CN114470202A - 一种aie-pet双模态显像剂及其制备方法和应用 - Google Patents
一种aie-pet双模态显像剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种AIE‑PET双模式显像剂及其制备方法和应用,它是在有机小分子和聚合物结构的基础上,加入具有PET成像效果的放射性核素,通过自组装形成纳米粒子,并螯合放射性核素离子,合成兼具PET和荧光双模态成像特性的纳米材料。所述纳米材料在不同激发光照射下可产生可见光荧光和近红外二区荧光;同时,所制得的AIE分子本身具有光热效应,因此该纳米材料可用于肿瘤光热治疗。所述纳米材料在水溶液中均匀分散,平均粒径为110nm,可通过增强透过与滞留(EPR)效应被动靶向肿瘤,因此可作为肿瘤成像试剂和治疗药物。
Description
技术领域
本发明属于肿瘤成像和抗肿瘤治疗领域,具体涉及一种AIE(聚集诱导发光)-PET(正电子发射断层扫描)双模态显像剂及其制备方法和应用,该显象剂能够用于肿瘤显像和光热治疗。
背景技术
癌症已成为仅次于心血管疾病的人类第二大死因,尽管针对肿瘤诊断和治疗的方法不断涌现,肿瘤的异质性和个体差异性导致这些技术在临床实践中受到很大局限,难以惠及大多数肿瘤患者,而且诊断和治疗往往采用不同的试剂和药物,加重患者负担。因此,开发高效的肿瘤成像和治疗一体化药物对于肿瘤的早期诊断和治疗具有重要意义。
分子影像技术的发展为肿瘤病灶及其状态的可视化分析提供了重要的工具,这对于肿瘤的早期诊断具有重要意义。荧光成像是一种广泛用于临床前模型研究的便捷性成像技术,由于荧光成像具有较高的空间分辨率,其在临床肿瘤荧光手术导航中也在发挥越来越重要的作用,然而荧光对人体组织的穿透力有限,难以用于全身检查,特别是深层组织中病灶将难以被发现。正电子发射断层扫描(PET)是一种依靠放射性核素衰变产生的正电子与负电子湮灭所释放光子的信号来检测病灶的技术,其对于人体组织具有无限的穿透力,从而可用于全身显像,不足之处在于其空间分辨率有限,难以对局部病灶进行精准定位。因此,将荧光成像与PET成像结合,可以发挥优势互补作用,利用PET成像对病灶进行初步的定位,再利用荧光成像进行局部显像定位,清晰地勾勒肿瘤边界。
聚集诱导发光(AIE)分子是近年来发展迅速的一类新型荧光材料,其在聚集条件下产生荧光增强,能够抵抗光漂白,从而使成像时间大大增加,相比于传统荧光材料具有更高的稳定性,可以更稳定和长时间地追踪疾病进展。荧光波长的增加可以增强组织穿透性,从而可以获取更准确地空间信息,因此,AIE分子的发射波长从可见光(400-700nm)延伸至近红外一区(700-900nm),进一步延伸至近红外二区(1000-1700nm),因此近红外二区AIE材料的开发和生物应用具有巨大潜力。此外,一些具有治疗特性的AIE材料也被开发出来,用于肿瘤荧光成像和治疗研究。其中,光热治疗利用AIE分子的光热效应使肿瘤组织温度升高,导致肿瘤细胞死亡,实现肿瘤定点杀伤,可以减轻如化疗药物对人体的副作用。因此,将具有光热效应的AIE分子与PET核素结合,开发肿瘤荧光-PET双模态成像与治疗试剂,对肿瘤诊疗一体化技术的发展和实践具有重要意义。
目前,还没有兼具荧光-PET双模态成像与光热治疗特性的AIE-PET显像剂的报道,本发明公开了一种能够用于肿瘤显像和光热治疗的AIE-PET双模态显像剂及其制备方法和应用,其在肿瘤诊疗一体化研究领域具有广阔的前景。
发明内容
本发明的目的是提供一种能够用于肿瘤显像和光热治疗的AIE-PET双模态显像剂及其制备方法和应用,本发明是以AIE分子为核心,以两亲性聚合物为包覆材料和螯合剂,通过螯合的方式实现放射性核素标记,从而制备具有荧光和PET双重显像和光热治疗特性的显像剂。
本发明所述的AIE分子具有如下所示结构:
其制备方法为:
(1)氮气保护下,将化合物1、4-碘苯甲醚加入甲苯中,以叔丁醇钾、碘化亚铜和1,10-菲啰啉为催化剂,反应获得化合物2;
(2)氮气保护下,将化合物2、联硼酸频那醇酯加入1,4-二氧六环中,以乙酸钾和1,1'-双二苯基膦二茂铁二氯化钯为催化剂,反应获得化合物3;
(3)氮气保护下,将化合物3、5-溴-2,2'-联噻吩-5'-甲醛加入甲苯/水/乙醇混合溶剂中,以碳酸钾和四三苯基膦钯为催化剂,反应获得化合物4;
