CN112010862B - 一种主动靶向叶酸受体近红外荧光分子及其制备方法 - Google Patents
一种主动靶向叶酸受体近红外荧光分子及其制备方法 Download PDFInfo
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Abstract
本发明涉及近红外手术导航荧光分子及细胞标记成像等领域，具体公开了一种主动靶向近红外荧光小分子的结构及其制备方法。本发明通过利用有机全合成的方法制备了培美曲塞二钠及其衍生物为主动靶向基团的主动靶向近红外荧光小分子。这种主动靶向近红外荧光分子具有主动靶向性高、特异性强，水溶性好和荧光量子产率高等优点。
Description
技术领域
本发明涉及近红外手术导航荧光分子及细胞标记成像等领域，具体涉及一种主动靶向近红外荧光小分子及其制备方法。
背景技术
吲哚菁绿(Indocyanine green，ICG)是一种亲水性荧光示踪剂，其分子量约为776Da。在被用于荧光示踪之前，其还广泛的应用于肝功能的评估、心输出量的评估以及眼底血管造影。在波长780nm的近红外荧光的照射下其能发出波长为830nm的荧光，具备良好的穿透性，一些深层的组织都能利用ICG进行荧光探测。当ICG进入血液后，能迅速与血浆蛋白结合，形成蛋白包裹的ICG纳米分子，能够通过EPR效应在肿瘤组织中富集并且被网状内皮吞噬***吞噬，从而参与肿瘤显影及***示踪。另外，研究显示ICG并不会提升患者短期及长期并发症的风险，生物安全性高。因此，利用ICG不仅能够实现非侵袭性的深部血管、***造影，还能用于即时的外科手术术中荧光示踪。但是根据文献报道近年在大量临床及动物活体实验所观察的结果，作为肿瘤荧光示踪剂，ICG还存在以下问题：
1)低荧光发射效率(量子产率在水溶液中<1％)，对设备灵敏度要求高。根据我国药监法规，人体ICG最大注射剂量应小于2mg/kg，在此剂量下，文献报道和我们自己检测数据发现，ICG在人体肿瘤的浓度在10-1000nM，而目前大多数设备有效检测范围在10-1000μM，两者相差1000倍。
2)临床实践中发现ICG在肿瘤及正常组织的代谢速率差别不大，至少需要等待12小时后才能产生足够的荧光对比度(肿瘤：正常组织)，增加了医院及病人的负担。
由此可见，研制高荧光量子产率、具有主动肿瘤靶向性、在正常组织可快速清除的新一代荧光示踪剂，可以弥补ICG在实际使用中的不足，具有很高的科研及临床应用价值。有研究表明整合素在多种恶性肿瘤细胞表面或肿瘤组织新生血管内皮细胞上具有较高水平的表达，例如胃癌、卵巢癌及乳腺癌等，而正常组织的细胞或成熟血管内皮细胞则表达很少。靶向肿瘤组织高表达的整合素或可实现药物的精准递送。目前培美曲塞二钠及其衍生物作为一种成熟、安全的靶向肿瘤药物能够同细胞表面的整合素紧密结合抑制破坏细胞内叶酸依赖性的正常代谢过程，抑制细胞复制，从而抑制肿瘤的生长。培美曲塞二钠及其衍生物在保证其良好靶向性的同时具备更佳的体内稳定性，在近红外荧光小分子的修饰中具备更大的潜力。
发明内容
本发明旨在提供一种主动靶向叶酸受体近红外荧光小分子以及该分子的制备方法，该分子的结构式为：
其中，X选自如下结构：
Y选自S0456及其衍生物；
Y通过与X的酪氨酸侧链的酚部分形成醚键而连接到X上。
进一步的，一种主动靶向叶酸受体近红外荧光小分子的结构如下：
M独立地选自H、Na和K。
以如下分子结构为例：
其制备过程包括以下步骤：
S1、S0456的合成；
S2、培美靶向药物合成以及Pemetrexed-Tyr的制备；
S3、Pemetrexed-Tyr和S0456反应生成Pemetrexed-Tyr-S0456。
进一步的，上述步骤S1中，包括以下步骤：
S11、将4-肼苯磺酸、3-甲基-2-丁酮、冰醋酸混合加热到110-130℃在氮气气氛下回流16-20h，在乙酸乙酯中沉淀后，以粉红色固体的形式过滤和收集粗产物，所得产物溶解在甲醇中，在温和的条件下，溶解液滴加入氢氧化钾和异丙醇的溶液中，粗混合物过滤洗涤，得到棕色固体，即产物1，其结构式如下：
S12、将产物1和1,4-丁磺酸内酯在氮气气氛下加入甲苯溶液中加热100-120℃，40-55h，将混合料冷却至室温，粗产物析出，将粗混合物中加入甲醇搅拌30分钟；沉淀，过滤，收集，重新在水:甲醇＝2:1混合物中溶解,用滴液漏斗将混合溶液慢慢加入乙腈中；沉淀物被过滤并收集为粉红色固体产物2，其结构式如下：
