CN109529034B - 近红外二区共轭纳米粒子及其制备方法和应用 - Google Patents
近红外二区共轭纳米粒子及其制备方法和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及共轭纳米粒子的制备领域,具体涉及一种近红外二区共轭纳米粒子及其制备方法和应用。
背景技术
当今世界,恶性肿瘤已成为威胁人类健康的头号杀手。尽管手术治疗、化学治疗和放射治疗等传统治疗手段已被广泛应用于临床,但这些治疗手段存在具有侵入性、副作用大和无靶向性等缺点。
近年来,由于具有非侵入性、副作用小和远程可控等优点,基于激光的光动力学治疗和光热治疗获得了人们的广泛关注。
目前,光热试剂主要包括:贵金属纳米材料、金属硫化物纳米晶、碳材料、二维材料和有机纳米粒子等。但这些材料中绝大部分的光学吸收处于近红外一区(650-950nm),而生物组织在该区域吸收较强且存在严重的光散射,导致穿透深度较浅,因此限制了其临床转化。
鉴于此,一些近红外二区(1000-1700nm)的光热材料被陆续开发出来用于深度光热治疗,比如:金纳米材料、硫化铜纳米粒子、二维材料和共轭聚合物纳米粒子等。如苏州大学的陈华兵(ADVANCED MATERIALS.Volume 29,Issue 31,August 18,2017,1700487)团队报道了一种供体-受体型(donor-acceptor,D-A)窄带隙共轭聚合物纳米粒子CP-NPs,并将其应用于近红外激光诱导的协同光热/光动力肿瘤治疗。尽管现存的近红外二区光热材料具有可观的光热转化效率和光热治疗效果。但无机材料潜在的长期体内毒性和共轭聚合物纳米粒子性质的批次依赖性限制了它们的大规模制备和临床转化。
共轭小分子具有化学结构明确、合成简便和易纯化的优点,因此共轭小分子纳米粒子有望具有较好的生物相容性和稳定的光热性质,但目前共轭小分子纳米粒子以近红外一区为主。
发明内容
本发明的目的在于针对现有技术的不足,提供一种近红外二区共轭纳米粒子,具有良好的生物相容性、较高的近红外二区光热转化效率、良好的光声成像效果以及近红外二区肿瘤光热治疗效果。
本发明所提供的技术方案为:
近红外二区共轭纳米粒子,包括近红外二区共轭小分子和两亲性高分子;
所述近红外二区共轭小分子的结构式如下:
所述两亲性高分子自组装包裹在近红外二区共轭小分子上。
本发明通过选择合适的供体、受体单元,利用Stille反应合成了光吸收同时覆盖近红外一区和二区的共轭小分子,然后包裹两亲性高分子,使得近红外二区共轭纳米粒子转化为水溶性,且具有合适的粒径,有利于EPR效应实现肿瘤靶向,纳米粒子良好的光热性质实现了光声成像引导的近红外二区肿瘤光热治疗。
本发明所述两亲性高分子是指在同一分子链中含有亲水链段和亲油链段的大分子化合物,亲水链段和亲油链段的不相容性会导致微相分离发生,使得两亲性高分子在选择性溶剂、本体及表、界面结构中表现出自组装特性。所述两亲性高分子可以选用功能性高分子,可以为市售的两亲性高分子。作为优选,所述两亲性高分子选自普朗尼克F68、普朗尼克F127和二硬脂酰磷脂酰乙醇胺-聚乙二醇中的一种或几种。
本发明所述近红外二区共轭纳米粒子的粒径小于300nm。优选为不大于200nm。进一步优选为80-200nm。近红外二区共轭纳米粒子借助其合适的粒径,通过高通透性和滞留效应(EPR效应)可以实现肿瘤组织靶向。
本发明还提供一种如上述的近红外二区共轭纳米粒子的制备方法,包括:
1)二溴代苯并双噻二唑与4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺在钯催化剂催化下发生的Stille偶联反应,得到近红外二区共轭小分子;
2)近红外二区共轭小分子与两亲性高分子进行自组装,两亲性高分子包裹在近红外二区共轭小分子上,得到近红外二区共轭纳米粒子。
反应过程如下:
本发明所述步骤1)具体包括:将二溴代苯并双噻二唑、4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺和钯催化剂加入到溶剂中,在惰性氛围下回流进行Stille偶联反应,分离得到近红外二区共轭小分子。
本发明所述步骤1)中钯催化剂选自双(三苯基膦)二氯化钯、四(三苯基膦)钯、双(二亚芐基丙酮)钯中的一种或几种。