氮气保护下,将化合物5、3-溴丙酸加入1,2-二氯苯中,反应获得化合物6;
(4)氮气保护下,将化合物4、化合物6加入乙醇中,反应获得化合物TPA-TTINC;
本发明还公开了所述AIE-PET双模态显像剂的制备方法,包括如下步骤:
(1)纳米粒子制备:将AIE分子、DSPE-PEG2k和DSPE-PEG2k-DOTA聚合物超声分散于二氯甲烷中,然后通过旋转蒸发除去有机溶剂二氯甲烷,加入去离子水,超声混合均匀,通过0.22μm滤头过滤,得到AIE纳米粒子溶液;其中,优选的,AIE分子、DSPE-PEG2k、DSPE-PEG2k-DOTA的质量比为1:2:0.5~1:10:10;
(2)放射性核素标记:向含有放射性核素的溶液中加入2N HEPES缓冲液(pH=7),将核素溶液加入上述AIE纳米粒子溶液中,室温反应完成核素标记,得到AIE-PET双模态显像剂。其中,优选反应10-20min。
其中,所述的核素可以为68Ga或64Cu,核素离子通过与DSPE-PEG2k-DOTA聚合物中的DOTA进行螯合,实现核素标记。
所述的AIE-PET双模态显像剂在制备肿瘤荧光和PET显像试剂中的应用。
所述的AIE-PET双模态显像剂在制备肿瘤光热治疗试剂中的应用。
所述的AIE-PET双模态显像剂在制备肿瘤诊疗一体化试剂中的应用。
本发明的有益效果是:
本发明首次提供了一个可同时用于肿瘤近红外二区荧光成像和PET成像及光热治疗的多功能显像剂。此显像剂在短波激发下可以产生绿色荧光,从而可以实现细胞成像;而在长波激发下可产生近红外二区荧光,从而可以实现活体荧光成像。所标记的放射性核素可用于PET显像,实现无创肿瘤诊断。此外,此显像剂具有光热效应,可以用于肿瘤局部组织的光热治疗。因此,所开发的AIE-PET双模态显像剂可以同时作为成像试剂和肿瘤治疗药物用于肿瘤成像与光热治疗。
附图说明
为了使本发明的内容更容易被清楚地理解,下面根据本发明的具体实施例并结合附图,对本发明作进一步详细地说明。
图1为本发明所述AIE分子的合成路线图;
图2为化合物2的1H NMR分析图;
图3为化合物3的1H NMR分析图;
图4为化合物4的1H NMR分析图;
图5为化合物6的1H NMR分析图;
图6为化合物TPA-TTINC的1H NMR分析图;
图7为本发明实施例1中显像剂的吸收光谱图;
图8为本发明实施例1中显像剂在(A)405nm和(B)640nm激发下的发射图谱;
图9为本发明实施例1中显像剂的粒径测试图;
图10为本发明实施例1中不同浓度显像剂在0.3W/cm2激光光照下温度随时间的变化图;
图11为本发明实施例1中0.1mM浓度的显像剂在0.3W/cm2激光光照下加热-冷却循环曲线图。
具体实施方式
试剂与材料
4-溴苯胺,4-碘苯甲醚,碘化亚铜,联硼酸频那醇酯,1,1'-双二苯基膦二茂铁二氯化钯,四三苯基膦钯,叔丁醇钾,3-溴丙酸等购于安耐吉试剂公司。1,1,2-三甲基-1H-苯并[e]吲哚,1,10-菲啰啉,5-溴-2,2'-联噻吩-5'-甲醛等购于阿拉丁试剂公司。碳酸钾,乙酸钾,甲苯,1,4-二氧六环,乙醇,1,2-二氯苯等购于国药化学试剂有限公司。
实施例1
本发明所述的AIE分子TPA-TTINC合成路线如图1所示,以下结合一个具体实例,对本发明做进一步说明:
化合物2
氮气保护下,5.06g(29.1mmol)化合物1,20.41g(87.3mmol)4-碘苯甲醚,9.80g(87.3mmol)叔丁醇钾,1.10g(5.9mmol)碘化亚铜和1.10g(5.9mmol)1,10-菲啰啉加入60mL甲苯中,125℃回流反应12h,冷却,过滤,真空除去溶剂,将固体进行柱层析分离,得到橙红色固体产物4.96g(产率:44.3%)。
化合物3
氮气保护下,8.00g(20.8mmol)化合物2,7.90g(31.2mmol)联硼酸频那醇酯,14.00g(143.2mmol)乙酸钾,1.20g(1.7mmol)1,1'-双二苯基膦二茂铁二氯化钯加入180mL1,4-二氧六环中,110℃回流反应18h,冷却,用二氯甲烷和水萃取,有机相通过无水硫酸镁干燥后过滤,真空除去溶剂,将固体进行柱层析分离,得到橙黄色固体产物4.93g(产率:54.9%)。
化合物4