S13、将氨基苯、环己酮、产物2、Vilsmeier-Haack试剂和无水乙酸钠在无水乙醇中，在氮气气氛下回流加热6-8h，反应混合物冷却至室温，然后过滤，用乙醇和甲醇洗涤，抽滤，干燥，收集为绿色固体产物3，其结构式如下：
进一步的，上述步骤S2中，培美靶向药物合成包括以下步骤：
将培美水解酸溶于DMF中，将HATU、O-叔丁基-L-酪氨酸叔丁基酯盐酸盐、DIEA依次加入烧瓶中，搅拌至完全溶解，氮气保护，室温反应25-35min，将反应后的溶液滴加在HCl溶液，产生淡黄色沉淀，干燥，得固体产物4，其结构式如下：
Pemetrexed-Tyr的制备包括以下步骤：
将产物4放入圆底烧瓶中，加入TFA水溶液，搅拌两小时，加入甲基叔丁基醚中，沉淀过滤，真空干燥，得产物5，其结构式如下：
进一步的，上述步骤S3中，包括以下步骤：
S31、在18-28℃下向S0456的水溶液中，滴加pH 10-12的Pemetrexed-Tyr三阴离子溶液；
S32、将反应混合物的温度升至85-95℃，搅拌40-55分钟，并通过TLC监测产物的形成；
S33、产物形成完成后，将反应混合物冷却至室温，并通过套管作为稳定流转移至搅拌的丙酮中，得到绿色沉淀；
S34、沉淀物在抽气机真空下在烧结漏斗上过滤，用丙酮洗涤；
S35、将绿色粉末状固体干燥，获得Pemetrexed-Tyr-S0456。
相比于现有技术，本发明的优点在于：
本发明公开一种主动靶向近红外荧光分子的制备方法，利用有机全合成的方法制备了培美曲塞二钠及其衍生物为主动靶向基团的主动靶向近红外荧光小分子。这种主动靶向近红外荧光分子具有主动靶向性高、特异性强，水溶性好和荧光量子产率高等优点，在肿瘤手术导航成像及医学细胞标记领域具有巨大的发展潜力。
附图说明
图1是本发明一种主动靶向近红外荧光分子的结构图；
图2是制备主动靶向近红外荧光分子的合成流程图；
图3是制备的主动靶向近红外荧光分子荧光性能图(荧光强度)；
图4是制备的主动靶向近红外荧光分子荧光性能图(检出限)；
图5是制备的主动靶向近红外荧光分子S0456氢谱图；
图6是制备的主动靶向近红外荧光分子S0456质谱图；
图7是制备的Pemetrexed-Tyr(OtBu)-OtBu质谱图；
图8是制备的Pemetrexed-Tyr-OH质谱图；
图9是制备的Pemetrexed-Tyr-S0456质谱图；
图10是KB细胞摄取Pemetrexed-Tyr-S0456的荧光显微图像。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述；显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例，基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
如图1所示，本发明以
为母体，结构上通过酪氨酸将S0456和Pemetrexed连接在一起最终形成主动靶向近红外荧光分子。图1中，a部分为Pemetrexed结构，b部分为酪氨酸结构，c部分为S0456结构，M独立地选自H、Na和K。
本实施例中，以如下结构式为例：
其合成流程如下。
如图2所示，本发明的主动靶向近红外荧光分子的合成流程，包括以下步骤：
S0456的合成：
(1)4-肼苯磺酸(1.6g，31.9mmol)、3-甲基-2-丁酮(2.10ml，90mmol)、冰醋酸(50ml)混合加热到120℃在氮气气氛下18h。在乙酸乙酯中沉淀后，以粉红色固体的形式过滤和收集粗产物，所得产物(6.5g，25.4mmol)溶解在甲醇(50mL)中。在温和的条件下，溶解液滴加入氢氧化钾(1.7g，30mmol)和异丙醇(20ml)的溶液中，粗混合物过滤洗涤，得到棕色固体，即产物1，产率97％，其结构式如下：
(2)将产物1(2.3g，8.3mmol)和1,4-丁磺酸内酯在氮气气氛下加入甲苯溶液中加热110℃，48h。将混合料冷却至室温，粗产物析出。在粗混合物中加入甲醇(10ml)搅拌30分钟，粗混合物沉淀，过滤，收集，重新在水:甲醇＝2:1混合物中溶解,用滴液漏斗将混合溶液慢慢加入乙腈(160ml)中；在2:1(v/v)水混合物中溶解(10ml)和甲醇(50ml)。沉淀物被过滤并收集为粉红色固体，产率40％，其结构式如下：
