CN116650679A - 一种靶向fgfr1的影像探针及其应用 - Google Patents
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Abstract
本发明公开了一种靶向FGFR1的影像探针及其应用,具体的,所述的影像探针具备以下通式:M‑L‑G;所述的放射性探针标记有放射性核素;所述的M表示螯合剂,L为连接基团,G为EncarminC。经实验证明,该影像探针的显像效果较好,也能用于核素标记FGFR1核素靶向治疗,从而实现肿瘤的精准诊疗,具有良好的临床应用前景。
Description
技术领域
本发明属于荧光、放射性核素造影剂技术领域,具体涉及一种靶向FGFR1的影像探针及其应用。
背景技术
成纤维细胞生长因子受体(Fibroblast growth factor receptor,FGFR)是近年来的研究的热门靶点之一。成纤维细胞生长因子(Fibroblast growth factor,FGF)与FGFR结合后,通过受体二聚化和特定细胞质酪氨酸残基的磷酸化介导下游的MAPK、AKT、PLCγ、STAT等信号通路,在多种生物学过程中,如肿瘤发生、侵袭、迁移、血管生成等多个环节发挥着重要调控作用。对4853例实体瘤患者二代基因测序的结果显示,几乎所有瘤种都存在FGFR表达异常,且FGFR作为致癌驱动因子比传统的BRAF、ALK或EGFR突变更具有异质性。此外,诸多研究亦表明,FGF/FGFR信号通路可能在肿瘤患者靶向及免疫治疗耐药方面发挥着一定程度的作用。由此可见,在肿瘤患者的综合治疗中,单用或联合应用FGFR抑制剂治疗可能会给更多患者带来新的生存获益。在FGFR的四种受体亚型中,对FGFR1的研究最为深入,多数FGFR抑制剂多FGFR1均具有良好的靶向性。早期、精准、实时对患者全身FGFR1状态进行准确检测在FGFR1阳性肿瘤早期特异性诊断、分期、FGFR1靶向治疗获益患者筛选、靶向治疗效果早期评价及预后评估方面价值巨大。
目前,临床中对FGFR1表达水平检测的主要方法是通过穿刺活检或手术取得组织标本进行病理免疫组化染色。在对获得标本进行石蜡包埋、切片后,还需多项精细步骤方可完成染色,FGFR1最终表达情况根据随机选取的5个高倍镜视野内的阳性细胞所占百分比及细胞染色强度综合判定,这确已成为现行阶段的金标准。但仍存在一定程度的不足之处,首先穿刺或手术系有创操作,耗时较长,部分患者由于确诊时已处于晚期,一般情况较差,难以耐受有创操作,另有部分患者对有创操作存在恐慌心理;其次,由于肿瘤中FGFR1的表达存在异质性,在肿瘤生长的不同阶段、肿瘤病灶的不同部位、原发与转移灶之间、各转移灶之间肿瘤FGFR1的表达水平可能存在差异,进行病理免疫组化染色的组织较少,并不能完全反应肿瘤整体乃至全身其他部位的FGFR1表达水平;此外,治疗前后FGFR1的表达水平也可能不同,有创操作难以重复,无法做到对FGFR1的表达水平进行实时、动态监测;且病理免疫组化检查在一定程度上依赖于肉眼视觉判断,不能完全做到对FGFR1的表达水平进行全面量化。故FGFR1靶点的全面、实时、精准检测至关重要,在FGFR1靶向治疗潜在获益患者的筛选、肿瘤综合治疗早期效果评价方面价值巨大。作为病理免疫组化方法的有益补充,分子影像无创、可重复、可实现对相关靶点的全身动态监测的优势逐渐凸显。高质量靶向分子探针的研发,在一定程度上决定了分子影像在临床诊疗应用中的高度与广度。
研发FGFR1靶向分子探针,联合分子影像设备进行肿瘤FGFR1靶向分子显像,有望无创、全面、实时动态监测患者全身FGFR1表达以及在治疗过程中FGFR1的变化情况,实现FGFR1阳性肿瘤靶向治疗潜在受益人群的筛选、治疗后疗效评价、复发转移及耐药性早期监测,实现肿瘤的精准诊疗。还可以用治疗作用的核素标记FGFR1,实现FGFR1表达的肿瘤的核素靶向治疗。
发明内容
本发明的目的是提供靶向FGFR1的分子探针,用于FGFR1阳性肿瘤原发、复发及转移灶的检出,FGFR1靶向治疗潜在受益人群筛选,以及FGFR1靶向治疗的疗效预测、疗效评价及预后评估。此外,还可以用治疗核素标记,从而实现FGFR1阳性肿瘤的核素靶向治疗。
为实现上述目的,本发明提供了一种放射性探针,所述的放射性探针具备以下通式:M-L-G;所述的放射性探针标记有放射性核素;所述的M表示螯合剂,L为连接基团,G为Encarmin C。
