CN114106581A - 一种有机小分子染料、j聚集纳米粒子及其制备方法和应用 - Google Patents
一种有机小分子染料、j聚集纳米粒子及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种有机小分子染料,并公开了该染料及其J聚集纳米粒子的制备方法和应用。本发明基于有机小分子染料与两亲性聚合物,通过纳米共沉淀方法制备得到的J聚集纳米粒子。利用J聚集独特的性质制备得到最大光学吸收及最大荧光发射均在NIR‑II区域的纳米诊疗粒子,同时纳米粒子荧光发射波长可延伸到NIR‑IIb区域,可应用于1064nm激光激发的活体血管及肿瘤的高分辨率成像。本发明的纳米粒子在1064nm激光照射下可产生光热和光动力性能,因此可应用于深层次肿瘤的联合治疗,从而显著提高治疗效果,具有较好的临床应用前景。
Description
技术领域
本发明属于生物光学诊疗领域,更具体地,涉及一种有机小分子染料、J聚集纳米粒子及其制备方法和应用。
背景技术
荧光成像在生物医学检测和成像引导手术等基础研究和临床应用方面发挥着重要的作用。与传统的成像方式,如X射线计算机断层扫描、正电子发射断层扫描和核磁共振成像相比,荧光成像具有高时空分辨率、实时检测和成本低等许多优点。这种成像技术可实现分子或细胞层面的可视化,因而帮助我们更好的了解生物功能或疾病机理。然而,过去的荧光成像主要集中在近红外一区(NIR-I,700-900nm),短波长的发光具有较差的穿透深度,这成为生物荧光成像应用的主要障碍之一。相比之下,近红外二区(NIR-II,1000-1700nm)成像具有低光散射和低自发荧光背景,因而具有更好的组织穿透深度和更高的成像信噪比,在血管造影和肿瘤检测等方面展现了巨大的应用潜力。在NIR-II范围中,NIR-IIb子窗口(1500-1700nm)具有近乎为零的自发荧光及组织散射特点,成为近年来研究的热点。
光动力(PDT)和光热疗法(PTT)属于无创、无害和高效的肿瘤治疗方式。光动力疗法通常使用光敏剂在一定激发光源的照射下产生高度细胞毒性的活性氧物种来杀死癌细胞;光热疗法利用光热剂吸收的外界光转换为热量来烧蚀癌细胞。两种治疗方式具有各有缺点,但光动力/光热联合疗法可以有效的弥补对方的不足,从而提高治疗的效果。然而,目前关于PDT/PTT联合治疗的相关工作其激发光源仍主要集中在NIR-I区域,NIR-II激光照射下同时产生两种治疗效果的研究却少有报道。
发明内容
本发明的目的是针对以上不足,提供一种有机小分子染料,以及基于该染料的J聚集纳米粒子,并公开了其制备方法,该纳米粒子在NIR-II激光照射下可以有效产生NIR-IIb荧光、活性氧及光热,从而用于NIR-IIb荧光成像指导的PDT/PTT联合治疗。
为实现上述目的,本发明是通过以下技术方案实现的:
一种有机小分子染料,其结构式如下:
上述的有机小分子染料在甲苯中的最大吸收波长在844nm,最大发射波长在944nm。
上述的有机小分子染料的合成路线为:
上述的有机小分子染料的制备方法,包括以下步骤:
A:将化合物2溶解于有机溶剂,在-75℃~-80℃,氮气保护下加入n-BuLi,搅拌混合后,加入Bu3SnCl,升温至室温后搅拌,反应1~1.2h,经萃取、干燥、去有机溶剂,得到化合物3;
B:将所述化合物3、化合物4和钯催化剂溶于有机溶剂,氮气保护下反应7~10h,提纯,得到化合物5;
C:将所述化合物5、化合物6和β-丙氨酸溶解、混合,50~60℃反应,反应完成后,层析纯化,制得式(1)所述有机小分子染料。
本发明还提供了一种J聚集纳米粒子,是由上述的有机小分子染料与两亲性聚合物通过纳米共沉淀方法制备得到的。
上述的J聚集纳米粒子,在水溶液中,其最大吸收波长在1029nm,最大荧光发射波长在1128nm,其荧光发射波长能够延伸到1700nm(NIR-IIb区域)。
上述的J聚集纳米粒子,在水溶液中,其在1064nm激光照射下具有光动力性能和光热性能。
