CN105682690A - 用于手术前和手术中胰岛素瘤诊断的临床多模式工具 - Google Patents
用于手术前和手术中胰岛素瘤诊断的临床多模式工具 Download PDFInfo
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Abstract
具有以下通式的化合物:Ex4-接头-Sar(64Cu)-Fl,其中Ex4是毒蜥外泌肽-4类似物;接头是聚乙二醇(PEG)链,例如用四个乙二醇残基形成的聚乙二醇链;Fl是光致发光部分,以及Sar(64Cu)是在sarcophagine部分中螯合的铜-64原子,该化合物可用作多重模式成像剂用于胰岛素瘤细胞和β-细胞群的检测和定位。
Description
相关申请的声明
本申请要求在2013年7月25日提交的美国临时申请号61/858,550的优先权,所述申请在允许这样的结合的所有权限内通过引用予以结合。
发明领域
本申请涉及一种用于多模式成像的化合物,以及该化合物在手术前和手术中胰岛素瘤和B-细胞群成像、定位和诊断中的用途。
发明背景
虽然胰岛素瘤是最常见形式的胰岛癌,但在一般人群中的发病率只有1-4人/百万人,这使其成为一种罕见的并且不幸的是经常被忽视的癌症形式。所述发病率在尸检研究中被报道为更高(0.8%至10%),这表明这些肿瘤经常保持为未确诊的。在大多数情况下,由于在不同的成像模式中它们的低信号和噪声对比,胰岛素瘤的诊断和去除都是困难的。除此之外,患者经常存在着非特异性的和/或不明的症状,所述症状导致含糊的诊断和假阳性/阴性结果。同样地,在胰岛素瘤的情况下肿瘤组织的切除可能是困难的,因为肿瘤边缘往往是不容易划定的。因此,对诊断工具存在着未满足的临床需求,所述诊断工具可以清楚而明确地诊断胰岛素瘤,以及一旦胰岛素瘤被检测,则协助它们的手术去除。此外,到目前为止,不存在用于胰岛素瘤的诊断工具,所述诊断工具是非侵入性的,广泛使用的,并且是易于实施的。
发明简介
为了解决这些需求,本发明提供了一种可用作多模式成像剂的化合物。该化合物具有通式:
Ex4-接头-Sar(64Cu)-Fl
其中
Ex4是毒蜥外泌肽-4(extendin-4)类似物;
接头是聚乙二醇(PEG)链,例如用四个乙二醇残基形成的聚乙二醇链;
Fl是光致发光部分,和
Sar(64Cu)是在sarcophagine部分中螯合的铜-64原子。
在优选的实施方案中,毒蜥外泌肽-4类似物经由SEQIDNO:1中氨基酸12的修饰与Sar(64Cu)偶联。一种具体的毒蜥外泌肽-4类似物显示在SEQIDNO:2中。
一种示例性的光致发光部分是磺基-Cy5。
所述化合物的一个具体实施方案具有在图1中所示的结构。在本申请中,该化合物是指64Cu-E4x12-Sar-Fl。
本发明的化合物可通过经由光致发光部分的光学成像技术和通过检测64Cu的成像技术例如正电子发射断层扫描术(PET)检测。因此,本发明进一步提供所述化合物在使用任一种或两种可检测元件的诊断成像中的用途。
本发明进一步提供了一种诊断方法,其中本发明的多模式成像剂,例如64Cu-E4x12-Sar-Fl,用于检测患者中的胰岛素瘤细胞,所述患者包括人类患者,所述方法通过引入多模式成像剂至患者,并且通过PET成像、光学检测或两者来检测该化合物,以确定胰岛素瘤细胞是否存在。该检测可以在诊断成像装置中进行,或用于定位肿瘤的手术中肿瘤检测以方便手术去除。
附图简述
图1显示本发明的化合物的一个具体实施方案的结构,64Cu-E4x12-Sar-Fl。
图2显示图1化合物的合成方案。
图3显示呈非放射性标记形式的本发明化合物的激发和发射光谱。
图4显示使用64CuCl2放射性标记图1化合物的流程。
发明详述
本发明提供了一类新的多模式成像剂,其可以用于胰岛素瘤的PET成像和手术中光学成像两者。通过将单个分子中的核和光学示踪剂与靶向部分组合,我们能够从每个模式的独特性质中受益;PET提供了显著更高的空间分辨率,和允许放射性示踪剂浓度的定量分析,并且荧光成像提供高分辨率的图像。
多模式成像剂的开发提出了在单一模式试剂中不一定发现的潜在挑战。首先,可检出部分的附接可能改变靶向部分的结合亲和力,产生风险,即与缺乏该化合物的检测组分时相比,靶向部分将变得不太有效。其次,所述检测组分的附接可能影响探针的药物动力学,其产生排泄率的变化从而导致延长或缩短的血液半衰期。这会影响所需的成像剂的量以及用于进行诊断或手术中定位的时间帧。