在本发明中,所述的Encarmin C的氨基酸序列为KAEWKSLGEEAWHSK(SEQ ID NO:1)。
在本申请中,术语“螯合剂”通常是指能够与金属离子形成络合物的有机分子。螯合剂常用来标记物蛋白质或肽。金属离子缀合物的终产物用于放射免疫检测、放射免疫疗法、磁共振成像、光动力疗法或其他相似的模式。螯合剂或络合剂的非限制性例子是DTPA(二亚乙基三胺五乙酸酐)和其衍生物,NOTA(1,4,7-三氮杂环壬烷-N,N’,N”-三乙酸)和其衍生物如NODA-GA(NODAGA)、Maleimide-NODAGA,DOTA(1,4,7,10-四氮杂环十二烷-N,N’,N”,N”’-四乙酸)(结合放射性金属离子)和其衍生物,TETA(1,4,8,11-四氮杂环十四烷-N,N’,N”,N”’-四乙酸)和其衍生物,DTTA(N-(对-异硫氰酸苄基)-二亚乙基三胺-N,N’,N”,N”’-四乙酸)。这些和其他螯合剂从商业来源轻易可获得。
作为一种实施方式,本发明的放射性探针中,所述的螯合剂可以为常规的各种用于放射性核素标记的双功能螯合剂。作为一种优选的实施方式,所述的螯合剂包括DOTA、NOTA、NODGA、NODA、DOTP、TETA、ATSM、PTSM、EDTA、EC、HBEDCC、DTPA、SBAD、BAPEN、Df、DFO、TACN、NO2A/NOTAM、CB-DO2A、Cyclen、NOTA-AA、DO3A、DO3AP中的一种或多种,更为优选的,所述的螯合剂为DOTA或NOTA。
术语“放射性核素”或“放射性同位素”是指表现出放射性衰变(例如,发射一种或多种γ射线或正电子)的富集同位素分子。这样的同位素在本领域中也被称为放射性同位素。放射性核素示踪物不包括放射性原始核素,但确实包括天然存在的同位素,这些同位素表现出具有富集的同位素分布的放射性衰变(例如比天然丰度高若干倍)。在某些实施例中,所考虑的是放射性核素限于具有半衰期小于1小时的那些和具有半衰期大于1小时但小于24小时的那些。在本文中使用各种常用的元素名称或符号及其质量数的组合来对放射性同位素命名(例如,18F、F-18,或氟-18)。可以在本披露的化合物中使用的元素包括:F-18;C-11;1-125、1-124、1-131和1-123;Cl-32、Cl-33、Cl-34;Br-74、Br-75、Br-76、Br-77,Br-78;Re-186,Re-188;Y-90,Y-86;Lu-177和Sm-153。典型地放射性同位素包括I-124、F-18氟化物、C-11、N-13,和O-15,这些同位素分别具有4.2天、110分钟、20分钟、10分钟和2分钟的半衰期。
作为一种实施方式,本发明的放射性探针中,所述的放射性核素包括18F、68Ga、177Lu、90Y、64Cu、124I、111In、89Zr、99mTc中的一种或多种。
作为一种优选的实施方式,所述的放射性核素包括18F、68Ga、177Lu、90Y、99mTc中的一种或多种。
本发明的放射性探针中,所述的连接基团包括2-(4-氨基哌啶-1-基)乙酸、6-氨基己酸、PEG3、PEG4、PEG6、G6、PEG2中的一种或多种。
作为一种优选的实施方式,所述的连接基团为PEG2。
作为一种优选的实施方式,所述的螯合剂为NOTA,所述的放射性核素包括18F、68Ga。
作为一种优选的实施方式,所述的螯合剂为DOTA,所述的放射性核素包括68Ga、177Lu、90Y。
作为一种优选的实施方式,所述的螯合剂为氨基酸序列,所述的氨基酸序列为GGGC(SEQ ID NO:2)。更为优选的,所述的放射性核素为99mTc。
本发明还提供了如下任一项所述的应用:
(1)Encarmin C在制备靶向FGFR1的显像剂中的应用;
(2)前面所述的放射性探针在制备靶向FGFR1的显像剂中的应用;
(3)前面所述的放射性探针在制备试剂盒中的应用,所述的试剂盒用于筛选FGFR1靶向治疗潜在受益人群;
(4)前面任一项所述的放射性探针在制备肿瘤诊断试剂中的应用;
(5)前面任一项所述的放射性探针在制备治疗肿瘤的药物中的应用。
作为一种优选的实施方式,所述的显像剂包含放射性探针。更为优选的,所述的放射性探针为如前面所述的放射性探针。
作为一种优选的实施方式,所述肿瘤诊断包括肿瘤分期、病灶定位、疗效监测。