氮气保护下,4.30g(10.0mmol)化合物3,2.50g(9.2mmol)5-溴-2,2'-联噻吩-5'-甲醛,20.5g(150.0mmol)碳酸钾,0.60g(0.5mmol)四三苯基膦钯加入30/15/7.5mL甲苯/水/乙醇混合溶剂中,100℃回流反应7h,冷却,用乙酸乙酯和水萃取,有机相通过无水硫酸钠干燥后过滤,真空除去溶剂,将固体进行柱层析分离,得到红色固体产物2.31g(产率:50.4%)。
化合物6
氮气保护下,5.81g(27.8mmol)化合物5和4.23g(27.7mmol)3-溴丙酸加入80mL1,2-二氯苯中,110℃回流反应18h,冷却,用二氯甲烷洗涤,得到固体产物通过甲醇/乙醚重结晶,得到灰白色固体产物4.12g(产率:52.9%)。
化合物TPA-TTINC
氮气保护下,1.50g(3.0mmol)化合物4和1.30g(27.7mmol)化合物6加入20mL乙醇中,85℃回流反应18h,冷却,真空除去溶剂,所得固体通过柱层析分离,得到暗红色固体产物1.07g(产率:42.4%)。
实施例2
(1)纳米粒子制备:将10mg AIE分子TPA-TTINC、15mg DSPE-PEG2k和5mg DSPE-PEG2k-DOTA超声分散于二氯甲烷中,然后通过旋转蒸发除去有机溶剂二氯甲烷,加入5mL去离子水,50W超声2min,溶液通过0.22μm滤头过滤,得到AIE纳米粒子溶液;
(2)放射性核素标记:向0.5mL含有放射性核素68Ga的溶液中加入0.5mL 2N HEPES缓冲液(pH=7),将核素溶液加入0.5mL上述AIE纳米粒子溶液中,室温反应10min,即完成核素标记,得到AIE-PET双模态显像剂。
实施例3
显像剂的体外光热性能检测
将实施例2制备的显像剂按比例稀释至不同浓度的溶液,分别置于不同的离心管中,用638nm激光在不同功率下照射溶液,同时用热成像仪实时监测溶液温度变化,每30s记录一次。
显像剂的光热效应检测结果见图10。随着照射时间增加,溶液温度逐渐上升并趋于平稳,提高显像剂浓度,可使溶液的温差不断增加,在0.1mM的浓度下,能够达到40℃的温度差,体现出较强的光热性能,在肿瘤光热治疗中具有潜在的应用价值。
实施例4
显像剂的体外光热稳定性测试
将实施例2制备的显像剂稀释至0.1mM,置于不同的离心管中,用638nm激光在不同功率下照射溶液,同时用热成像仪实时监测溶液温度变化,每30s记录一次。
显像剂的光热稳定性检测结果见图11。随着照射时间增加,溶液温度逐渐上升,停止照射后,溶液温度快速下降,循环往复9次,可以看到,溶液温度在开启加热和中止加热的时刻没有显著变化,体现出显像剂较强的光热稳定性,可以在维持光热性能的同时承受较长时间的光照。
本发明得到的纳米材料在水溶液中可均匀分散,平均粒径为110nm,且可以看出,所得产物可以在短波激发下产生绿色荧光,从而可以实现细胞成像;而在长波激发下可产生近红外二区荧光,从而可以实现活体荧光成像。而所标记的放射性核素可用于PET显像,可实现无创肿瘤诊断。由此,本发明得到一种AIE-PET双模态显像剂;
此外,此显像剂具有稳定、优异的光热效应,可以用于肿瘤局部组织的光热治疗。因此,本发明所制备得到的AIE-PET双模态显像剂可以同时作为成像试剂和肿瘤治疗药物用于肿瘤成像与光热治疗中。可通过增强透过与滞留(EPR)效应被动靶向肿瘤,可作为肿瘤成像试剂和治疗药物。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和修饰,这些改进和修饰也应视为本发明的保护范围。
Claims (10)
1.一种AIE-PET双模态显像剂的制备方法,其特征在于,包括以下步骤:
(1)纳米粒子制备:将AIE分子、DSPE-PEG2k和DSPE-PEG2k-DOTA聚合物超声分散于二氯甲烷中,然后通过旋转蒸发除去有机溶剂二氯甲烷,加入去离子水,超声混合均匀,过滤,得到AIE纳米粒子溶液;
(2)放射性核素标记:向含有放射性核素的溶液中加入2N HEPES缓冲液(pH=7),将所得核素溶液加入上述AIE纳米粒子溶液中,室温下反应完成核素标记,得到AIE-PET双模态显像剂。
3.如权利要求2所述的AIE-PET双模态显像剂的制备方法,其特征在于,所述AIE分子的制备方法包括:
(1)氮气保护下,将化合物1、4-碘苯甲醚加入甲苯中,以叔丁醇钾、碘化亚铜和1,10-菲啰啉为催化剂,反应获得化合物2;
