CN111375072A - 可靶向葡萄糖调节蛋白grp78高表达肿瘤的放射性核素药物及其应用 - Google Patents
可靶向葡萄糖调节蛋白grp78高表达肿瘤的放射性核素药物及其应用 Download PDFInfo
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Abstract
本发明属于肿瘤放射诊断与治疗领域,涉及可靶向葡萄糖调节蛋白GRP78高表达的肿瘤放射性核素药物,具体涉及以D构型多肽DVAP、SVAP),以及L构型多肽LVAP为靶向分子,放射性同位素为显像基团,构建的肿瘤分子影像探针,以及以治疗用放射性同位素、放射增敏剂等为治疗基团,构建的肿瘤放射性治疗药物,结果显示VAP修饰的放射性核素能够特异性浓集于GRP78高表达的肿瘤组织,microPET/CT活体成像结果表明其对肿瘤组织具有靶向成像效果,且显著优于临床广泛使用的18F‑FDG;结果表明,以DVAP、SVAP、LVAP为靶向分子,可有效实现探针信号基团和治疗活性基团在GRP78高表达肿瘤组织的特异性分布,在肿瘤靶向诊断和治疗中具备良好的应用前景。
Description
技术领域
本发明属于肿瘤放射诊断与治疗技术领域,涉及可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物,具体涉及以D构型多肽DVAP(D构型氨基酸序列DPDADVDRDTDNDS)、SVAP(D构型氨基酸序列DSDNDTDRDVDADP),以及L构型多肽LVAP(氨基酸序列SNTRVAP))为靶向分子,放射性同位素为显像基团,构建的肿瘤分子影像探针,以及以治疗用放射性同位素、放射增敏剂、光敏剂等为治疗基团,构建的肿瘤放射性治疗药物。
背景技术
世界卫生组织2017年最新公布数据表明,全球每年有1400多万新发癌症病例,同时每年有880万人死于癌症,占全球每年死亡总人数近六分之一。癌症的早期发现、早期诊断、早期治疗是预防和控制癌症的基本策略,而分子影像学技术的高灵敏性、高特异性、高分辨率、实时、非侵入性等特点使其成为最有效的癌症早期诊断手段之一。该技术应用特异性的分子影像探针可以显示癌症组织、细胞和亚细胞水平的特定分子,反映活体状态下癌症的分子水平变化,从而揭示癌症的发生、发展、转移等变化过程。
现有技术公开了肿瘤放射性治疗是利用放射性核素释放的α、β、γ等射线的电离辐射作用杀死肿瘤组织和细胞、抑制肿瘤生长的一种局部治疗方法;大约70%的癌症患者在治疗癌症的过程中需要用到放射性治疗,约有40%的癌症可以用放射性治疗根治。放射性治疗在肿瘤治疗中的作用和地位日益突出,已成为治疗恶性肿瘤的主要手段之一。放射性治疗面临的主要问题是如何提高肿瘤区域的放射性剂量,减少在正常组织和器官的分布,降低其毒副作用。放射性治疗的新技术——利用靶向分子介导治疗性放射性核素特异性浓集于肿瘤靶区,实现对肿瘤的精准治疗,提高治疗效果,目前已成为放射性治疗研究的重要方向。
葡萄糖调节蛋白GRP78是内质网主要的分子伴侣之一,在蛋白质的折叠以及内质网应激反应中发挥着重要的作用。研究表明,GRP78蛋白在乳腺癌、肝癌、结肠癌、胃癌等多种实体肿瘤中均高表达,并且与这些肿瘤的发生、发展、转移、预后和耐药密切相关;以及,GRP78在肿瘤细胞中可以转移到细胞膜表面,使其在细胞膜表面的表达量显著增加,而在正常细胞的膜表面却未观察到这种转移,GRP78的分布上的差异使具有开发成为分子影像探针和治疗药物作用靶点的潜力,对提高肿瘤的诊断效率和治疗效果具有重要价值。LVAP(L构型氨基酸序列SNTRVAP)是通过噬菌体展示技术筛选出的一条七肽,研究证明其对GRP78具有高亲和活性;DVAP(D构型氨基酸序列DPDADVDRDTDNDS)和SVAP(D构型氨基酸序列DSDNDTDRDVDADP)是通过非天然氨基酸改造得到两条D构型多肽,研究表明其不但保留了对GRP78的高亲合性,同时克服了L多肽易被降解的缺点。迄今,这类多肽尚未有应用于肿瘤放射性核素诊断与治疗方面的研究报道。
基于现有技术的现状,本发明提供了VAP多肽连接放射性核素,构建肿瘤分子影像探针和肿瘤放射性治疗药物、光动力治疗药物,实现肿瘤的靶向诊断和治疗。
发明内容