作为一种优选的实施方式,所述的疗效监测包括FGFR1靶向治疗的疗效预测、疗效评价、预后评估。
作为一种优选的实施方式,所述的药物为用于靶向治疗FGFR1阳性肿瘤的药物。
术语“显像剂”是指包括成像部分的任何化合物。“成像部分”是指本身能够或在暴露于外部能量来源(例如电磁辐射、超音波等等)时能够产生可检测信号的原子或原子团。成像部分的非限制性实例包括11C、13N、18F、76Br、123I、124I、125I、131I、99mTc、95Tc、111In、62Cu、64Cu、67Ga和68Ga。在一些实施例中,成像部分选自由18F、76Br、124I、131I、64Cu、89Zr、99mTc和111In组成的群组。在某些实施例中,成像部分直接(即通过共价键)与化合物结合(例如在18F、76Br、124I或131I的情况下)。在其它实施例中,成像部分通过螯合剂与化合物结合(例如在64Cu、89Zr、99mTc和111In的情况下)。显像剂允许检测、成像和/或监测病状、病理病症和/或疾病的存在和/或进展。通常,显像剂可投与个体以提供与个体(例如人类)的至少一部分有关的信息。在一些情况下,显像剂可用以突显个体的特定区域,使器官、血管、组织和/或其它部分更可检测且更清楚地成像。通过提高所研究区域的可检测性和/或图像品质,可确定疾病和/或损伤的存在和程度。
在本发明中,所述试剂盒中可以包括使用说明书。使用说明书典型地包括有形表示,其描述了使用所述试剂盒的组分实现所期望的筛选结果。任选地,所述试剂盒还含有本领域技术人员容易了解的其他有用组分,诸如稀释剂、缓冲剂、药学上可接受的载体、注射器、导管、敷涂器、吸移工具或测量工具、包扎材料或其他有用的附件。
装配在试剂盒中的材料和组分可以提供给从业人员,以保持其可操作性和效用的任何便利且适合的方式储存。举例来说,这些组分可以在室温、冷藏温度或冷冻温度下提供。这些组分典型地包含在合适的包装材料中。在某些实施方案中,包装材料是由众所周知的方法构造,优选地以提供无菌、无污染的环境。包装材料可以具有指示所述试剂盒和/或其组分的内含物和/或目的的外部标签。
本发明描述的肿瘤诊断试剂根据常规程序配制为适合于本申请描述的施用模式的组合物。施用途径包括例如:口服、皮内、肌肉内、腹膜内、静脉内、皮下、鼻内、硬膜外、舌下、鼻内、脑内、叶鞘内、经皮、直肠、通过吸入或局部。施用可以是局部的或全身的。在一些实施方案中,所述施用是通过注射实现。施用模式可以留给医师判断,并且部分取决于医学病状的部位。
在本发明中,术语“诊断”通常是指检测疾病或病症,或测定疾病或病症的状态或程度。术语“诊断”也可以包括检测疾病或病症的诱因,测定药物治疗的治疗效果,或预测对药物治疗的响应模式。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状,预防其它症状,改善或预防导致症状的潜在代谢原因,抑制疾病或病症,例如阻止疾病或病症的发展,缓解疾病或病症,使疾病或病症好转,缓解由疾病或病症导致的症状,或者中止疾病或病症的症状。其针对的对象可以是人或动物。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外,对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果,例如尽管患者可能仍然受到潜在疾病的影响,但观察到患者情况改善。
在本申请中,术语“肿瘤”和“癌症”可互换使用,通常是指赘生性或恶性细胞生长。本申请的肿瘤可能是良性的,也可能是恶性的。本申请的肿瘤可能是实体的,也可能是非实体的。在某些实施方式中,所述癌症包括脑癌、膀胱癌、肛门癌、子宫癌、结肠直肠癌、宫颈癌、精原细胞瘤、睾丸淋巴瘤、前列腺癌、卵巢癌、肺癌、直肠癌、乳腺癌、皮肤鳞状细胞癌、结肠癌、肝癌、胰腺癌、睾丸癌、胃癌、食管癌、甲状腺癌、膀胱移行上皮癌、胃癌、腹膜癌、头颈癌、子宫内膜癌、肾癌、雌性生殖道癌、原位癌、神经纤维瘤、骨癌、皮肤癌、胃肠道间质瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、造血系肿瘤、多发性骨髓瘤、非霍奇金氏淋巴瘤、急性髓性白血病、B细胞淋巴瘤、T细胞淋巴瘤。在本发明的具体实施例中,所述的癌症为肺癌。