(2)氮气保护下,将化合物2、联硼酸频那醇酯加入1,4-二氧六环中,以乙酸钾和1,1'-双二苯基膦二茂铁二氯化钯为催化剂,反应获得化合物3;
(3)氮气保护下,将化合物3、5-溴-2,2'-联噻吩-5'-甲醛加入甲苯/水/乙醇混合溶剂中,以碳酸钾和四三苯基膦钯为催化剂,反应获得化合4;
氮气保护下,将化合物5、3-溴丙酸加入1,2-二氯苯中,反应获得化合物6;
(4)氮气保护下,将化合物4、化合物6加入乙醇中,反应获得化合物TPA-TTINC。
4.如权利要求1所述的AIE-PET双模态显像剂的制备方法,其特征在于,所述的核素为68Ga或64Cu。
5.如权利要求1所述的AIE-PET双模态显像剂的制备方法,其特征在于,所述的AIE分子、DSPE-PEG2k、DSPE-PEG2k-DOTA的质量比为1:2:0.5~1:10:10。
6.一种AIE-PET双模态显像剂,其特征在于,采用如权利要求1-5任一项所述方法制得。
7.如权利要求6所述的AIE-PET双模态显像剂在制备肿瘤荧光和PET显像试剂中的应用。
8.如权利要求6所述的AIE-PET双模态显像剂在制备肿瘤光热治疗试剂中的应用。
9.如权利要求6所述的AIE-PET双模态显像剂在制备肿瘤诊疗一体化试剂中的应用。
10.一种AIE分子,其特征在于,所述AIE分子为TPA-TTINC。
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---|---|---|---|---|
CN116768874A (zh) * | 2023-05-10 | 2023-09-19 | 华南理工大学 | 一种基于苯并吲哚的i型aie光敏剂及其制备方法和应用 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013029340A1 (en) * | 2011-09-01 | 2013-03-07 | The Hong Kong University Of Science And Technology | Biocompatible nanoparticles with aggregation induced emission characteristics as fluorescent bioprobes and methods of using the same for in vitro and in vivo imaging |
CN108904818A (zh) * | 2018-09-03 | 2018-11-30 | 国家纳米科学中心 | Ttd核杂化纳米颗粒、其制备方法及应用 |
CN109867591A (zh) * | 2019-03-12 | 2019-06-11 | 浙江大学 | 18f标记的aie荧光/pet双模态探针及其制备方法和应用 |
WO2020015700A1 (en) * | 2018-07-18 | 2020-01-23 | The Hong Kong University Of Science And Technology | Photothermal agents |
CN110862340A (zh) * | 2019-11-19 | 2020-03-06 | 西北大学 | 一种探针分子的合成方法 |
CN111978313A (zh) * | 2020-08-28 | 2020-11-24 | 深圳大学 | 具备聚集诱导发光性质的多模态光诊疗剂及其制备与应用 |
CN112852426A (zh) * | 2021-01-29 | 2021-05-28 | 深圳大学 | 基于聚集诱导发光的多功能纳米模板及其制备方法与应用 |
CN113498411A (zh) * | 2019-01-16 | 2021-10-12 | 香港科技大学 | 具有广泛颜色可调性以及聚集诱导发光特征的荧光化合物 |
-
2022