本发明所述步骤1)中溶剂选自甲苯、二氢呋喃、二甲苯、氯苯中的一种或几种。
本发明所述步骤1)中二溴代苯并双噻二唑与4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺的摩尔投料比为1:2.0-2.5。
本发明所述步骤1)中二溴代苯并双噻二唑与钯催化剂的摩尔投料比为1:0.01-0.1。进一步优选为1:0.04-0.06。
本发明所述步骤1)中回流的时间优选为10-50h,进一步优选为20-30h。
本发明所述步骤1)中分离方法优选为硅胶柱层析法。
本发明所述步骤2)具体包括:将近红外二区共轭小分子与两亲性高分子溶解于良溶剂中,然后将该混合溶液快速注入剧烈搅拌的水中,最后将良溶剂挥发或透析,得到近红外二区共轭纳米粒子。
本发明所述步骤2)中两亲性高分子可以选用功能性高分子,可以为市售的两亲性高分子。作为优选,所述两亲性高分子选自普朗尼克F68、普朗尼克F127和二硬脂酰磷脂酰乙醇胺-聚乙二醇中的一种或几种。
本发明所述步骤2)中近红外二区共轭小分子与两亲性高分子的质量投料比为1:10-20。
本发明所述步骤2)中良溶剂选自四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜中的一种或多种。
本发明还提供一种如上述的近红外二区共轭纳米粒子在制备肿瘤光热治疗药物中的应用。近红外二区共轭纳米粒子借助其合适的粒径,通过高通透性和滞留效应(EPR效应)可以实现肿瘤组织靶向。通过光声成像实时监测纳米粒子在肿瘤部位的累积,获得最大累积的时间点,然后在该时间点施加激光照射,纳米粒子的光热效应使肿瘤部位温度迅速升高,导致肿瘤细胞死亡,达到肿瘤治疗的效果。
同现有技术相比,本发明的有益效果体现在:
(1)本发明通过选择合适的供给、受体单元,利用Stille反应合成了光吸收同时覆盖近红外一区和二区的共轭小分子。
(2)本发明制备的近红外二区共轭纳米粒子具有合适的粒径,有利于EPR效应实现肿瘤靶向,纳米粒子良好的光热性质实现了光声成像引导的近红外二区肿瘤光热治疗。
(3)本发明涉及反应体系温和,条件可控,纳米粒子性质稳定,具有良好的临床转化可能性。
附图说明
图1为实施例1中的近红外二区共轭小分子的核磁共振氢谱;
图2为实施例1中的近红外二区共轭小分子的MALDI-TOF质谱;
图3为实施例6中的近红外二区共轭纳米粒子的透射电镜图;
图4为实施例6中的近红外二区共轭纳米粒子的动态光散射粒径分布图;
图5为应用例中尾静脉注射后不同时间点肿瘤部位的光声成像图;
图6为应用例中不同激光照射条件下肿瘤部位的红外热成像图;
图7为应用例中治疗结束时各组的肿瘤照片。
具体实施方式
下面结合具体的实施例和说明书附图详细地阐述本发明。
实施例1:共轭小分子
二溴代苯并双噻二唑(88.0mg,0.25mmol),4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺(342.3mg,0.50mmol)和双(三苯基膦)二氯化钯(8.77mg,0.0125mmol)溶解于30mL干燥的甲苯中,惰性氛围下回流24小时,最后硅胶柱层析(洗脱剂为二氯甲烷)得到近红外二区共轭小分子,产率60%。
对得到的近红外二区共轭小分子进行核磁共振氢谱和MALDI-TOF质谱表征,结果分别如附图1和附图2所示。
实施例2:共轭小分子
二溴代苯并双噻二唑(88.0mg,0.25mmol),4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺(342.3mg,0.50mmol)和四(三苯基膦)钯(14.4mg,0.0125mmol)溶解于30mL干燥的甲苯中,惰性氛围下回流24小时,最后硅胶柱层析(洗脱剂为二氯甲烷)得到近红外二区共轭小分子,产率65%。
实施例3:共轭小分子
二溴代苯并双噻二唑(88.0mg,0.25mmol),4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺(342.3mg,0.50mmol)和双(二亚芐基丙酮)钯(7.19mg,0.0125mmol)溶解于30mL干燥的甲苯中,惰性氛围下回流24小时,最后硅胶柱层析(洗脱剂为二氯甲烷)得到近红外二区共轭小分子,产率61%。