上述的J聚集纳米粒子,有机小分子染料在纳米粒子内部为J聚集形态,J-聚集是一种荧光分子“头-尾相连”的堆积方式,相对于常见的H-聚集,这种堆积方式具有更高强度的荧光。同时,由于有机小分子染料的结构特性,使其相对于其他的J聚集纳米粒子,吸收及发射波长更长,成像范围更广。
本发明还提供了上述的J聚集纳米粒子的制备方法,包括以下步骤:
将上述的有机小分子染料与两亲性聚合物F127共同溶解于有机溶剂;
在超声下加入去离子水中,并在超声下进行反应;
反应完成后去除有机溶剂得到J聚集纳米粒子的水溶液。
优选地,所述有机小分子染料与两亲性聚合物F127的质量比为1:(20~25),有机溶剂与去离子水的体积比为1:(8~10)。
本发明还提供了一种上述的J聚集纳米粒子在激光照射下NIR-IIb区荧光成像中的应用,是指将其水溶液用作NIR-IIb成像造影剂,可以实现活体血管及肿瘤高分辨成像。
本发明还提供了一种上述的J聚集纳米粒子在制备激光照射下肿瘤的光热及光动力联合治疗试剂中的应用,是指将其水溶液用于制备激光照射下肿瘤的光热及光动力联合治疗试剂。
与现有技术相比,本发明的有益效果为:
本发明所述有机小分子染料,结构特征明显,且其本身的光吸收和荧光发射波长较长,使得以其为基体的J聚集纳米粒子,相对于其他基体的J聚集纳米粒子,吸收及发射波长更长,成像范围更广,还有更好的光动力效果。
本发明利用J聚集独特的性质制备得到最大光学吸收及最大荧光发射均在NIR-II区域的纳米诊疗粒子,同时纳米粒子荧光发射波长可延伸到NIR-IIb区域,可应用于1064nm激光激发的活体血管及肿瘤的高分辨率成像。本发明的纳米粒子在1064nm激光照射下可产生光热和光动力性能,因此可应用于深层次肿瘤的联合治疗,从而显著提高治疗效果,具有较好的临床应用前景。
附图说明
图1为实施例所述J聚集纳米粒子在水溶液中的吸收及发射图谱。
图2为实施例所述J聚集纳米粒子在水溶液中随不同激光功率变化的升温曲线。
图3为实施例所述J聚集纳米粒子在水溶液中随不同浓度变化的升温曲线。
图4为实施例所述J聚集纳米粒子与DPBF混合后,经不同功率的1064nm激光照射下DPBF在414nm处吸收强度随时间的变化曲线。
图5为实施例所述J聚集纳米粒子经尾静脉注射后小鼠的全身血管成像。
具体实施方式
下面将结合附图和具体实验方法对本发明做更详细地描述。以下实施例仅用于更加清楚地说明本发明的技术方案,而不能以此来限制本发明的保护范围。
本发明的实施所使用的试剂皆为市购,
1.一种有机小分子染料,该染料的结构式为:
所述有机小分子染料的合成路线为:
其具体制备步骤如下:
A、将化合物2(2.5g,5mmol)溶解于50mL无水四氢呋喃中,将溶液冷却至-78℃,氮气保护下缓慢加入n-BuLi(5.2mL,12.5mmol,2.4M己烷溶液)。保持-78℃搅拌混合溶液1.5h后,加入Bu3SnCl(4.1g,12.5mmol);将反应混合物升至室温并搅拌1h,混合物用石油醚萃取,有机相用无水硫酸镁干燥,旋蒸除去有机溶剂,无需进一步纯化;
B、将化合物3(800mg,0.74mmol)、化合物4(770mg,1.8mmol)、Pd(PPh3)4(50mg)加入到无水甲苯(12mL)中,氮气保护下反应8h;硅胶柱层析提纯,得橙色粘性液体(720mg,81%);
C、将化合物5(120mg,0.1mmol)、6(137mg,0.5mmol)和β-丙氨酸(1.8mg,20μmol)溶解于1,2-二氯乙烷(20mL)和乙醇(4mL)的混合溶剂中,55℃加热反应至数小时;通过硅胶柱层析纯化残余物,得黑色固体产物式(1)化合物(130mg,76%)。
上述有机小分子染料在甲苯中的最大吸收峰及最大发射峰分别位于844nm及944nm。
2.上述有机小分子染料的J聚集纳米粒子,其制备方法包括以下步骤:
(1):称取0.5mg的有机小分子染料,10mg的F127溶于1mL四氢呋喃中,超声溶解。
(2):超声下将上述混合物溶液快速加入5mL去离子水中,并继续超声5min。
