA、NOTA、p-SCN-Bn-NOTA、DOTA或MPAA-NODA等。
所述放射性核素可选自18F、64Cu、68Ga等中的至少一种。
前述的方法,步骤B中,所述双功能螯合剂中的-COOH基团通过缩合反应与多肽KE108中Tyr中的-NH2基团连接。
优选地,当所述双功能螯合剂为NODA,放射性核素为18F时,制备方法包括:向浓度为0.5mg/mL的10-50μL标记前体NODA-KE108中依次加入pH3-5的含AlCl3的醋酸缓冲溶液100-500μL以及3.7-370MBq的[18F]F-生理盐水溶液,于80-120℃反应10-30min,然后用Sep-pakC18柱分离纯化。其中,含AlCl3的醋酸缓冲溶液中,AlCl3的浓度为1-30mM,醋酸缓冲液的浓度为0.1M。
优选地,当所述双功能螯合剂为NODA,放射性核素为68Ga时,制备方法包括:向浓度为0.5mg/mL的10-50μL标记前体NODA-KE108中依次加入92.5MBq的68GaCl3洗脱液和0.1-10M的甲酸钠溶液10-100μL,于80-120℃反应10-30min,标记率小于90%时,用Sep-pakC18柱分离纯化。
第三方面,本发明提供所述生长抑素类似物的以下任一应用:
1)用于制备癌症检测试剂或试剂盒;
2)用于制备抗癌药物或组合物;
3)用于制备靶向癌症的分子探针。
第四方面,本发明提供一种肿瘤显像剂,其有效成分为式I)的生长抑素类似物。可用于PET显像。
借由上述技术方案,本发明至少具有下列优点及有益效果:
(一)本发明的多肽KE108衍生物结构中保留了对生长抑素受体具有高亲和力的Phe-D-Trp-Lys-Thr基序,通过不同螯合剂和不同核素对探针结构进行修饰,设计出广谱型靶向生长抑素受体的放射性标记生长抑素类分子探针。靶向所有亚型的生长抑素受体,将其作为更灵敏的神经内分泌肿瘤的早期诊断探针。以实现对神经内分泌肿瘤的早诊断、早发现、早治疗的精准化医疗。
(二)本发明提供的生长抑素类似物的制备方法,具有标记时间短、条件温和等特点,有利于标记物的商业化应用与临床推广。
(三)本发明具有在生长抑素受体阳性荷瘤鼠中显像,在给药后30min可见肿瘤部位具有明显的放射性摄取,表明探针具有良好的靶向性。
附图说明
图1为本发明较佳实施例中NODA-MPAA-KE108多肽的合成路线图。
图2为本发明较佳实施例中NODA-MPAA-KE108多肽质谱图。
图3为本发明较佳实施例中NODA-MPAA-KE108多肽的HPLC图谱。
图4为本发明较佳实施例中[Al18F]NODA-MPAA-KE108标记率图。
图5为本发明较佳实施例中[68Ga]NODA-MPAA-KE108标记率图。
图6为本发明较佳实施例中[Al18F]NODA-MPAA-KE108探针在生理盐水(a)和10%胎牛血清(b)中的体外稳定性色谱图。
图7为本发明较佳实施例中[Al18F]NODA-MPAA-KE108在AR42J荷瘤鼠中micro-PET显像图。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段,所用原料均为市售商品。实施例1生长抑素类似物NODA-MPAA-KE108及其标记化合物的制备
本实施例提供的生长抑素类似物的结构如式I)所示:
其中,R为双功能螯合基团,R1为放射性核素。
所述双功能螯合基团为-DTPA、-NOTA、-p-SCN-Bn-NOTA、-DOTA或-MPAA-NODA等。
R1可选自18F、64Cu、68Ga等放射性核素中的至少一种。
1、生长抑素类似物的制备方法如下:
(1)NODA-MPAA-KE108多肽的合成(合成过程见图1)
①树脂脱保护及洗涤:称取固相合成树脂Fmoc-Phe-CTC Resin(0.3-0.5mmol/g)约5g,置于合成管中,加入二甲基酰胺(DMF)浸泡1-2h,抽干溶液并使用DMF重复洗涤3次,之后添加20%哌啶(PIP)/DMF反应10min后将溶液抽干,重复两次,脱保护过程约30min,之后用DMF反复洗涤5-6次,抽干备用。
②脱保护完全检测:从合成管中取出少量树脂,通过茚三酮反应检测,若树脂颜色呈深蓝色,则表明Fmoc保护基已经脱除。