在本申请中,术语“包含”和其变形形式,包括“含有”、“包括”等其它形式,通常是指包含其它组分、元素、数值、步骤等。
在本申请中,术语“亲和力”通常是指分子(例如,多肽或抗体)的单个结合位点与其结合配偶体(例如,靶标或抗原)之间的非共价相互作用的总和的强度。分子X对其配偶体Y的亲和力通常可以由解离常数(Kd)表示。亲和力可以通过本领域已知的的常用方法测量,诸如表面等离子体共振,并且还包括本申请所报道的那些方法。分子X对其结合配偶体Y的较高的亲和力可见于较低的Kd值和/或EC50值。
有益效果:
本发明首次提供了一种FGFR1靶向分子探针,该分子探针灵敏度高,有利于癌症的无创性早期诊断、分期、靶向治疗早期疗效评价和预后评估,具有良好的临床应用前景。
附图说明
图1为18F标记Encarmin C的过程方法及化学结构式图;
图2为NOTA-PEG2-FGFR1-peptide MS鉴定结果;
图3为NOTA-PEG2-FGFR1-peptide HPLC分析结果;
图4为[18F]AlF-NOTA-PEG2-FGFR1-peptide RP-HPLC分析结果;
图5为18F-RP-HPLC分析结果;
图6为与血清及生理盐水混合后,18F-NOTA-PEG2-FGFR1-peptide的4h内放射化学纯度检测结果图;
图7是不同肿瘤细胞FGFR1表达情况,其中,图A是蛋白质免疫印迹实验结果,图B是FGFR1在四种肿瘤细胞中的相对表达量图;
图8是在不同时间点注射11.1MBq[18F]F-FGFR1后荷瘤鼠PET/CT成像,其中,图A是RT-112高表达FGFR1荷瘤鼠图像,图B是低表达FGFR1 A549荷瘤鼠图像,图C是低表达FGFR1SNU-16荷瘤鼠图像,图D是低表达FGFR1 Calu-3荷瘤鼠图像;
图9是在不同时间点注射11.1MBq[18F]F-FGFR1的高表达FGFR1 RT-112荷瘤鼠PET/CT图像;
图10是通过PET/CT显像检测Encamin C靶向FGFR1的亲和力的结果图(图左为30min时体内显像剂浓聚情况,图右为60min时体内显像剂浓聚情况);
图11是通过PET/CT显像检测Encamin A靶向FGFR1的亲和力的结果图(图左为30min时体内显像剂浓聚情况,图右为60min时体内显像剂浓聚情况);
图12是通过PET/CT显像检测Encamin E靶向FGFR1的亲和力的结果图(图左为30min时体内显像剂浓聚情况,图右为60min时体内显像剂浓聚情况);
图13是在FGFR阴性荷瘤鼠中通过PET/CT显像检测显像剂浓聚的结果图(图左为30min时体内显像剂浓聚情况,图右为60min时体内显像剂浓聚情况);图14是正电子核素18F标记Encarmin A和Encarmin E在FGFR高表达荷瘤鼠体内分布图,其中,图a为30min时体内各个脏器显像剂分布情况图,图b为60min时体内各个脏器显像剂分布情况图,图c为120min时体内各个脏器显像剂分布情况图;
图15是正电子核素18F标记Encarmin A和Encarmin E在FGFR高表达荷瘤鼠中PET/CT图像;
图16是将68Ga标记Encarmin C注入肿瘤患者体内进行PET/CT显像的结果图;
图17是将68Ga标记Encarmin C注入肿瘤患者体内进行PET/CT显像的结果图;
图18是将68Ga标记Encarmin C注入肿瘤患者体内进行PET/CT显像的结果图;
图19是将68Ga标记Encarmin C注入肿瘤患者体内进行PET/CT显像的结果图。
图20是三种肽对FGFR的亲和力对比结果图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例影像探针的构建及相关试验研究
实验方法
一、影像探针的构建
1、通过化学合成法偶联并获得以NOTA或DOTA为螯合剂的FGFR1-peptide前体,利用PEG2作为连接基团对螯合剂NOTA或DOTA与FGFR1-peptide前体进行偶联,合成NOTA(DOTA)-PEG2-FGFR1-peptide,并通过多种表征手段确认结构,从而实现其与正电子核素18F或68Ga标记,获得高活度的18F/68Ga标记FGFR1-peptide PET分子探针(如图1所示)。具体方法如下:
(1)FGFR1靶向肽NOTA-PEG2-FGFR1-peptide的合成与鉴定