本发明的目的是提供可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素分子探针和治疗药物,达到更好的肿瘤诊断效果和治疗作用。具体涉及将VAP多肽(DVAP(D构型氨基酸序列DPDADVDRDTDNDS)、SVAP(D构型氨基酸序列DSDNDTDRDVDADP)或LVAP(L构型氨基酸序列SNTRVAP))为靶向分子,通过双功能螯合剂与诊断用放射性同位素连接构建的肿瘤分子影像探针,以及与治疗用放射性同位素、放射增敏剂连接构建肿瘤放射性治疗药物和光动力治疗药物。
更具体的,本发明提供了可靶向GRP78的肿瘤分子探针和治疗药物,其特征是由放射性核素、双功能螯合剂和VAP靶向多肽组成,所述VAP靶向多肽包括D构型多肽DVAP(D构型氨基酸序列DPDADVDRDTDNDS)和SVAP(D构型氨基酸序列DSDNDTDRDVDADP),L构型多肽LVAP(L构型氨基酸序列SNTRVAP)。
所述GRP78靶向多肽DVAP、SVAP、LVAP连接半胱氨酸、赖氨酸、精氨酸、门冬酰胺、谷氨酰胺、脯氨酸、组氨酸、色氨酸、酪氨酸、丝氨酸、谷氨酸、门冬氨酸或其他中间体结构后,可通过硫醚键、仲(叔)胺基、醚键、酰胺键、酯键、异硫氰基、1.2,3-三氮唑等连接基团,共价连接探针信号基团、治疗活性基团、探针-治疗双功能复合基团,制备肿瘤分子探针、肿瘤治疗药物、探针-治疗双功能复合物。
本发明中,GRP78靶向多肽DVAP、SVAP、LVAP修饰的双功能螯合剂选自DOTA、DOTAGA、NOTA、NOTAGA、NODA、DTPA、TETA、CB-TE2A、Cyclam、DFO、MAG3、EC、EDTA、DADT、HYNIC、CE-DTS、NS3等
本发明中,GRP78靶向多肽DVAP、SVAP、LVAP修饰的肿瘤分子探针,其探针信号单元包括诊断用放射性同位素(18F、32P、35S、64Cu、67/68Ga、75Se、89Zr、86Y、99mTc、111/111mIn、123/125I、149/161Tb、177Lu等)。
本发明中,GRP78靶向多肽DVAP、SVAP、LVAP修饰的肿瘤治疗药物,其治疗活性单元包括治疗用放射性同位素(90Y、131I、152/155Tb、153Sm、177Lu、186/188Re、211At、212/213Bi、212Pb、225Ac、227Th等)、放射增敏剂、光敏剂等的一种或几种材料的结合。
本发明中,GRP78靶向多肽DVAP、SVAP、LVAP修饰的探针-治疗双功能复合物是将探针信号单元的一种或几种材料,与治疗活性单元的一种或几种材料相结合,使其具有分子探针和肿瘤治疗的双重功能。
本发明的GRP78靶向多肽DVAP、SVAP、LVAP可介导肿瘤分子探针、肿瘤治疗药物、探针-治疗双功能复合物靶向葡萄糖调节蛋白GRP78高表达的细胞及其组织,用于肿瘤的靶向诊断和治疗。
本发明中,GRP78靶向多肽DVAP、SVAP、LVAP修饰的肿瘤分子探针、探针-治疗双功能复合物应用的分子影像模式包括正电子发射断层成像、单光子发射断层成像、契伦科夫成像等的单模态成像和多模态成像,或在成像系统中引入荧光染料、量子点、磁性材料、超声微泡、光声纳米颗粒、光敏剂等,与近红外一区光学成像、近红外二区光学成像、磁共振成像、超声成像、光声成像等的多模态成像。
本发明的GRP78靶向多肽DVAP、SVAP、LVAP修饰的肿瘤治疗药物、探针-治疗双功能复合物应用的治疗方式包括放射性同位素治疗、光动力治疗,或二者的联合治疗。
本发明所设计的靶向GRP78的肿瘤诊断试剂盒是以DVAP、SVAP、LVAP饰的肿瘤分子探针作为诊断试剂,应用于体外分析研究和临床分子成像诊断。
本发明所设计的靶向GRP78的肿瘤治疗药物制剂是以DVAP、SVAP、LVAP修饰的肿瘤放射性治疗药物、探针-治疗双功能复合物为主要成分,以注射剂、混悬剂、乳剂、脂质体、聚合物胶束、微囊、纳米粒等为剂型,可同时包载一种或多种化学治疗药物实现联合治疗。
本发明经试验,结果显示:VAP修饰的放射性核素能够特异性浓集于GRP78高表达的肿瘤组织,microPET/CT活体成像结果表明其对肿瘤组织具有靶向成像效果,且效果显著优于临床广泛使用的18F-FDG,结果表明,以DVAP、SVAP、LVAP为靶向分子,可有效实现探针信号基团和治疗活性基团在GRP78高表达肿瘤组织的特异性分布,在肿瘤靶向诊断和治疗中具备良好的应用前景。
附图说明
图1、NOTA-DVAP的HPLC紫外图,其中,
色谱方法:色谱柱(Diamonsil C18):250×4.6mm;流动相A:水(含0.1%三氟乙酸),流动相B:乙腈(含0.1%三氟乙酸);洗脱程序:0-5min 5%B,5-25min 5%B-40%B,25-30min40%B;流速:1.0mL/min;柱温:25℃;检测:UV 220nm,,保留时间:15.6min。