③氨基酸Fmoc-Tyr(tBu)-OH偶联:称取Fmoc-Tyr(tBu)-OH 1g,溶解于二氯甲烷(DCM)中,加入1.2当量的1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl)和1-羟基苯并三唑(HOBT),2当量的N-甲基吗啡啉(NMM),搅拌反应过夜,旋蒸浓缩得到环化后的粗品。
④重复步骤①、②。
⑤用步骤③的方法继续连接NODA得到粗产品NODA-Tyr(tBu)-Cyclo(D-Dab-Arg(NO2)-Phe-Phe-D-Trp(Boc)-Lys(Z)-Thr(tBu)-Phe)。
⑥Pd/C氢化反应:将步骤⑤中的粗产品溶解于甲醇中,加入Pd/C氢化得到粗产物NODA-Tyr(tBu)-Cyclo(D-Dab-Arg-Phe-Phe-D-Trp(Boc)-Lys-Thr(tBu)-Phe)。
⑦切割及洗涤:将步骤⑥中粗产品溶解于三氟乙酸(TFA)/1,2-乙二硫醇(EDT)/水(H2O)=95/2.5/2.5切割液中,摇床控温3h;加入到6倍体积冰乙醚中,离心机沉淀收集固体,将沉淀的粗品用乙醚洗3遍,得到最后粗产品;
⑧干燥及纯化:将步骤⑦中的粗产品放置在干燥锅中,真空干燥过夜,用反相制备HPLC纯化,流动相为:A:0.1%TFA水溶液;B:0.1%TFA的80%乙腈(ACN)溶液,梯度洗脱,检测波长220nm,收集主峰。
⑨冷冻干燥:收集主峰溶液,加入少量纯化随,-20℃冷冻过夜,之后使用冷冻干燥机进行冷冻干燥48-72h,当内容物为白色粉末时即可取出样品,按照要求进行多肽的分装至冻存管中保存,取少量样品进行质谱(MS)和HPLC检测。
⑩质量分析
分子量检测:质谱采用Waters SYNAPT G2 HDMS系统。NODA-MPAA-KE108的高分辨质谱图如图2所示,由图得知m/z=551.2[(M+3H)/3],NODA-MPAA-KE108理论分子量为:1650.8Da。说明制备得到的多肽分子量与NODA-MPAA-KE108理论分子量相符。
纯度检测:
HPLC分析条件为:
色谱柱:Agilent ZORBAX XDB-C18,5μm,4.6mm×250mm
检测波长:220nm,运行时间:15min。
流动相:A:0.1%TFA水溶液;B:0.1%TFA的80%ACN溶液。
梯度洗脱:
经过HPLC检测,确认纯度>95%,结果见图3。
(2)标记与纯化
放射性核素为18F时,制备方法为:向浓度为0.5mg/mL的10~50μL标记前体NODA-KE108中依次加入100μL的0.1M醋酸缓冲液(pH4),100μL含有AlCl3的醋酸缓冲溶液(1mM),3.7MBq的[18F]F-生理盐水溶液,100℃反应10min,然后用Sep-pakC18柱分离纯化,得到[Al18F]NODA-MPAA-KE108探针,[Al18F]NODA-MPAA-KE108标记率图如图4所示。
放射性核素为68Ga时,制备方法为:向浓度为0.5mg/mL的10μL标记前体NODA-KE108中依次加入92.5MBq的68GaCl3洗脱液,10μL的0.1M的甲酸钠溶液,80℃反应10min,标记率小于90%时,用Sep-pakC18柱分离纯化,得到[68Ga]NODA-MPAA-KE108。[68Ga]NODA-MPAA-KE108标记率图如图5所示。
实施例2与SSTR的亲和力测试
生长抑素类似物与各亚型SSTR亲和力研究采用表面等离子共振技术(SPR)进行测试。采用超滤离心将SSTR1-5五种亚型受体脱tris处理,利用葡聚糖芯片,每张芯片设置一个参比通道,其他通道用于偶联SSTR蛋白。SSTR蛋白用pH4.5醋酸钠缓冲液(10mM)配制成浓度为200μg/mL溶液用于偶联芯片。将生长抑素类似物(1mM)用膦酸盐吐温溶液(PBST)依次倍比稀释成10个梯度(0.1-100μM),每隔5个梯度增加一个空白PBST,从低浓度开始进样上机测试。测试结果如表1所示。
表1生长抑素及其类似物与五种蛋白亚型的亲和常数Kd值(M)
注:SST14和SST28参见Gao J,Tong H,Huang Z,et al.Affinity analysis ofsomatostatin and somatostatin receptor by surface plasmon resonance[J].Analytical Methods,2013,5(13):3201.