(3)将氨基苯、环己酮、产物2(1.5g，2.79mmol)、Vilsmeier-Haack试剂(0.5g，1.39mmol)和无水乙酸钠(0.342g，4.17mmol)在20mL的无水乙醇中，在氮气气氛下回流加热6h。反应混合物冷却至室温，然后过滤，用乙醇和甲醇洗涤，收集为棕绿色固体(S0456)，产率90％，其结构式如下：
图5和图6分别显示了S0456的氢谱图和质谱图。
靶向药物合成：将培美水解酸(1.05g，3.52mmol)溶于DMF中，搅拌至溶解，将HATU(2.007g，5.28mmol)O-叔丁基-L-酪氨酸叔丁基酯盐酸盐(1.161g，3.52mmol)DIEA(1.364g，10.56mmol)依次加入烧瓶中，搅拌至完全溶解，氮气保护，室温反应30min将反应后的溶液滴加在0.1N aq.HCl(1.0L，0.14M)，产生淡黄色沉淀，抽滤真空干燥，得固体产物4(2.04g)，产率95％，其结构式如下：
Pemetrexed-Tyr(OtBu)-OtBu的质谱图如图7所示。
将产物4(2.04g，3.34mmol)放入圆底烧瓶中，加入TFA：H2O(95：5，10mL),搅拌两小时，加入甲基叔丁基醚中，沉淀过滤，真空干燥。得1.507g，产率98％，其结构式如下：
Pemetrexed-Tyr-OH质谱图如果图8所示。
Pemetrexed-Tyr-S0456制备：在23℃下向S0456(2.909g，3.276mmol)的水(18mL)溶液中，滴加pH 11的Pemetrexed-Tyr(1.507g，3.276mmol)三阴离子溶液。将反应混合物的温度升至90℃，在90℃下搅拌45分钟，并通过TLC监测产物的形成。产物形成完成后，将反应混合物冷却至室温，并通过套管作为稳定流转移至搅拌的丙酮(0.5L)中，得到绿色沉淀。沉淀物在抽气机真空下在烧结漏斗上过滤，用丙酮(3×500mL)洗涤。将绿色粉末状固体在高真空下干燥12h，定量获得6(4.34g)。
经测定，Pemetrexed-Tyr-S0456产物的荧光性能谱图如图3和图4所示，图3中，Excitation(785nm)，Emission(811nm)，图4中，针对不同浓度的样品测试荧光强度，进行线性模拟求出此检出限。
质谱图如图9所示。
为了验证本发明的效果，进行了如下验证实验：
用1x10-6mol/L的Pemetrexed-Tyr-S0456孵育KB细胞2h，用PBS清洗细胞2-3遍，然后用实验室自制近红外荧光显微镜对KB细胞进行成像，得到白光、荧光图像，用Image-J融合图像，如图10所示。亮光的KB细胞表示小分子靶向到KB细胞的叶酸受体，在激发光的激发下检测出荧光强度。
以上所述，仅为本发明较佳的具体实施方式；但本发明的保护范围并不局限于此。任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其改进构思加以等同替换或改变，都应涵盖在本发明的保护范围内。
Claims (2)
1.一种主动靶向叶酸受体近红外荧光分子，其结构式如下：
M独立地选自H、Na和K。
2.一种主动靶向叶酸受体近红外荧光分子的制备方法，其特征在于，包括以下步骤：
S1、S0456的合成，包括以下步骤：
S11、将4-肼苯磺酸、3-甲基-2-丁酮、冰醋酸混合加热到110-130℃在氮气气氛下回流16-20h，在乙酸乙酯中沉淀后，以粉红色固体的形式过滤和收集粗产物，所得产物溶解在甲醇中，在温和的条件下，溶解液滴加入氢氧化钾和异丙醇的溶液中，粗混合物过滤洗涤，得到棕色固体，即产物1；
S12、将产物1和1,4-丁磺酸内酯在氮气气氛下加入甲苯溶液中加热100-120℃，40-55h，将混合料冷却至室温，粗产物析出，将粗混合物中加入甲醇搅拌30分钟；沉淀，过滤，收集，重新在水:甲醇＝2:1混合物中溶解,用滴液漏斗将混合溶液慢慢加入乙腈中；沉淀物被过滤并收集为粉红色固体产物2；
S13、将氨基苯、环己酮、产物2、Vilsmeier-Haack试剂和无水乙酸钠在无水乙醇中，在氮气气氛下回流加热6-8h，反应混合物冷却至室温，然后过滤，用乙醇和甲醇洗涤，收集为绿色固体产物3；
S2、培美靶向药物合成以及Pemetrexed-Tyr的制备：
培美靶向药物合成：将培美水解酸溶于DMF中，将HATU、O-叔丁基-L-酪氨酸叔丁基酯盐酸盐、DIEA依次加入烧瓶中，搅拌至完全溶解，氮气保护，室温反应25-35min，将反应后的溶液滴加在HCl溶液，产生淡黄色沉淀，干燥，得固体产物4，即所述的培美靶向药物；
