CN110172084A - 68Ga标记NODAGA修饰c-Met分子探针及制备与应用 - Google Patents
68Ga标记NODAGA修饰c-Met分子探针及制备与应用 Download PDFInfo
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Abstract
本发明涉及具有生物活性的线状多肽,尤其涉及具有c‑Met靶向性的放射性核素68Ga标记的分子探针68Ga‑NODAGA‑cMBP及其制备方法,本发明还涉及该示踪剂作为非小细胞肺癌(NSCLC)PET成像显像剂的应用,属生物医药领域。本发明所提供的分子成像探针68Ga‑NODAGA‑cMBP采用短半衰期放射性核素68Ga(T1/2~68min)标记,不但可以快速而精准地识别肿瘤病灶(0.5h),借助体外成像设备PET提供高分辨率图像,还可以减少不必要的放射性损伤。此外,从成像图上可以观察到该分子成像探针主要经过肾脏‑膀胱系统从体内快速排泄,进一步减少放射性核素和多肽物质对生物体的潜在影响。
Description
技术领域:
本发明涉及具有生物活性的线状多肽,尤其涉及具有c-Met靶向性的放射性核素68Ga标记的分子探针68Ga-NODAGA-cMBP及其制备方法,本发明还涉及该示踪剂作为非小细胞肺癌(NSCLC)PET成像显像剂的应用,属生物医药领域。
背景技术:
肝细胞生长因子受体(c-Met)在肿瘤的发生发展过程中发挥重要作用,针对c-Met的靶向抑制剂已经广泛开展临床试验,并有部分药物完成临床转化,取得重要成果。研究表明,c-Met异常表达水平及表达状态与分子靶向治疗反应、治疗效果和预后密切相关,因此准确评价c-Met异常表达水平和表达状态显得尤为重要。PET分子成像可以在体、实时对肿瘤分子靶点的异常表达水平及状态进行定性定量研究,并能提供高分辨率、高对比度图像,对于指导肿瘤治疗、判断肿瘤预后具有重要意义。但开展PET分子成像研究的基础和技术难点主要存在于PET分子成像探针的开发及优化。
1、c-Met广泛参与NSCLC的发生、进展
c-Met基因是由染色体7q21~q31编码的酪氨酸激酶跨膜受体,属于受体型酪氨酸激酶家族一员,其天然配体为间质起源细胞产生的肝细胞生长因子,共同形成HGF/c-Met信号通路。成熟的c-Met受体是由跨膜片段β链(145kDa)和胞外片段α链(50kDa)组成的异二聚体复合物,其胞外功能区的sema结构域(β链)为特异性HGF结合区域,胞内则包含具有负性调控激酶活性的JM结构域、酪氨酸激酶结构域等。当c-Met与HGF结合后,c-Met胞内区的4个酪氨酸残基发生自身磷酸化,进而募集Gab-1、Grb-2、Shc和c-Cb1等衔接蛋白,接着通过复杂的机制引发一系列的磷酸化反应,活化PI-3K、ERK1/2、PLC-γ、STATs和FAK等重要的信号分子,进而调节细胞正常的增殖、存活、分化、形态发生和运动调控,从而广泛参与人体的多种正常生理活动。
正常情况下,c-Met与HGF的结合是维持正常生理功能所必须的,并且受到机体严密调控,但NSCLC患者中存在HGF/c-Met信号通路的异常活化。活化后,c-Met能促进DNA合成和细胞分裂、抑制癌细胞凋亡、促进癌细胞增殖,可以促进癌细胞的侵袭和转移,并通过多种方式直接或间接促进新生血管的形成,进而促进肿瘤的发生发展。另外,研究表明包括受体超表达、基因扩增在内的c-Met信号通路的的异常活化还与NSCLC表皮生长因子受体(EGFR)靶向治疗获得性耐药的产生直接相关。
鉴于c-Met在NSCLC发生发展过程中的重要作用,c-Met靶向治疗在NSCLC的应用受到越来越多的关注。
2、c-Met靶向药物治疗NSCLC的疗效现状
在全世界范围内,肺癌具有最高的发病率和癌症相关死亡率,并且NSCLC约占肺癌发病总数的80%。以放化疗为主的肿瘤治疗的传统治疗方式并不能很好的改善NSCLC预后,因此有效提高NSCLC治疗效果的治疗方案极为迫切。随着越来越多的研究证实c-Met受体超表达和基因扩增存在于相当比例的NSCLC病例中,并被认为是NSCLC发生发展的重要始动因素。c-Met信号通路活化后可进一步激活下游信号通路,介导肿瘤的生长、迁移、血管生成等。此外c-Met基因扩增还是介NSCLC EGFR靶向治疗获得性耐药的重要机制。