实施例4:共轭小分子
二溴代苯并双噻二唑(88.0mg,0.25mmol),4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺(342.3mg,0.50mmol)和双(三苯基膦)二氯化钯(8.77mg,0.0125mmol)溶解于30mL干燥的四氢呋喃中,惰性氛围下回流24小时,最后硅胶柱层析(洗脱剂为二氯甲烷)得到近红外二区共轭小分子,产率62%。
实施例5:共轭小分子
二溴代苯并双噻二唑(88.0mg,0.25mmol),4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺(342.3mg,0.50mmol)和双(三苯基膦)二氯化钯(8.77mg,0.0125mmol)溶解于30mL干燥的二甲苯中,惰性氛围下回流24小时,最后硅胶柱层析(洗脱剂为二氯甲烷)得到近红外二区共轭小分子,产率65%。
实施例5:共轭小分子
二溴代苯并双噻二唑(88.0mg,0.25mmol),4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺(376.5mg,0.55mmol)和双(三苯基膦)二氯化钯(10.5mg,0.015mmol)溶解于30mL干燥的甲苯中,惰性氛围下回流24小时,最后硅胶柱层析(洗脱剂为二氯甲烷)得到近红外二区共轭小分子,产率62%。
实施例6:近红外二区共轭纳米粒子
将2.47mg近红外二区共轭小分子(实施例1制备)和37.1mg普朗尼克F127加入到2.0mL四氢呋喃中,室温下搅拌使其充分溶解,然后将该溶液快速注入剧烈搅拌的水中,最后将四氢呋喃挥发得到近红外二区共轭纳米粒子。
对得到的近红外二区共轭纳米粒子进行透射电镜和动态光散射表征,结果分别如附图3和附图4所示,形貌为球形,粒径范围80-200nm。
实施例7:近红外二区共轭纳米粒子
将2.47mg近红外二区共轭小分子(实施例3制备)和37.1mg普朗尼克F68加入到2.0mL四氢呋喃中,室温下搅拌使其充分溶解,然后将该溶液快速注入剧烈搅拌的水中,最后将四氢呋喃挥发得到近红外二区共轭纳米粒子,形貌为球形,粒径范围80-200nm。
实施例8:近红外二区共轭纳米粒子
将2.47mg近红外二区共轭小分子(实施例4制备)和37.1mg二硬脂酰磷脂酰乙醇胺-聚乙二醇加入到2.0mL四氢呋喃中,室温下搅拌使其充分溶解,然后将该溶液快速注入剧烈搅拌的水中,最后将四氢呋喃挥发得到近红外二区共轭纳米粒子,形貌为球形,粒径范围80-200nm。
实施例9:近红外二区共轭纳米粒子
将2.47mg近红外二区共轭小分子(实施例2制备)和37.1mg普朗尼克F127加入到2.0mL N,N-二甲基甲酰胺中,室温下搅拌使其充分溶解,然后将该溶液快速注入剧烈搅拌的水中,最后透析得到近红外二区共轭纳米粒子,形貌为球形,粒径范围80-200nm。
实施例10:近红外二区共轭纳米粒子
将2.47mg近红外二区共轭小分子(实施例5制备)和37.1mg普朗尼克F127加入到2.0mL二甲基亚砜中,室温下搅拌使其充分溶解,然后将该溶液快速注入剧烈搅拌的水中,最后透析得到近红外二区共轭纳米粒子,形貌为球形,粒径范围80-200nm。
实施例11:近红外二区共轭纳米粒子
将2.47mg近红外二区共轭小分子(实施例1制备)和49.4mg普朗尼克F127加入到2.0mL四氢呋喃中,室温下搅拌使其充分溶解,然后将该溶液快速注入剧烈搅拌的水中,最后将四氢呋喃挥发得到近红外二区共轭纳米粒子,形貌为球形,粒径范围80-200nm。
应用例:用于光声成像引导的近红外二区肿瘤光热治疗
荷瘤裸鼠经尾静脉注射近红外二区共轭纳米粒子(实施例6制备),然后利用光声成像实时监测(0,0.5,1,3,5,8,12和24小时)纳米粒子在肿瘤的富集,发现在注射8小时后,如附图5所示,纳米粒子在肿瘤部位富集达到最大。
获得肿瘤富集最大时间点后,将裸鼠随机分成6组(Control组,纳米粒子组,808nm激光组,1064nm激光组,纳米粒子+808nm激光组和纳米粒子+1064nm激光组)进行肿瘤光热治疗,同时以红外热成像仪监测四个激光照射组肿瘤部位的温度变化,如附图6所示了,发现纳米粒子+1064nm激光组肿瘤部位的温度显著上升,而其他组温度变化不大,显示出该纳米粒子具有良好的近红外二区肿瘤光热治疗效果。