FGFR1靶向肽基础序列为KAEWKSLGEEAWHSK(SEQ ID NO:1),该序列源自欧洲一项已公开的专利(European Patent EP1765861)中的一段靶向FGFR1的肽序列。采用手工多肽固相合成法合成该序列,引入聚乙二醇(Polyethylene glycol,PEG)基团改变FGFR1靶向肽的空间结构,减少新型分子影像探针在肝胆系统的排泄,将适宜[18F]AlF标记法的螯合剂NOTA与上述序列的N端偶联,即得到序列为NOTA-PEG2-KAEWKSLGEEAWHSK的FGFR1靶向肽(NOTA-PEG2-FGFR1-peptide)。取适量合成后的NOTA-PEG2-FGFR1-peptide,使用质谱分析(Mass spectrometry,MS)进行分子量鉴定,与理论分子量对比,验证所合成的化合物的准确性。而后用高效液相色谱法(High performance liquid chromatography,HPLC)对目标化合物进行纯化。纯化条件:HPLC柱为Agela(250×4.6mm I.D.)C18,探测波长为220nm,流动相A为0.05%三氟乙酸与2%乙腈的混合溶液,流动相B为0.05%三氟乙酸与90%乙腈的混合溶液,梯度设置为流动相B12%~35%,时间为23min。
(2)FGFR1靶向肽NOTA-PEG2-FGFR1-peptide的正电子核素18F标记
通过[18F]AlF标记法对质量鉴定合格且经HPLC纯化的FGFR1靶向肽NOTA-PEG2-FGFR1-peptide进行标记。标记前需配置0.1mol/L的NaHCO3溶液(2.1gNaHCO3粉末溶于250mL蒸馏水)、0.5mol/L的邻苯二甲酸氢钾(Potassium acidphthalate,KHP)溶液(0.2042g KHP粉末溶于2mL蒸馏水)、0.05mol/L的KHP溶液(400μL浓度为0.5mol/L的KHP溶液+3600μL蒸馏水)、2mol/L的AlCl3·6H2O溶液(0.0020g AlCl3·6H2O粉末溶于4000μL浓度为0.05mol/L的KHP溶液)、80%的乙醇溶液备用。吸取已配置好的NaHCO3溶液10mL活化QMA离子交换柱待用。另予10mL无水乙醇和10mL蒸馏水依次淋洗Waters Wat054925Sep-PakC18固相萃取小柱,将Sep-Pak C18小柱活化待用。
将回旋加速器轰击H218O靶生产出的无载体18F-缓慢注入QMA离子交换柱,使其得到充分吸附,用0.4mL生理盐水淋洗,收集淋洗液即Na18F溶液至EP管A中备用。另取一EP管B,向其中加入6μL AlCl3·6H2O溶液、11μL浓度为0.5mol/L的KHP溶液及100μL Na18F溶液,充分混匀。于室温状态静置5min后,加入24μL(22nmol)NOTA-PEG2-FGFR1-peptide,混合均匀后110℃加热15min。待反应体系温度降至室温后,将全部反应体系缓慢注入Sep-Pak C18小柱,并用15mL蒸馏水洗脱Sep-Pak C18小柱上的杂质。最后用0.5mL 80%乙醇溶液缓慢淋洗Sep-Pak C18小柱,固相萃取得标记后产物,将标记后产物引流入洁净EP管C。
(3)分子影像探针[18F]AlF-NOTA-PEG2-FGFR1-peptide的质量控制
使用反相高效液相色谱法(Reverse-phase high performance liquidchromatography,RP-HPLC)对标记后的新型分子影像探针[18F]AlF-NOTA-PEG2-FGFR1-peptide进行质量控制。配置体积分数为1%的乙腈-三氟乙酸溶液(250mL乙腈+250μL三氟乙酸)为流动相A,体积分数为1%的水-三氟乙酸溶液(250mL蒸馏水+250μL三氟乙酸)为流动相B。RP-HPLC流速设置为1mL/min,紫外探测器波长260nm。进样前先以流动相A 5%、流动相B 95%的浓度充分润洗C18反向柱,一定时间后,将浓度梯度设置为流动相A 20%~80%,流动相B 80%~20%,流速与紫外探测器波长不变。用微量进样针吸取20μL标记后的分子影像探针[18F]AlF-NOTA-PEG2-FGFR1-peptide,通过微量进样环进样,检测时间20min。