图2、NOTA-DVAP的质谱图,其中,
ESI-MS:636.8(+2H+),425.0(+3H+),与理论分子量相符合。
图3、Al18F-NOTA-DVAP放化纯度鉴定图,其中,
色谱方法同上,保留时间:14.1min,经半制备纯化,标记化合物的放化纯度大于98%,符合实验要求。
图4、DOTA-DVAP的HPLC紫外图,其中,
色谱方法:色谱柱(Diamonsil C18):250×4.6mm;流动相A:水(含0.1%三氟乙酸),流动相B:乙腈(含0.1%三氟乙酸);洗脱程序:0-5min 5%B,5-25min 5%B-20%B,25-30min20%B;流速:1.0mL/min;柱温:25℃;检测:UV 220nm,,保留时间:8.4min。
图5、DOTA-DVAP的质谱图,其中,
ESI-MS:687.4(+2H+),458.8(+3H+),与理论分子量相符合。
图6、177Lu-DOTA-DVAP放化纯度鉴定图,其中,
色谱方法同上,保留时间:12.5min。经半制备纯化,标记化合物的放化纯度大于95%,符合实验要求。
图7、Al18F-NOTA-DVAP荷瘤小鼠生物分布图,其中,
图为荷瘤小鼠各脏器在不同时间点的Al18F-NOTA-DVAP放射性分布%ID/g柱状图。Al18F-NOTA-DVAP的分布结果显示该显像剂在荷瘤小鼠的体内清除较快,肾脏的高分布表明该显像剂主要通过肾脏进行消除,在肿瘤部位,给药后15min时Al18F-NOTA-DVAP的分布量可达4.49%ID/g,60min时其分布量仍有2.47%ID/g,表明该显像剂可特异性的浓集于GRP78高表达的肿瘤组织。
图8、18F-FDG荷瘤小鼠生物分布图,其中,
显示了荷瘤小鼠各脏器在不同时间点阳性对照18F-FDG放射性分布%ID/g柱状图,18F-FDG除了在肿瘤部位有显著性分布外,心脏、脑、肌肉、脾、肺等脏器和组织有分布,表明18F-FDG对肿瘤具有较好的成像效果,但其他脏器的高分布情况也严重干扰了对肿瘤部位的分子影像学诊断,不利于对肿瘤的精确定位,特别是对转移病灶的显像和判断。
图9、Al18F-NOTA荷瘤小鼠生物分布图,其中,
显示了荷瘤小鼠各脏器在不同时间点阴性对照Al18F-NOTA放射性分布%ID/g柱状图,Al18F-NOTA作为肾功能显像剂,在肾脏具有显著性分布,而在肿瘤部位无特异性高分布的情况,表明缺少了靶向基团DVAP-Cys的介导,Al18F-NOTA不能特异性浓集于GRP78高表达的肿瘤组织。
图10、Al18F-NOTA-DVAP、Al18F-NOTA、18F-FDG生物分布肿瘤/血液比,
图为不同时间点Al18F-NOTA-DVAP、Al18F-NOTA、18F-FDG在荷瘤小鼠的肿瘤和血液中分布量的比值,三种显像剂放射性分布的肿瘤/血液比值随着时间变化均逐渐增大,Al18F-NOTA-DVAP的放射性分布的肿瘤/血液比值在120min时达到最大值10.67,接近18F-FDG。
图11、Al18F-NOTA-DVAP、Al18F-NOTA、18F-FDG生物分布肿瘤/肌肉比
图为不同时间点Al18F-NOTA-DVAP、Al18F-NOTA、18F-FDG在荷瘤小鼠的肿瘤和肌肉中分布量的比值,Al18F-NOTA-DVAP的放射性分布的肿瘤/肌肉比在各个时间点均高于Al18F-NOTA和18F-FDG,表明该显像剂能够特异性的浓集于GRP78高表达的肿瘤组织,该显像剂的放射性分布的肿瘤/肌肉比在60min时达到最大值5.02,表明其最佳显像时间窗口为给药后60min。
图12、Al18F-NOTA-DVAP荷瘤小鼠microPET/CT活体成像图
图为给药后60min时Al18F-NOTA-DVAP的荷瘤小鼠microPET/CT活体成像图,显示了肿瘤部位显著的放射性特异性分布,而其他主要的脏器未见放射性的浓集,表明Al18F-NOTA-DVAP能够特异性靶向活体肿瘤,并在肿瘤部位高度聚集,形成高质量的分子显像图像。
图13、18F-FDG荷瘤小鼠microPET/CT活体成像图
图为给药后60min时阳性对照18F-FDG的荷瘤小鼠microPET/CT活体成像图,显示了18F-FDG在肿瘤部位显著的放射性分布,但脑、心、脾等其他脏器也有很强的放射性浓集,表明18F-FDG能够实现对肿瘤部位的显像和定位,但在其他脏器的高分布会显著干扰对肿瘤组织的显像效果。