经过14天治疗周期后,如附图7所示,解剖出各组的肿瘤测量其大小,对比治疗效果发现纳米粒子+1064nm激光组的肿瘤明显变小,而其他各组的肿瘤生长没有得到明显抑制。
以上所述实施例对本发明的技术方案和有益效果进行了详细说明,应理解的是以上所述仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改,补充和等同替换等,均应包含在本发明的保护范围之内。
Claims (9)
2.根据权利要求1所述的近红外二区共轭纳米粒子,其特征在于,所述近红外二区共轭纳米粒子的粒径小于300nm。
3.如权利要求1~2任一所述的近红外二区共轭纳米粒子的制备方法,其特征在于,包括:
1)二溴代苯并双噻二唑与4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺在钯催化剂催化下发生的Stille偶联反应,得到近红外二区共轭小分子;
2)近红外二区共轭小分子与两亲性高分子进行自组装,两亲性高分子包裹在近红外二区共轭小分子上,得到近红外二区共轭纳米粒子。
4.根据权利要求3所述的近红外二区共轭纳米粒子的制备方法,其特征在于,所述步骤1)具体包括:将二溴代苯并双噻二唑、4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺和钯催化剂加入到溶剂中,在惰性氛围下回流进行Stille偶联反应,分离得到近红外二区共轭小分子。
5.根据权利要求3所述的近红外二区共轭纳米粒子的制备方法,其特征在于,所述钯催化剂选自双(三苯基膦)二氯化钯、四(三苯基膦)钯、双(二亚基丙酮)钯中的一种或几种。
6.根据权利要求3所述的近红外二区共轭纳米粒子的制备方法,其特征在于,所述二溴代苯并双噻二唑与4-叔丁基-N-(4-叔丁基苯基)-N-(4-(5’-三甲基锡基)-(2,2’-联噻吩基)-5-苯基)苯胺的摩尔投料比为1:2.0-2.5。
7.根据权利要求3所述的近红外二区共轭纳米粒子的制备方法,其特征在于,所述步骤2)具体包括:将近红外二区共轭小分子与两亲性高分子溶解于良溶剂中,然后将该混合溶液快速注入剧烈搅拌的水中,最后将良溶剂挥发或透析,得到近红外二区共轭纳米粒子。
8.根据权利要求3所述的近红外二区共轭纳米粒子的制备方法,其特征在于,所述近红外二区共轭小分子与两亲性高分子的质量投料比为1:10-20。
9.如权利要求1~2任一所述的近红外二区共轭纳米粒子在制备肿瘤光热治疗药物中的应用。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102816131A (zh) * | 2011-06-09 | 2012-12-12 | 中国科学院化学研究所 | 基于三苯胺-噻唑的d-a-d共轭分子及其制备方法和应用 |
CN106147755A (zh) * | 2016-06-24 | 2016-11-23 | 华南理工大学 | 抗体修饰的荧光纳米粒子及在癌细胞靶向成像中的应用 |
US9675713B2 (en) * | 2012-06-29 | 2017-06-13 | The Board Of Trustees Of The Leland Stanford Junior University | Nanoprobes for sensing of reactive oxygen and reactive nitrogen species |
WO2018108070A1 (en) * | 2016-12-15 | 2018-06-21 | The Hong Kong University Of Science And Technology | Luminogens for biological applications |
US10124111B2 (en) * | 2015-02-24 | 2018-11-13 | The Board Of Trustees Of The Leland Stanford Junior University | Small molecule dye for molecular imaging and photothermal therapy |