这些挑战得以满足,并且根据本发明提供化合物,其具有通式:
Ex4-接头-Sar(64Cu)-Fl。
在这种化合物中,Ex4表示毒蜥外泌肽-4类似物。毒蜥外泌肽-4为具有SEQIDNO:1所示序列的39个氨基酸的肽。如在本申请中所使用的,术语“毒蜥外泌肽-4类似物”是指39个残基序列,其中一个氨基酸被修饰以提供用于毒蜥外泌肽-4连接至接头的位点。具体的残基可以变化,虽然在具体的实施方案中,修饰的残基是SEQIDNO:1的氨基酸12。选择残基修饰的性质以与接头的官能性相适应,以促进在毒蜥外泌肽-4类似物与接头之间结合的形成。在下面的具体实例中,带有叠氮化物的聚乙二醇接头被用于带有非天然氨基酸的毒蜥外泌肽-4类似物,所述非天然氨基酸具有炔部分(S)-2-氨基-4-戊炔酸。然而,其他的修饰的氨基酸可以被用于提供与接头上的其它官能团的反应性。
所述式的“接头”部分包括用于连接到式中Ex4和Sar部分的官能团,其通过聚乙二醇链隔开。该聚乙二醇链的长度可以变化以改变特性,所述特性如化合物在体内的半衰期和毒蜥外泌肽-4类似物的结合亲和力。在具体的实例中,接头包含4个聚乙二醇部分。
在通式中的Sar(64Cu)元件表示与64Cu原子螯合的sarcophagine部分。在图1的具体实例中,氨基甲基-苄基修饰的铜螯合剂sarcophagine被用于连接磺基-Cy5荧光示踪剂Fl。
使用在图2A-D中列出的流程,合成图1的多模式成像剂64Cu-E4x12-Sar-Fl。这个流程基于已建立的反应顺序(15-17)。最终分子的组成部分的最初评价确定了经由合成Cu-E4x12-Sar-Fl,64Cu-E4x12-Sar-Fl的非放射性版本的流程的可行性。Sarcophagine(DiAmSar)连接荧光示踪剂(磺基-Cy5)以及螯合剂和生物标记之间的聚乙二醇(PEG)接头。DiAmSar也可以作为用于放射性铜的螯合剂。在N-Boc-4-(氨基甲基)-苄基溴(携带受保护的伯胺的高反应性的亲电子试剂)存在的条件下,所述DiAmSar被官能化,使得在用三氟乙酸处理后,荧光示踪剂和PEG接头的连接相较于之前使用苯胺衍生物的尝试(20)是更成功的。经由氨基甲基-苄基单元的DiAmSar延长创造了对亲核取代反应在空间上有利的环境。最后,在K12位点修饰的新肽E4x12,允许双官能sarcophagine成像剂经由铜(I)催化的叠氮化物-炔1,3-偶极环加成反应(21)而连接到生物分子示踪剂上。通过HPLC和ESI-MS确认Cu-E4x12-Sar-Fl的五步合成。图3显示Cu-E4x12-Sar-Fl的特定吸收和发射色谱,具有648nm的最大吸收和660nm的最大发射;这与磺基-Cy5的文献值相一致。
图4显示使用64CuCl2放射性标记所述化合物的流程。
本发明的化合物,包括64Cu-E4x12-Sar-Fl,满足了未满足的临床需求。即使肿瘤尺寸小于2cm,它允许医师对胰岛素瘤肿瘤定位。此外,在肿瘤的外科手术切除期间,可以使用相同的药物进行手术中光学成像。
此外,本发明的化合物,包括64Cu-E4x12-Sar-Fl,可以被用于在评估1型糖尿病的自身免疫性破坏程度中量化β细胞群。
本发明的化合物提供了允许胰岛素瘤肿瘤的诊断和手术中光学去除的模块化平台。通常,多模式成像系统,如此处所提出的多模式成像系统,具有许多优于传统标记探针(PET或荧光)的优点。相比于PET成像(虽然其已经成为在当今的临床实践中的主力技术之一),手术中光学成像和增强的外科手术系统仍然必须证明它们的临床适用性。本发明的化合物,包括64Cu-E4x12-Sar-Fl,满足了这种未满足的临床需要。
对于在活体小鼠中胰岛素瘤的PET成像,64Cu-E4x12-Sar-Fl在类似于先前的已开发方案(15-17)的条件下被使用。带有INS-1、MIN6或916-1肿瘤异种移植物的每只小鼠,接受溶解在磷酸盐-缓冲盐水(PBS,150μL)中的饱和剂量(0.2nmol/g)的64Cu-E4x12-Sar-Fl。在静脉注射64Cu-E4x12-Sar-Fl之后,化合物通过血流循环和积聚在表达GLP-1受体的细胞上。同时,非特异性结合的物质将通过肾脏而被系统性排泄。在循环期间,动态全身PET扫描将跟踪64Cu-E4x12-Sar-Fl的积累过程,并且允许在活体小鼠中胰岛素瘤肿瘤和胰腺β细胞的特异性定位。