测试结果表明,采用SPR方法检测得到KE108和修饰得到的NODA-MPAA-KE108与SSTR各亚型的亲和力常数在10-4~10-5M左右。查询文献采用SPR方法测试天然生长抑素SST14、28对SSTR2、4的亲和力常数在10-4~10-6范围内。说明KE108和修饰得到的NODA-MPAA-KE108对SSTR各亚型有很好的亲和力。
实施例3体外稳定性研究
取100μL的[Al18F]NODA-MPAA-KE108加入到生理盐水溶液中(pH7.4),置于室温条件下孵育0.5h、1h、2h,之后用HPLC进行检测,同样取100μL的[Al18F]NODA-MPAA-KE108加入到1.9mL 10%胎牛血清中,37℃孵育0.5h、1h、2h,取400μL上述血清加入100μL乙腈进行混匀、涡旋,离心过膜后进行HPLC检测。检测结果见图6(a和b),结果表明[Al18F]NODA-MPAA-KE108在生理盐水(a)和10%胎牛血清(b)中保持较好的稳定性,放化纯度>95%。
实施例4荷瘤鼠PET显像
取肿瘤直径约为0.5-1cm的AR42J荷瘤鼠(BALB/c裸鼠,雄性,20g左右)经尾静脉注射[Al18F]NODA-MPAA-KE108(3.7MBq/100μL·只),分别在给药后0.5h和1h进行PET显像,小鼠呈俯卧位,使用异氟烷和氧气混合全身麻醉下扫描。结果如图7所示,在肿瘤部位有明显的高放射性摄取,摄取值为2.57±0.60%ID/g,肌肉摄取值为1.22±0.50%ID/g,具有较好的靶与非靶比值。Block对照组则通过尾静脉将[Al18F]NODA-MPAA-KE108和NODA-MPAA-KE108多肽共注射至AR42J荷瘤鼠体内,在给药后1h进行PET显像,小鼠呈俯卧位,使用异氟烷和氧气混合全身麻醉下扫描。结果如图7所示,在肿瘤部位无放射性摄取,摄取值为0.53±0.24%ID/g,表明探针具有较好的特异性。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之做一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (7)
2.权利要求1所述生长抑素类似物的制备方法,其特征在于,包括以下步骤:
A、多肽KE108经过双功能螯合剂修饰,得到标记前体;
B、对标记前体进行放射性核素标记;
其中,所述双功能螯合剂为DTPA、NOTA、p-SCN-Bn-NOTA、DOTA或MPAA-NODA;
所述放射性核素选自18F、64Cu、68Ga中的至少一种。
3.根据权利要求2所述的方法,其特征在于,步骤B中,所述双功能螯合剂中的-COOH基团通过缩合反应与多肽KE108中的Tyr中的-NH2基团连接。
4.根据权利要求2所述的方法,其特征在于,当所述双功能螯合剂为NODA,放射性核素为18F时,制备方法包括:向浓度为0.5mg/mL的10-50μL标记前体NODA-KE108中依次加入pH3-5的含AlCl3的醋酸缓冲溶液100-500μL以及3.7-370MBq的[18F]F-生理盐水溶液,于80-120℃反应10-30min,然后用Sep-pakC18柱分离纯化;其中,含AlCl3的醋酸缓冲溶液中,AlCl3的浓度为1-30mM,醋酸缓冲液的浓度为0.1M。
5.根据权利要求2所述的方法,其特征在于,当所述双功能螯合剂为NODA,放射性核素为68Ga时,制备方法包括:向浓度为0.5mg/mL的10-50μL标记前体NODA-KE108中依次加入92.5MBq的68GaCl3洗脱液和0.1-10M的甲酸钠溶液10-100μL,于80-120℃反应10-30min,标记率小于90%时,用Sep-pakC18柱分离纯化。
6.权利要求1所述生长抑素类似物的以下任一应用:
1)用于制备癌症检测试剂或试剂盒;
2)用于制备抗癌药物或组合物;
3)用于制备靶向癌症的分子探针;
其中,所述癌症为表达生长抑素受体的癌症。
7.肿瘤显像剂,其特征在于,有效成分为权利要求1所述的生长抑素类似物。
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