图14、Al18F-NOTA荷瘤小鼠microPET/CT活体成像图
图为给药后60min时阴性对照Al18F-NOTA的荷瘤小鼠microPET/CT活体成像图,显示了Al18F-NOTA在肿瘤部位几乎无放射性的分布,表明在缺少靶向基团的介导作用下,Al18F-NOTA不能浓集与肿瘤组织。
具体实施方式
通过下述实施例将有助于进一步理解本发明,但本发明不局限于如下描述范围。
实施例1 放射性核素标记DVAP的制备与表征
1)NOTA-DVAP的合成与表征
将D构型氨基酸DVAP-Cys溶于0.1M的PBS溶液中(pH7.2),取Mal-NOTA溶于DMF,两者混合后,室温磁力搅拌反应过夜,HPLC监测,待DVAP-Cys反应完全后停止反应,半制备纯化,用乙腈/水(含0.1%TFA)体系分离纯化。冷冻干燥得NOTA-DVAP,HPLC图谱、质谱图如图1、图2所示。
2)Al18F-NOTA-DVAP的标记和纯化
取74MBq18F的0.4M KHCO3洗脱液,加入10μL冰醋酸和100μL 2mM AlCl3溶液,室温下温育5分钟后,加入150μL 4mg/mL NOTA-DVAP溶液,再加入0.1M NaOAc溶液补足总体积1mL,105~110℃加热反应15分钟,反应完毕后用中性氧化铝小柱分离游离18F,半制备纯化,减压浓缩,生理盐水溶解,HPLC鉴定放化纯度,HPLC放射性图谱如图3所示。
3)DOTA-DVAP的合成与表征
将D构型氨基酸DVAP-Cys溶于0.1M的PBS溶液中(pH7.2),取Mal-DOTA溶于DMF,两者混合后,室温磁力搅拌反应过夜,HPLC监测,待DVAP-Cys反应完全后停止反应,半制备纯化,用乙腈/水(含0.1%TFA)体系分离纯化。冷冻干燥得DOTA-DVAP,HPLC图谱、质谱图如图4、图5所示。
4. 177Lu-DOTA-DVAP的标记和纯化
取110MBq177LuCl3溶液,加入400μL 1M醋酸钠溶液调节pH值为4,再加入120μL4mg/mL DOTA-DVAP溶液,70~80℃加热反应30分钟,反应完毕后用中性氧化铝小柱分离游离177Lu,半制备纯化,减压浓缩,生理盐水溶解,HPLC鉴定放化纯度,HPLC放射性图谱如图6所示。
实施例2
Al18F-NOTA-DVAP的体内分布实验
首先构建皮下瘤动物模型,将处于对数生长期的4T1乳腺癌细胞胰酶消化,调整细胞浓度为3×106个/mL,接种100μL至BALB/c小鼠右侧乳垫部皮下,接种后饲养于SPF级,定期观察肿瘤大小,待肿瘤大小为200mm3时,筛选出无坏死、肿瘤形状规则的荷瘤裸鼠,分组进行试验,荷瘤小鼠尾静脉给予100μCi Al18F-NOTA-DVAP,n=3,分别于时间点15、30、60、120min处死,解剖取脏器:血、心、肝、脾、肺、肾、脑、肌肉、肿瘤,放射性计数,以18F-FDG为阳性对照,Al18F-NOTA为阴性对照,结果如图7~11所示。
实施例3
Al18F-NOTA-DVAP的活体成像实验
4T1乳腺癌荷瘤小鼠尾静脉给予100~120μCi Al18F-NOTA-DVAP,异氟烷麻醉后,用microPET/CT进行全身扫描成像,计算肿瘤部位感兴区的放射性分布情况。以18F-FDG为阳性对照,Al18F-NOTA为阴性对照,结果如图12~14所示。
上述实施例仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物,其特征是,由放射性核素、双功能螯合剂和VAP靶向多肽组成。
2.按权利要求1所述的可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物,其特征是,所述的放射性核素选自18F、32P、35S、64Cu、67/68Ga、75Se、89Zr、86Y、99mTc、111/111mIn、123/125I、149/161Tb、177Lu诊断用放射性同位素的一种或几种,用于肿瘤的分子影像学诊断。
3.按权利要求1所述的可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物,其特征是,所述的放射性核素选自90Y、131I、152/155Tb、153Sm、177Lu、186/188Re、211At、212/213Bi、212Pb、225Ac、227Th治疗用放射性同位素、放射增敏剂、光敏剂的一种或几种,用于肿瘤放射治疗。