Pemetrexed-Tyr的制备：将产物4放入圆底烧瓶中，加入三氟乙酸，搅拌两小时，加入甲基叔丁基醚中，沉淀过滤，真空干燥，得产物5，即所述的Pemetrexed-Tyr；
S3、Pemetrexed-Tyr和S0456反应生成Pemetrexed-Tyr-S0456，包括以下步骤：
S31、在18-28℃下向S0456的水溶液中，滴加pH 10-12的Pemetrexed-Tyr三阴离子溶液；
S32、将反应混合物的温度升至85-95℃，搅拌40-55分钟，并通过TLC监测产物的形成；
S33、产物形成完成后，将反应混合物冷却至室温，并通过套管作为稳定流转移至搅拌的丙酮中，得到绿色沉淀；
S34、沉淀物在抽气机真空下在烧结漏斗上过滤，用丙酮洗涤；
S35、将绿色粉末状固体干燥，获得Pemetrexed-Tyr-S0456，
其中，所述产物1的结构式为：
所述产物2的结构式为：
所述产物3，即S0456的结构式为：
所述产物4，即所述培美靶向药物的结构式为：
所述产物5，即所述Pemetrexed-Tyr的结构式为：
所述Pemetrexed-Tyr-S0456，即所述的主动靶向叶酸受体近红外荧光分子的结构式为：
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| JP7227123B2 (ja) * | 2016-08-12 | 2023-02-21 | エル．イー．エー．エフ． ホールディングス グループ エルエルシー | αおよびγ－Ｄポリグルタミン酸化抗葉酸剤およびその使用 |
| KR20190103154A (ko) * | 2016-11-14 | 2019-09-04 | 체엠엠 - 포르슝스첸트룸 퓨어 몰레쿨라레 메디친 게엠베하 | 암의 치료법을 위한 brd4 억제제 및 항폴레이트의 조합 |
| CN110167577B (zh) * | 2016-11-16 | 2024-05-10 | 普渡研究基金会 | 配体离子载体共轭物 |
| WO2019157145A1 (en) * | 2018-02-07 | 2019-08-15 | L.E.A.F. Holdings Group Llc | Gamma polyglutamated pemetrexed and uses thereof |
| KR102129522B1 (ko) | 2018-07-26 | 2020-07-02 | 한국과학기술연구원 | 암세포 특이적 항암 단백질-형광 복합체 및 이를 포함하는 암의 진단 및 영상화용 조성물 |
| CN112010862B (zh) | 2020-10-23 | 2021-03-30 | 南京诺源医疗器械有限公司 | 一种主动靶向叶酸受体近红外荧光分子及其制备方法 |
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| WO2019018238A1 (en) * | 2017-07-15 | 2019-01-24 | The Regents Of The University Of California | CATHEPSIN K OSTEOADSORBENT FLUOROGEN SUBSTRATE FOR THE IMAGING OF OSTEOCLAST ACTIVITY AND MIGRATION |
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| WO2022082932A1 (zh) | 2022-04-28 |
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| EP4015518A4 (en) | 2022-08-24 |
| US11718625B2 (en) | 2023-08-08 |
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| CN112010862A (zh) | 2020-12-01 |
| JP2023512341A (ja) | 2023-03-24 |
| JP7308366B2 (ja) | 2023-07-13 |
| EP4015518A1 (en) | 2022-06-22 |
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