CN108864106A (zh) * | 2018-07-17 | 2018-11-23 | 南京邮电大学 | 新型近红外二区有机小分子荧光探针的制备与应用 |
-
2018
- 2018-12-13 CN CN201811523521.XA patent/CN109529034B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102816131A (zh) * | 2011-06-09 | 2012-12-12 | 中国科学院化学研究所 | 基于三苯胺-噻唑的d-a-d共轭分子及其制备方法和应用 |
US9675713B2 (en) * | 2012-06-29 | 2017-06-13 | The Board Of Trustees Of The Leland Stanford Junior University | Nanoprobes for sensing of reactive oxygen and reactive nitrogen species |
US10124111B2 (en) * | 2015-02-24 | 2018-11-13 | The Board Of Trustees Of The Leland Stanford Junior University | Small molecule dye for molecular imaging and photothermal therapy |
CN106147755A (zh) * | 2016-06-24 | 2016-11-23 | 华南理工大学 | 抗体修饰的荧光纳米粒子及在癌细胞靶向成像中的应用 |
WO2018108070A1 (en) * | 2016-12-15 | 2018-06-21 | The Hong Kong University Of Science And Technology | Luminogens for biological applications |
CN108864106A (zh) * | 2018-07-17 | 2018-11-23 | 南京邮电大学 | 新型近红外二区有机小分子荧光探针的制备与应用 |
Non-Patent Citations (4)
Title |
---|
A dual-functional benzobisthiadiazole derivative as an effective theranostic agent for near-infrared photoacoustic imaging and photothermal therapy;Shuo Huang等;《J. Mater. Chem. B》;20161231;第1-8页 * |
Band Gap Tunable, Donor-Acceptor -Donor Charge-Transfer Heteroquinoid-Based Chromophores: Near Infrared Photoluminescence and Electroluminescence;Gang Qian等;《Chem. Mater.》;20081231;第20卷;第6208-6216页 * |
Novel benzo-bis(1,2,5-thiadiazole) fluorophores for in vivo NIR-II imaging of cancer;Yao Sun等;《Chem . Sci.》;20161231;第7卷;第6203-6207页 * |
Single-Molecular Near-Infrared-II Theranostic Systems: Ultrastable Aggregation-Induced Emission Nanoparticles for Long-Term Tracing and Efficient Photothermal Therapy;Nuernisha Alifu等;《ACS Nano》;20181011;第12卷;第11282-11293页 * |
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