- 2022-01-11 CN CN202210027809.8A patent/CN114470202B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013029340A1 (en) * | 2011-09-01 | 2013-03-07 | The Hong Kong University Of Science And Technology | Biocompatible nanoparticles with aggregation induced emission characteristics as fluorescent bioprobes and methods of using the same for in vitro and in vivo imaging |
WO2020015700A1 (en) * | 2018-07-18 | 2020-01-23 | The Hong Kong University Of Science And Technology | Photothermal agents |
CN108904818A (zh) * | 2018-09-03 | 2018-11-30 | 国家纳米科学中心 | Ttd核杂化纳米颗粒、其制备方法及应用 |
CN113498411A (zh) * | 2019-01-16 | 2021-10-12 | 香港科技大学 | 具有广泛颜色可调性以及聚集诱导发光特征的荧光化合物 |
CN109867591A (zh) * | 2019-03-12 | 2019-06-11 | 浙江大学 | 18f标记的aie荧光/pet双模态探针及其制备方法和应用 |
CN110862340A (zh) * | 2019-11-19 | 2020-03-06 | 西北大学 | 一种探针分子的合成方法 |
CN111978313A (zh) * | 2020-08-28 | 2020-11-24 | 深圳大学 | 具备聚集诱导发光性质的多模态光诊疗剂及其制备与应用 |
CN112852426A (zh) * | 2021-01-29 | 2021-05-28 | 深圳大学 | 基于聚集诱导发光的多功能纳米模板及其制备方法与应用 |
Non-Patent Citations (5)
Title |
---|
KAIWU YU等: "Radiolabeled AIE Probes as Dual-modality Imaging Agents for PET/NIR-II Fluorescence-Guided Photothermal Therapy", 《CHEMISTRY AN ASIAN JOURNAL》, vol. 18, no. 11, pages 1 - 8 * |
XINGGUI GU等: "Corannulene-Incorporated AIE Nanodots with Highly Suppressed Nonradiative Decay for Boosted Cancer Phototheranostics In Vivo", 《ADVANCED MATERIALS》 * |
XINGGUI GU等: "Corannulene-Incorporated AIE Nanodots with Highly Suppressed Nonradiative Decay for Boosted Cancer Phototheranostics In Vivo", 《ADVANCED MATERIALS》, vol. 30, 16 May 2018 (2018-05-16), pages 1 - 9 * |
巩冠斐: "基于三足萘酰亚胺和功能化柱芳烃的AIE材料的合成及性能", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
巩冠斐: "基于三足萘酰亚胺和功能化柱芳烃的AIE材料的合成及性能", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》, no. 1, 15 January 2021 (2021-01-15), pages 1 - 100 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116768874A (zh) * | 2023-05-10 | 2023-09-19 | 华南理工大学 | 一种基于苯并吲哚的i型aie光敏剂及其制备方法和应用 |
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