在前期试验阶段,本发明研究了三种靶向FGFR1的肽Encarmin A,Encarmin C和Encarmin E,如图20所示,三种肽的亲和力为Encarmin E>Encarmin A>Encarmin C(来源:Hansen SM,LB,Li S,et al.NCAM-derived peptides function as agonists forthe fibroblast growth factor receptor.J NEUROCHEM,2008,106(5):2030-2041.),但连接NOTA(DOTA)-PEG2-基团后,通过具体实验,本发明证实靶向FGFR1的亲和力为EncarminC>Encarmin E>Encarmin A,Encarmin C的亲和力最佳,体内分布好,疾病显像诊断效果最佳,这是首创性重要发现。因此,本发明最终选择NOTA(DOTA)-PEG2-Encarmin C作为本专利的FGFR1-peptide前体,利用NOTA(DOTA)-PEG2-进行偶联,然后利用核素18F/68Ga进行标记。
2、将螯合剂更换为DOTA,合成DOTA-PEG2-FGFR1-peptide,可完成核素68Ga、177Lu及90Y的标记,进一步实现肿瘤FGFR靶向诊疗一体化,并成为肽受体放射性核素治疗(Peptide receptor radionuclide therapy,PRRT)的一部分。
3、在PEG2作为连接基团的基础上,将螯合剂改变为氨基酸序列GGGC(SEQ ID NO:2),可合成FGFR1-peptide-PEG2-GGGC,可用单光子核素99mTc进行标记,获得99mTc标记FGFR1-peptide分子探针,用于SPECT或SPECT/CT显像。连上4个氨基酸GGGC,性质不变,可实现结合单光子核素99mTc用于SPECT显像。二、18F-NOTA-PEG2-FGFR1-peptide相关试验研究
1.将探针与生理盐水及血清等体积混合,测得相应时间的放射化学纯度,从而检测探针的体外稳定性。
2.于标准条件(37℃,CO2浓度5%)下进行细胞培养,通过蛋白质免疫印迹和免疫荧光实验评估各细胞系表达的FGFR亚型的情况。
3.将标记分子探针分别与表达FGFR不同亚型的细胞共同孵育,分别于加药一定时间后,收集细胞培养板中上清及沉淀,测上清及沉淀的放射性计数,计算“沉淀/(上清+沉淀)”放射性计数的比值,得出细胞对分子探针的摄取率,进一步验证分子探针对FGFR1的靶向性。
4.将标记分子探针分别与表达FGFR不同亚型的细胞共同孵育,于加药一定时间后,弃上清,用pH值为2.5的醋酸缓冲液进行冲洗,收集冲洗液并标记为膜结合,后用胰酶进行消化,收集沉淀,分别测得膜结合及沉淀的放射性计数,计算“沉淀/(膜结合+沉淀)”比值,比较各细胞系对分子探针的内化率的差异。
5.将前述实验中表达FGFR不同亚型的细胞接种至裸鼠右前肢外侧皮下,待肿瘤长至直径0.5-1.3cm待用。
6.经荷瘤裸鼠尾静脉注射分子探针,分别与注射后一定时间进行Micro-PET/CT显像,观察分子探针在肿瘤内的浓聚情况,计算不同时间点肿瘤区域与肌肉区域放射性计数的比值,即T/M比值。组间及组内比较不同时刻及两组间各时间节点显像的差异,分析分子探针在肿瘤模型中的摄取情况。
7.体内外阻断实验:
体外细胞阻断实验:将200倍过量未标记的NOTA-PEG2-FGFR1-peptide加入FGFR1高表达的细胞中,并与适量放射性核素标记的分子探针共同孵育,一定时间后测上清及沉淀的放射性计数,并算出细胞摄取率,并与未阻断组细胞摄取率进行比较。
体内阻断实验:FGFR1高表达细胞荷瘤裸鼠经尾静脉注射200倍过量未标记的NOTA-PEG2-FGFR1-peptide的同时,注射适量放射性核素标记的分子探针,于相应时间进行Micro-PET/CT显像,观察肿瘤部位放射性核素标记分子探针的浓聚情况,计算T/M比值,并与未阻断组进行比较。
8.连接NOTA(DOTA)-PEG2-基团后,利用正电子核素进行标记对比分析EncarminA、Encarmin C、Encarmin E三种肽靶向FGFR1的亲和力。
制备RT112(FGFR+)细胞荷瘤裸鼠,分别静脉注射正电子核素标记Encarmin A、Encarmin C、Encarmin E三种肽,然后上机进行PET/CT检查,通过显像对比三种肽在活体内的靶向结合特性。