PET示踪剂如64Cu允许宏观地成像和检测肿瘤。在与PET示踪剂的组合中,额外的光致发光标记允许广泛领域的手术中成像和在肿瘤组织的鉴定和外科手术切除中的提供帮助。在单个分子中的放射性示踪剂和光致发光标记的组合提供了组合深部组织穿透与高分辨率宽场成像的能力。活体高分辨率内部检查允许医生快速鉴定肿瘤边缘和微浸润。这另外协助外科手术边缘的分析,其可以实时和现场提供,因为不需更免疫组织化学染色以从健康组织上描绘损害。
实施例
虽然在上面的公开中对本发明进行了全面描述和使其可行,但提供以下的实施例以证明本发明的益处。
体外受体结合测定法。先前描述的受体结合测定法(26)被用于确定64Cu-E4x12-Sar-Fl的受体结合亲和力。将HEK-hGLPR1R人胚胎肾细胞接种在96孔板(每孔5.5×104个细胞)上,并且在37℃下生长48小时。用结合缓冲液(120mM的NaCl,1.2mM的MgSO4,13mM的乙酸钠,5mM的KCl,1.2g/L的Tris,2g/L的牛血清白蛋白(BSA)和1.8g/L的葡萄糖,pH7.6)洗涤之后,细胞用30pM的125I-毒蜥外泌肽4(9-39,PerkinElmer,Boston,MA)和64Cu-E4x12-Sar-Fl(最终浓度范围:10-12-10-6M)共处理。在37℃下培养2小时后,用含有1mg/mLBSA的PBS(3×150μL)洗涤细胞,并裂解(RIPA1×缓冲液,15分钟)和使用Wallac3″1480自动γ计数器测量内含物的反应活性。
相比于具有4.7±0.8nM的IC50的毒蜥外泌肽-4,双模式成像示踪剂64Cu-E4x12-Sar-Fl的略微较高的IC50值50.3±3.7nM。在共焦细胞成像中证实64Cu-E4x12-Sar-Fl的结合亲和力,其中GLP-1R阳性916-1胰岛素瘤细胞表现出强吸收。用64Cu-E4x12-Sar-Fl(10nM或100nM,90分钟)培养之后,将细胞固定并用Cellomics蓝全细胞染色(ThermoScientific,MA,USA)将细胞染色,表明荧光成像探针的内在化,其类似于之前所观察到的(16)。为了显示64Cu-E4x12-Sar-Fl对GLP-1R的特异性,在用64Cu-E4x12-Sar-Fl培养916-1细胞之前用过量的未修饰的肽E4x12(1μM)预培养916-1细胞,并且在NIR中观察到抑制的荧光信号。
体内实验
动物。按照由MemorialSloanKetteringCancerCenter的机构动物护理和使用委员会设置的指导方针,进行所有的动物实验和流程。转基因纯合B6.Cg-Tg(Ins1-GFP)1Hara/J小鼠,其在小鼠胰岛素1启动子(MIP-GFP)的控制下表达GFP,获自Jackson实验室,并且在6-8周龄饲养。得到的同窝仔被用于胰腺β细胞群成像。雌性无胸腺裸鼠(Taconic实验室;CrTac:NCr-Foxnlnu,6-8周,20-22克)在右肩用肿瘤诱导。916-1胰岛素瘤细胞(3.0×106)悬浮在1∶1的培养基和基质胶混合物(150μL)中,并且皮下注射以在3周后建立异种移植肿瘤小鼠模型(<2mm的肿瘤体积)。
血液半衰期。通过侧尾静脉,雌性裸鼠(6-8周,n=4)被注射含6464Cu-E4x12-Sar-Fl(30-35μCi)的PBS(5%的DMSO,200μL)。在预定的时间点(2,4,8,16,30,60,90,120,150和180分钟),从每只动物的大隐静脉中获得血液样品。用来自PerkinElmer的WIZARD2自动γ计数器记录所述血液样品的放射性,并且测定收集的血液样本的重量。表示为百分比注射剂量/克(%ID/g)的示踪剂摄取的百分比,按血液重量中存在的活性/实际注射剂量进行计算,其对计数时间进行衰减校正。
测定加权t1/2为10.1分钟。半衰期拟合为两相指数衰减曲线,类似于具有快速试剂分布和慢速试剂消除阶段的多室模型。