4.按权利要求1所述的可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物,其特征是,所述的双功能螯合剂选自DOTA、DOTAGA、NOTA、NOTAGA、NODA、DTPA、TETA、CB-TE2A、Cyclam、DFO、MAG3、EC、EDTA、DADT、HYNIC、CE-DTS、NS3可螯合放射性核素。
5.按权利要求1或4所述的可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物,其特征是,所述的双功能螯合剂为通过硫醚键、仲(叔)胺基、醚键、酰胺键、酯键、异硫氰基、1.2,3-三氮唑定位结合于VAP多肽的双功能螯合剂。
6.按权利要求1所述的可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物,其特征是,所述的VAP靶向多肽为序列中含DPDADVDRDTDNDS、或DSDNDTDRDVDADP、或LSLNLTLRLVLALP的由非天然氨基酸或天然氨基酸组成的多肽,其特异性结合葡萄糖调节蛋白GRP78;优选的VAP靶向多肽为D构型多肽DPDADVDRDTDNDS、DSDNDTDRDVDADP和L构型多肽LSLNLTLRLVLALP。
7.权利要求1所述的可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物在制备用于介导葡萄糖调节蛋白GRP78途径,实现肿瘤的靶向分子影像诊断和靶向治疗制剂中的用途。
8.按权利要求7所述的用途,其特征在于,所述的肿瘤分子影像包括正电子发射断层成像、单光子发射断层成像、契伦科夫成像的单模态成像和多模态成像,或在成像系统中引入荧光染料、量子点、磁性材料、超声微泡、光声纳米颗粒、光敏剂等,与近红外一区光学成像、近红外二区光学成像、磁共振成像、超声成像、光声成像的多模态成像。
9.按权利要求7所述的用途,其特征在于,所述的肿瘤治疗是包括放射性同位素治疗、光动力治疗的一种或几种方式联合。
10.权利要求1所述的可靶向葡萄糖调节蛋白GRP78高表达肿瘤的放射性核素药物在制备肿瘤诊断试剂盒或肿瘤治疗药物制剂的用途。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160045626A1 (en) * | 2007-01-11 | 2016-02-18 | Immunomedics, Inc. | Methods and Compositions for Improved Labeling of Targeting Peptides |
CN105713075A (zh) * | 2014-12-04 | 2016-06-29 | 北京睿德欧生物科技有限公司 | 一种EphB4 受体靶向多肽及其应用 |
CN108164584A (zh) * | 2016-12-07 | 2018-06-15 | 复旦大学 | Vap多肽及其在制备靶向诊疗肿瘤药物中的应用 |
-
2018
- 2018-12-29 CN CN201811653840.2A patent/CN111375072A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160045626A1 (en) * | 2007-01-11 | 2016-02-18 | Immunomedics, Inc. | Methods and Compositions for Improved Labeling of Targeting Peptides |
CN105713075A (zh) * | 2014-12-04 | 2016-06-29 | 北京睿德欧生物科技有限公司 | 一种EphB4 受体靶向多肽及其应用 |
CN108164584A (zh) * | 2016-12-07 | 2018-06-15 | 复旦大学 | Vap多肽及其在制备靶向诊疗肿瘤药物中的应用 |
Non-Patent Citations (1)
Title |
---|
沈周俊: "现代肾上腺外科诊疗学", 上海交通大学出版社, pages: 124 - 126 * |
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