9.临床转化
将正电子核素68Ga标记的Encarmin C注入肿瘤患者体内,通过PET/CT实现在肿瘤患者中无创实时显示肿瘤。
实验结果
1.FGFR1靶向肽NOTA-PEG2-FGFR1-peptide的合成与鉴定
通过手工固相多肽合成法合成了FGFR1靶向肽NOTA-PEG2-FGFR1-peptide,序列为NOTA-PEG2-KAEWKSLGEEAWHSK,连接在该短肽序列的N端的PEG2可用以改变多肽的空间结构,有助于减少放射性药物在肝胆系统中的代谢,以NOTA为螯合基团实现[18F]AlF的标记。MS鉴定表明,所合成底物的分子量M+H+为2216.95,M+Na+为2239.41(图2),与理论分子量2216.60的差异在误差允许范围内,证明了合成底物的结构正确性。HPLC纯化后分析显示,合成物纯度为95.34%(图3),具有良好的化学纯度。
2.分子影像探针[18F]AlF-NOTA-PEG2-FGFR1-peptide的标记和质量控制
选用NOTA作为螯合基团,KHP作为pH调节缓冲剂,有助于稳定的八面体F-Al配合物的形成,完成了分子影像探针[18F]AlF-NOTA-PEG2-FGFR1-peptide的标记。标记过程可在30min内完成,未经衰减校正的标记率约为16.67%。标记产物经RP-HPLC质控,可见单一、高尖放射峰,保留时间约为8.7分钟(图4),放化纯为98.66%±0.30%(n=3)。无载体18F-在流动相梯度相同的条件下经RP-HPLC质控,可见放射峰保留时间约为4分钟(图5),可与[18F]AlF-NOTA-PEG2-FGFR1-peptide放射峰的保留时间明显区分。
3.探针与血清及生理盐水混合后,4h内放射化学纯度仍>90%,体外稳定性好(如图6所示)。
4.不同肿瘤细胞FGFR1表达(如图7所示),RT-112高表达,A549、SNU-16、Calu-3低表达。将18F-NOTA-PEG2-FGFR1-peptide分子探针与表达FGFR不同亚型的细胞共同孵育15min、30min、60min和120min,FGFR1高表达的人膀胱癌细胞RT-112对分子探针的摄取率分别为2.12%、3.64%、4.05%、5.11%,该摄取率明显高于FGFR2-4高表达的细胞及过量未标记肽阻断后RT-112细胞对分子探针的摄取率。
5.将分子探针经尾静脉注入各细胞系荷瘤裸鼠体内,于注射后30min、60min、120min进行显像,FGFR1高表达的RT-112细胞系荷瘤裸鼠的肿瘤部位可见分子探针18F-NOTA-PEG2-FGFR-peptide的浓聚,肿瘤显影清晰。FGFR2、FGFR3、FGFR4高表达的荷瘤裸鼠的肿瘤部位未见明显影,显像如图8所示,[18F]F-FGFR1显像显示在肾脏、膀胱和高表达FGFR1RT-112肿瘤中浓聚较多。[18F]F-FGFR1在FGFR1阳性肿瘤中的浓聚随时间延长减低。箭头表示肿瘤。
6.经荷瘤裸鼠尾静脉注射分子探针18F-NOTA-PEG2-FGFR-peptide的同时,注射200倍过量未标记肽以封闭肿瘤细胞表面的FGFR1,Micro-PET/CT显像示,相较于未阻断组,阻断后的RT-112荷瘤裸鼠右前肢近腋下部位肿瘤组织内18F-NOTA-PEG2-FGFR-peptide的浓聚程度显著减低,显像如图9所示。在注射未标记冷肽封闭肿瘤细胞表面的FGFR1后,[18F]F-FGFR1的浓聚明显减低。箭头表示肿瘤。
7.连接NOTA(DOTA)-PEG2-基团后,正电子核素标记Encarmin A、Encarmin C、Encarmin E三种肽,通过PET/CT显像发现靶向FGFR1的亲和力为Encarmin C>Encarmin E>Encarmin A(如图10-12所示),将与FGFR亲和力最强的Encarmin C,用核素标记后注入FGFR阴性荷瘤鼠中,PET/CT显示肿瘤部位无显像剂浓聚,证明核素标记Encarmin C确实是与FGFR靶向结合(如图13所示)。正电子核素18F标记Encarmin A和Encarmin E在FGFR高表达荷瘤鼠体内分布图(分别为30min,60min,120min时体内各个脏器显像剂分布情况,如图14所示),及18F标记Encarmin A和Encarmin E在FGFR高表达荷瘤鼠中PET/CT图像如图15所示,显示肿瘤部位显像剂浓聚偏低。