PET成像。小动物PET成像数据被记录在微PET聚焦120上。含64Cu-E4-Fl(335±35μCi)的PBS(4%的DMSO,200μL)通过尾静脉被注射到荷瘤裸鼠(n=7)中。在注射之后5-6小时,用在氧气中以2L/分钟的1.5-2.0%异氟烷(BaxterHealthcare)麻醉小鼠并且记录PET图像经过10分钟。用与作为封闭剂的含未标记毒蜥外泌肽-4(100倍过量)的PBS(4%的DMSO,200μL)预混合的64Cu-E4x12-Sar-Fl(335±35μCi),注射另一组裸鼠(n=5),并且确定毒蜥外泌肽-4对GLP-1受体的特异性。使用AsiProVM软件(ConcordeMicrosystems)分析图像。通过绘制在四个不同切片中感兴趣的区域(ROI)和将最大值平均,进行在异种移植肿瘤中活性浓度的定量。在所得到的PET图像中,GLP-1R阳性916-1肿瘤是易于可视化的。
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Claims (24)
1.以下通式的化合物:
Ex4-接头-Sar(64Cu)-Fl
其中
Ex4是毒蜥外泌肽-4类似物;
接头是聚乙二醇链;
Fl是光致发光部分,和
Sar(64Cu)是在sarcophagine部分中螯合的铜-64原子。
2.根据权利要求1的化合物,其中所述毒蜥外泌肽-4类似物经由SEQIDNO:1中氨基酸12的修饰与Sar(64Cu)偶联。
3.根据权利要求2的化合物,其中所述毒蜥外泌肽-4类似物是SEQIDNO:2。
4.根据权利要求3的化合物,其中Fl是磺基-Cy5。
5.根据权利要求3的化合物,其中所述接头的聚乙二醇链由四个乙二醇残基组成。
6.根据权利要求1的化合物,其中Fl是磺基-Cy5。
7.根据权利要求6的化合物,其中所述接头的聚乙二醇链由四个乙二醇残基组成。
8.根据权利要求1的化合物,其中所述化合物具有结构
9.一种用于在患者中检测胰岛素瘤细胞的方法,所述患者包括人类患者,所述方法包括将权利要求1至8中任一项的化合物引入到患者中,并且通过64Cu的检测、光致发光部分的光学检测或两者来检测该化合物,以确定胰岛素瘤细胞是否存在。
10.根据权利要求10的方法,其中所述检测步骤包括用于肿瘤可视化的手术中光学检测步骤。
11.根据权利要求9的方法,其中所述检测步骤包括诊断图像的创建。
12.权利要求1至8中任一项的化合物用于检测和/或定位胰岛素瘤细胞的用途。
1.以下通式的化合物:
Ex4-接头-Sar(64Cu)-Fl
其中
Ex4是毒蜥外泌肽-4类似物;
接头是聚乙二醇链;
Fl是光致发光部分,和
Sar(64Cu)是在sarcophagine部分中螯合的铜-64原子。
2.根据权利要求1的化合物,其中所述毒蜥外泌肽-4类似物经由SEQIDNO:1中氨基酸12的修饰与Sar(64Cu)偶联。
3.根据权利要求2的化合物,其中所述毒蜥外泌肽-4类似物是SEQIDNO:2。
4.根据权利要求3的化合物,其中Fl是磺基-Cy5。
5.根据权利要求3的化合物,其中所述接头的聚乙二醇链由四个乙二醇残基组成。
6.根据权利要求1的化合物,其中Fl是磺基-Cy5。
7.根据权利要求6的化合物,其中所述接头的聚乙二醇链由四个乙二醇残基组成。
8.根据权利要求1的化合物,其中所述化合物是64Cu-E4x12-Sar-Fl。
9.一种用于在患者中检测β-细胞群和胰岛素瘤细胞的方法,所述患者包括人类患者,所述方法包括将权利要求1至8中任一项的化合物引入到患者中,并且通过64Cu的检测、光致发光部分的光学检测或两者来检测该化合物,以确定β-细胞群或胰岛素瘤细胞是否存在。
10.根据权利要求10的方法,其中所述检测步骤包括用于肿瘤可视化的手术中光学检测步骤。
11.根据权利要求9的方法,其中所述检测步骤包括诊断图像的创建。
12.权利要求1至8中任一项的化合物用于检测和/或定位胰岛素瘤细胞和/或β-细胞群的用途。
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WO2012121746A2 (en) * | 2011-03-09 | 2012-09-13 | The General Hospital Corporation | Imaging beta cell mass |
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