近年来,以c-Met为靶点的分子靶向药物研究广泛,发展迅速。c-Met分子靶向药物主要分为拮抗剂、抗体、小分子抑制剂,具体包括与HGF竞争性结合c-Met的生物拮抗剂NK1、NK2、NK4;中和HGF活性的抗HGF单克隆抗体AMG102、AV-299等,他们可与其他分子靶向药物发挥协同作用;可以阻断HGF与c-Met结合及抑制c-Met二聚化的抗c-Met单克隆抗体met-MAb、LY2875358等,临床研究显示此类药物能够延长c-Met阳性NSCLC患者的PFS及OS;非选择性c-Met小分子抑制剂主要有Crizotinib、Cabozantinib、Foretinib等,以及选择性c-Met小分子抑制剂有Tivantinib、AMG337、BMS-777607等。此外,c-Met抑制剂联合EGFR抑制剂用于NSCLC EGFR靶向治疗耐药的研究已经取得令人鼓舞的临床前成果,其临床试验成果也已在JCO、Lancet Oncology等深度报道。虽然已经有多种药物经FDA批准用于临床,但不加筛选的患者治疗使用导致以c-Met为分子靶点的靶向治疗总体有效率偏低。研究表明约40%的肺癌患者有c-Met的过表达,且表达水平在NSCLC细胞系中存在异质性。
由此可见,即使c-Met靶向药物在临床前研究中展示了非常有前景的NSCLC治疗效果,但由于缺乏有效筛选收益患者的方法,而使得c-Met靶向治疗整体疗效并不高。
3、c-Met分子成像研究现状及对于NSCLC诊疗的重要意义
目前c-Met异常活化的检测方法主要是分子病理以及血清学检查。分子病理学检查主要有1)免疫组化(IHC)、westren-blot,2)荧光原位杂交法(FISH)、实时荧光定量PCRTaqMan探针法,3)DNA直接测序。这些方法虽然因其准确性很高而被视作“金标准”,但分子病理检查作为有创检查其适用人群有限,无法反复取病理组织,且无法准确诊断异质性丰富的肿瘤,因此不能合理的制定和调整治疗方案;血清学检查因其简单、便捷、可重复性强而广泛用于肿瘤的初步筛查,但同时血清学检查敏感性较低、无法准确提供肿瘤位置信息、检查结果滞后于肿瘤进展,且检查结果与病理学检查存在一定差异。因此,亟需一种实时、在体、准确监测肿瘤c-Met异常表达状态的方法,以指导临床治疗方案的制定和调整。
分子成像技术借助靶向分子成像探针,对体内特异性的分子靶点进行在体、实时、动态、定性定量成像,将复杂的生物学过程变成直观的图像进行揭示。PET成像设备因其高灵敏度、高准确性、高稳定性及无创性等特点而被广泛应用于分子成像领域的研究。c-Met靶向分子成像可在体实时显示c-Met的表达水平、活化状态,对于存在c-Met表达肿瘤的早期检出、c-Met靶向治疗药物受益人群的筛选、抗肿瘤药物的疗效监测与评价、预后评估等有重要意义。但当前c-Met分子成像研究多是基于单克隆抗体或者荧光标记的分子探针。其不足之处明显,首先,单克隆抗体因其较大的分子量(>150KDa)在生物体内清除缓慢,半衰期可长达数周,且其免疫原性易造成较高的背景信号;其次,荧光标记的探针信号穿透能力较弱,只适于表浅器官,故难于临床转化。
鉴于c-Met靶向多肽(cMBP)具有较高的c-Met受体亲和力(Kd<0.1μM),本发明基于cMBP构建一种正电子核素68Ga标记c-Met靶向分子探针,并通过PET全身成像(可获得较高分辨率,可以清晰分辨肿瘤区域)进行c-Met受体阳性表达肿瘤模型在体识别的临床前验证,对于c-Met高表达NSCLC的早期检出、c-Met靶向治疗药物收益人群的筛选、抗肿瘤药物的疗效监测与评价、预后评估等有重要意义,具有非常大的临床转化潜力。
发明内容:
本发明的目的之一是提供一种全新的放射性核素68Ga标记的NSCLC c-Met靶向的PET分子成像探针68Ga-NODAGA-cMBP。
所述68Ga-NODAGA-cMBP是具有PET成像功能的多肽探针,是在c-Met特异性原多肽cMBP的末端赖氨酸上连接linker,再经放射性核素68Ga标记而成,其结构式(I)如下:
(I)
其中,原多肽cMBP的结构式如式(Ⅱ),与双功能螯合剂(即linker,linker可为NOTA、DOTA、NODAGA等,本文以NODAGA为例)连接后结构如式(Ⅲ);
本发明还提供制备所述多肽化合物即PET成像探针的方法,包括如下步骤:
1)将c-Met靶向多肽cMBP与linker在DIPEA条件下反应,得到产物;
2)将步骤1)得到的产物采用放射性核素标记;
进一步地,所述放射性核素包括但不限于68Ga、64Cu、89Zr或18F;
优选地,所述所述放射性核素为68Ga、64Cu或18F;
更优选地,所述放射性核素为68Ga;