(3):利用氮气除去所得溶液中的四氢呋喃,浓缩得到1mg/mL的纳米粒子溶液。
上述方法制备的J聚集纳米粒子水溶液的紫外吸收及荧光发射光谱如图1所示,其在水溶液中的最大吸收峰在1029nm,与有机小分子染料单体相比红移了185nm。同时纳米粒子在水溶液中的最大发射峰位于1128nm,相比于有机小分子染料DTT单体而言红移了184nm,表明DTT在纳米粒子内部发生了J聚集。另外,纳米粒子的荧光发射波长可延伸到1700nm,表明它可用作NIR-IIb成像造影剂。
3.J聚集纳米粒子的光热性能
图2为本发明的J聚集纳米粒子在水溶液中随不同激光功率变化的升温曲线。实验中采用1064nm激光器作为照射光源,功率分别为0.1、0.25、0.5、0.75、1W/cm2,照射时间为5min,纳米粒子的浓度为100μg/mL。从图中可以发现,随着激光功率的上升,纳米粒子水溶液的最终温度在不断上升,特别是当1W/cm2时,其最高温可升至90℃,表明了纳米粒子的优良的光热性能。
图3为本发明的J聚集纳米粒子在水溶液中随不同浓度变化的升温曲线。实验中采用1064nm激光器(1W/cm2)作为照射光源,纳米粒子的浓度分别为100、50、25、12.5、6.25、0μg/mL,照射时间为5min。从图中可以发现,纳米粒子的光热温度随着材料浓度的增加而上升。
图4为本发明的J聚集纳米粒子与DPBF混合后,经不同功率的1064nm激光照射下DPBF在414nm处吸收强度随时间的变化曲线。使用的激光器功率分别为0、0.1、0.25、0.5、0.75、1W/cm2,照射时间间隔为10s。从图中可以发现,经激光器照射后DPBF的吸收值不断下降,且随着激光功率的增强,下降的速度越快,表明纳米粒子在1064nm激光照射下具有极好的光动力性能。
4.J聚集纳米粒子的荧光成像
图5为本发明的J聚集纳米粒子经尾静脉注射后小鼠的全身血管成像。纳米粒子注射剂量为200μL,1mg/mL,激光器为1064nm,20mW/cm2,滤光片为1500nm长通滤光片。从图中可以发现,小鼠全身血管清晰可见,表明纳米粒子具有出色的NIR-IIb荧光成像性能。
以上已经描述了本发明的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和技术原理的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的,这些修改和变更也应视为本发明的保护范围。
Claims (10)
2.根据权利要求1所述的有机小分子染料,其特征在于,所述的有机小分子染料在甲苯中的最大吸收波长在844nm,最大发射波长在944nm。
4.一种J聚集纳米粒子,其特征在于,是由权利要求1所述的有机小分子染料与两亲性聚合物通过纳米共沉淀方法制备得到的。
5.根据权利要求4所述的J聚集纳米粒子,其特征在于,在水溶液中,该纳米粒子最大吸收波长在1029nm,最大荧光发射波长在1128nm,荧光发射波长能够延伸到1700nm。
6.根据权利要求4所述的J聚集纳米粒子,其特征在于,在水溶液中,该纳米粒子在1064nm激光照射下具有光动力性能和光热性能。
7.一种权利要求4所述的J聚集纳米粒子的制备方法,其特征在于,包括以下步骤:
将权利要求1所述的有机小分子染料与两亲性聚合物F127共同溶解于有机溶剂;
在超声下加入去离子水中,并在超声下进行反应;
反应完成后去除有机溶剂得到J聚集纳米粒子的水溶液。
8.根据权利要求7所述的J聚集纳米粒子的制备方法,其特征在于,所述有机小分子染料与两亲性聚合物F127的质量比为1:(20~25),有机溶剂与去离子水的体积比为1:(8~10)。
9.一种权利要求4所述的J聚集纳米粒子在激光照射下NIR-IIb区荧光成像中的应用。
10.一种权利要求4所述的J聚集纳米粒子在制备激光照射下肿瘤的光热及光动力联合治疗试剂中的应用。
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