8.临床转化结果
将68Ga标记Encarmin C注入肺癌患者体内进行PET/CT显像,结果显示肿瘤病变部位明显摄取该显像剂,提示肿瘤高表达FGFR(如图16-19所示),其中,图16-图18显示,左肺癌明显摄取该显像剂,提示FGFR高表达;图19显示,右肺癌明显摄取该显像剂,提示FGFR高表达。该系列图像在全球首创性将正电子核素标记Encarmin C PET/CT靶向FGFR显像实现了临床转化,并取得良好显像效果,为临床肿瘤诊疗提供了重要依据。
上述实验及临床转化结果表明,分子探针18F-NOTA-PEG2-FGFR-peptide具有良好的稳定性及代谢特征,荷瘤裸鼠的Micro-PET/CT显像效果良好。68Ga-DOTA-PEG2-FGFR-peptide肿瘤患者PET/CT显像临床转化也取得良好的显像效果,为全身、动态、无创监测FGFR1的表达水平的奠定了基础,更换相应螯合剂后,可实现放射性核素99mTc、68Ga、177Lu和90Y的标记,不同核素用于诊断和治疗,进一步实现肿瘤FGFR靶向诊疗一体化,并有望成为PRRT的一部分,为更多肿瘤患者诊疗带来好的生存获益。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据已经公开的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (10)
1.一种放射性探针,其特征在于,所述的放射性探针具备以下通式:M-L-G;所述的放射性探针标记有放射性核素;所述的M表示螯合剂,L为连接基团,G为Encarmin C。
2.根据权利要求1所述的放射性探针,其特征在于,所述的螯合剂包括DOTA、NOTA、NODGA、NODA、DOTP、TETA、ATSM、PTSM、EDTA、EC、HBEDCC、DTPA、SBAD、BAPEN、Df、DFO、TACN、NO2A/NOTAM、CB-DO2A、Cyclen、NOTA-AA、DO3A、DO3AP中的一种或多种。
3.根据权利要求2所述的放射性探针,其特征在于,所述的螯合剂为DOTA或NOTA。
4.根据权利要求1所述的放射性探针,其特征在于,所述的放射性核素包括18F、68Ga、177Lu、90Y、64Cu、124I、111In、89Zr、99mTc中的一种或多种。
5.根据权利要求4所述的放射性探针,其特征在于,所述的放射性核素包括18F、68Ga、177Lu、90Y、99mTc中的一种或多种。
6.根据权利要求1所述的放射性探针,其特征在于,所述的连接基团包括2-(4-氨基哌啶-1-基)乙酸、6-氨基己酸、PEG3、PEG4、PEG6、G6、PEG2中的一种或多种,优选的,所述的连接基团为PEG2。
7.根据权利要求1-6任一项所述的放射性探针,其特征在于,所述的螯合剂为NOTA,所述的放射性核素包括18F、68Ga。
8.根据权利要求1-6任一项所述的放射性探针,其特征在于,所述的螯合剂为DOTA,所述的放射性核素包括68Ga、177Lu、90Y。
9.根据权利要求1-6任一项所述的放射性探针,其特征在于,所述的螯合剂为氨基酸序列,所述的氨基酸序列为GGGC,优选的,所述的放射性核素为99mTc。
10.如下任一项所述的应用:
(1)Encarmin C在制备靶向FGFR1的显像剂中的应用,
优选的,所述的显像剂包含放射性探针,优选的,所述的放射性探针为如权利要求1-9任一项所述的放射性探针;
(2)权利要求1-9任一项所述的放射性探针在制备靶向FGFR1的显像剂中的应用;
(3)权利要求1-9任一项所述的放射性探针在制备试剂盒中的应用,所述的试剂盒用于筛选FGFR1靶向治疗潜在受益人群;
(4)权利要求1-9任一项所述的放射性探针在制备肿瘤诊断试剂中的应用;
(5)权利要求1-9任一项所述的放射性探针在制备治疗肿瘤的药物中的应用;优选的,所述肿瘤诊断包括肿瘤分期、病灶定位、疗效监测,
优选的,所述的疗效监测包括FGFR1靶向治疗的疗效预测、疗效评价、预后评估,
优选的,所述的药物为用于靶向治疗FGFR1阳性肿瘤的药物。
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