进一步地,所述linker包括但不限于NOTA、DOTA或NODAGA;
优选地,所述linker为NODAGA;
所述放射性核素标记的方法为:将步骤1)的产物溶于醋酸钠缓冲溶液或去离子水中;在所得溶液中加入放射性核素溶液,加热密闭反应约5-15min,冷却后,即生成所述的放射性核素标记的多肽配合物;
进一步地,所述放射性核素标记的方法为:将cMBP与NODAGA连接后的产物溶于醋酸钠缓冲溶液或去离子水中;在其中加入新鲜淋洗的68GaCl3盐酸溶液,密闭60-90℃,反应5-15min,冷却后,将反应液通过事先活化好的C18固相萃取小柱,再用水冲C18柱子,除去未反应的68Ga离子,再经50%乙醇溶液将产品从C18柱子洗脱,即得结构如式(Ⅰ)所示的68Ga标记的多肽产品,将乙醇浓度稀释至10%以下做成注射液。
本发明的目的之二是提供上述方法制备的放射性标记的多肽化合物的应用,特别是示踪剂68Ga-NODAGA-cMBP在PET成像中的应用;
进一步地,是示踪剂68Ga-NODAGA-cMBP在作为c-Met分子靶向示踪剂中的应用;
特别是在测定高表达c-Met的NSCLC中的应用,该示踪剂可特异性结合NSCLC细胞膜上的c-Met受体,并可通过各种正电子核素检测设备定性、定量分析。
有益效果:
相较于其他c-Met分子靶向示踪剂,本发明所提供的分子成像探针68Ga-NODAGA-cMBP采用短半衰期放射性核素68Ga(T1/2~68min)标记,不但可以快速而精准地识别肿瘤病灶(0.5h),借助体外成像设备PET提供高分辨率图像,还可以减少不必要的放射性损伤。此外,从成像图上可以观察到该分子成像探针主要经过肾脏-膀胱系统从体内快速排泄,进一步减少放射性核素和多肽物质对生物体的潜在影响。
附图说明:
图1实施例1制备的68Ga-NODAGA-cMBP及中间产物结构式
其中,式I为68Ga-NODAGA-cMBP;式Ⅱ为cMBP;式Ⅲ为cMBP与双功能螯合剂NODAGA连接产物的结构式;
图2不同c-Met表达水平的NSCLC裸鼠模型(H1993,H1299)注射本发明68Ga-NODAGA-cMBP探针后的PET/CT成像
其中,图A为H1993及H1299代表性冠状位PET图像,箭头所指代表肿瘤区域,k代表肾脏,b代表膀胱;
图B为H1993及H1299模型在体PET成像的定量分析结果。
具体实施方式:
为了使本专利的目的、技术方案及优点更加清楚明白,以下结合具体实施例,对本专利进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本专利,并不用于限定本发明。
本发明所使用的原多肽cMBP的氨基酸序列为:KSLSRHDHIHHH,cMBP已公开于KimK,Hur Y,Ryu EK,et al.Aneutralizable epitope is induced on HGF upon itsinteraction with its receptor cMet.Biochem Biophys Res Commun.2007;354:115–121.,可通过化学合成方法获得。
本发明所使用的缩写分别代表以下含义:
DIPEA:N,N-二异丙基乙胺;
以下将结合附图及编号对本发明做进一步的解释说明。
实施例1 68Ga-NODAGA-cMBP及其制备
1)制备NODAGA-cMBP:将3mg的cMBP溶于200μLDMF中,加入与cMBP摩尔比1:1的NODAGA-NHS ester,然后加入DIPEA(N,N-二异丙基乙胺)5-10μL将pH调节至8.0~8.5,密封室温搅拌过夜,经HPLC分离纯化,收集目标产物的馏分,合并后冻干,经过质谱分析确认后得到NODAGA-cMBP(化合物(Ⅲ),如图1式Ⅲ)。
上述的HPLC分离,第一流动相为0.1%三氟乙酸水溶液,第二流动相为0.1%三氟乙酸乙腈溶液,梯度洗脱条件:0~10min,95-34%第一流动相;10~15min,34~5%第一流动相;15~17min,5~0%第一流动相;流动相的流速为1ml/min,检测波长为220nm。
MS,m/z:数字([M+H]+)
2)制备68Ga-NODAGA-cMBP:通过锗镓反生器,用0.05M HCl盐酸溶液淋洗得到185~370MBq(5~10mCi)的68GaCl3盐酸溶液1ml。向1.5ml的EP管中加入0.45mL的0.5mol/L pH=3.5-4醋酸钠缓冲液,溶解10μg的NODAGA-cMBP,然后加入1ml的185~370MBq(5~10mCi)的68GaCl3盐酸溶液。混合物摇匀后在密闭条件下90℃反应15min,冷却至室温;
将以上反应液缓慢注入事先活化的Sep-Pak C18light柱,再用10ml去离子水冲洗除去未反应的68Ga离子及水溶性杂质,吹干后用500μL的50%的乙醇水溶液淋洗,即得结构如(Ⅰ)(如图1式Ⅰ)所示的68Ga标记的多肽产品,淋洗液用生理盐水稀释至乙醇含量小于10%,用放射性HPLC测定其放化纯度,观察其外观性状为无色澄清透明液体,经衰变校正,探针68Ga-NODAGA-cMBP合成产率≥62%,放化纯度≥95%。
实施例2探针68Ga-NODAGA-cMBP的在体靶向验证
在体靶向验证实验中选用高表达c-Met的NSCLC细胞系H1993和无表达c-Met的NSCLC细胞系H1299建立裸鼠肿瘤模型(BALB/c雌鼠,5周龄,约20g,2×106细胞数皮下右肩部种植,待4周左右后肿瘤体积约300mm3进行在体成像实验),经鼠尾注射68Ga-NODAGA-cMBP探针溶液后(注射剂量是9.25MBq,150μL),在异氟烷-氧气麻醉情况下进行0.5h、1h和2h的PET/CT扫描(Discovery 790Elite,GE healthcare),扫描时长5min,图像后处理平台AW4.6软件(GE Healthcare)。
成像结果如图2所示,H1993肿瘤摄取探针明显高于本底,并显著高于H1299,表明探针68Ga-NODAGA-cMBP可特异性识别高表达c-Met的NSCLC肿瘤模型,且从全身图像可观察到较高分辨率的肿瘤区域。
图像量化分析结果图2-B显示在0.5h时间点,H1993肿瘤摄取探针的值为0.77±0.04%ID/g,而H1299肿瘤摄取探针的值为0.38±0.07%ID/g,明显低于H1993(P<0.01),进一步表明可特异性摄取探针68Ga-NODAGA-cMBP,即该探针可特异性积聚于高表达c-Met的H1993,而无表达c-Met的H1299则没有明显探针摄取,证明了探针的在体靶向性能优异。
PET扫描图像结果可见肾脏和膀胱活度非常高,在各时间点膀胱和肾脏活度之和占全身活度之比均超过86%,表明该探针主要通过泌尿系统排出体外。该探针快速的清除半衰期(<45min)和68Ga的短半衰期(t1/2=68min)有机结合可快速而精准的得到高分辨率图像,以达到诊断NSCLC的目的。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本专利构思的前提下,上述各实施方式还可以做出若干变形、组合和改进,这些都属于本专利的保护范围。因此,本专利的保护范围应以权利要求为准。
Claims (10)
1.一种化合物,其特征在于,所述化合物为68Ga-NODAGA-cMBP,结构式如式(I):
(I)
2.如权利要求1所述的化合物,其特征在于,所述68Ga-NODAGA-cMBP是在c-Met特异性原多肽cMBP的末端赖氨酸上连接linker,再经放射性核素68Ga标记而成;其中,原多肽cMBP的结构式如式(Ⅱ),与双功能螯合剂NODAGA连接后结构如式(Ⅲ):
(Ⅱ)
(Ⅲ)
3.如权利要求1或2所述的化合物,其特征在于,其中的放射性核素还可以是64Cu、89Zr或18F。
4.如权利要1-3任意一项所述的化合物,其特征在于,其中的linker还可以是NOTA、DOTA。
5.权利要求1-4任意一项所述化合物的制备方法,其特征在于,具体如下:
1)将c-Met靶向多肽cMBP与linker在DIPEA条件下反应,得到产物;
2)将步骤1)得到的产物采用放射性核素标记。
6.如权利要求5所述的制备方法,其特征在于,所述放射性核素标记的方法为:将cMBP与linker的连接产物溶于醋酸钠缓冲溶液或去离子水中;在其中加入新鲜淋洗的68GaCl3盐酸溶液,密闭60-90℃,反应5-15min,冷却后,将反应液通过事先活化好的C18固相萃取小柱,再用水冲C18柱子,除去未反应的68Ga离子,再经50%乙醇溶液将产品从C18柱子洗脱即得。
7.用于诊断、治疗和/或预防疾病的组合物或试剂盒,其包含权利要求1-4任意一项所述的化合物。
8.权利要求1-4任意一项所述化合物在制备用于诊断、治疗和/或预防疾病的组合物中的用途。
9.权利要求1-4任意一项所述化合物在制备PET成像探针中的应用。
10.权利要求1-4任意一项所述化合物在作为c-Met分子靶向示踪剂中的应用。
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