CN116751215A - 一种含苯并噻二唑大共轭受体衍生物、纳米粒子荧光探针及其制备方法与应用 - Google Patents
一种含苯并噻二唑大共轭受体衍生物、纳米粒子荧光探针及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种含苯并噻二唑大共轭受体衍生物、纳米粒子荧光探针及其制备方法与应用；所述含苯并噻二唑大共轭受体衍生物的结构式为本发明的纳米粒子荧光探针包括含苯并噻二唑大共轭受体衍生物和两亲性聚合物；所述两亲性聚合物包裹含苯并噻二唑大共轭受体衍生物。本发明的化合物和纳米粒子荧光探针集高热转化系数、可观的吸光能力和高荧光量子产率的于一体，相比于现有的NIR‑II区荧光探针具有更高的光热转化能力和光致发光强度。
Description
技术领域
本发明属于有机荧光材料技术领域，具体涉及一种含苯并噻二唑大共轭受体衍生物、纳米粒子荧光探针及其制备方法与应用。
背景技术
集合光成像诊断和光热治疗的荧光探针正在蓬勃发展。它们具有小的侵袭性、高时空分辨率、高生物安全性等特点，在成像和治疗中发挥着越来越重要的作用。特别是，近年来具有近红外II区(NIR-II，1000-1700nm)发射的荧光探针因其较高的信噪比、更深的穿透和更高的分辨率而引起了广泛的关注。大多数报道的NIR-II探针不能同时具有高的荧光量子产率(fluorescence quantum yield,QY)和光热转换效率(photothermal conversionefficiency,PCE)，限制了其在成像引导下进行精确光热治疗的应用(B.Guo,Z.Huang,Q.Shi,E.Middha,S.Xu,L.Li,M.Wu,J.Jiang,Q.Hu,Z.Fu,B.Liu,Adv.Funct.Mater.2020,30,1907093)。因此，同时提高NIR-II探针的QY和PCE对成像诊断和光热治疗研究具有重要意义。然而，同时具有高PCE和QY的NIR-II荧光探针很少被报道，有效平衡增强NIR-II荧光探针的PCE和QY的策略仍很少。
提高材料QY的常用策略是通过设计大的刚性π共轭体系来抑制非辐射跃迁。然而具有大共轭体系的分子分散在水中时，会出现聚集，从而导致荧光猝灭，这是由于π-π堆积导致非辐射弛豫途径占主导。聚集诱导发光近些年来成为构建高发光聚集态材料的可靠方法。聚集诱导发光分子常常具有高扭曲和多转子结构，可以有效抑制聚集态的π-π堆积，同时分子处于聚集态时，之间的相互作用可以有效地抑制转子的运动，抑制非辐射跃迁通道，从而提高QY。
提高材料的光热效果通常通过提高其摩尔吸光系数(ε)和PCE来实现。提高ε，常见的方法是通过扩展共轭体系来实现的。但大共轭体系在聚集态时很容易π-π堆积从而猝灭发光，使得聚集体给出很低的QY。提高PCE，通常是使分子的非辐射跃迁增强，减弱辐射跃迁，这也会使得QY降低。如何平衡QY、ε和PCE三者，从而获得集高光热转化系数、可观的吸光能力和荧光量子产率于一体的聚集体材料是本领域面临的挑战。
NIR-II区荧光成像由于其较小的自发荧光和光子散射特别适合生物的深层组织成像，从而定位病灶部位；同时光热治疗可以通过光来精准产生热来消融病灶部位，但现有技术中缺乏在NIR-II区发光且具有高光热转化能力和荧光量子产率的材料。因此，迫切需要发光在NIR-II区乃至NIR-IIb区，集高热转化系数、可观的吸光能力和荧光量子产率的于一体的荧光探针。
发明内容
针对现有技术存在的不足，本发明的目的是提供一种含苯并噻二唑大共轭受体衍生物、纳米粒子荧光探针及其制备方法与应用。本发明提出一种获得集高热转化系数、可观的荧光量子产率和吸光能力的于一体的荧光探针的方法。分子设计策略是：将合适的大共轭受体核、多烷基链和多转子扭曲结构合为一体。大共轭受体结构可以有效提高ε，同时大共轭核周围多条烷基链和扭曲的多转子结构和可以有效地防止分子之间的π-π堆积从而提高QY；与此同时多条烷基链会使得转子具有足够的运动空间，多转子结构会使得分子运动单元变多，有利于PCE。在这里本发明采用合适的大共轭受体核，其具有更多的位点连接给体，使得分子具有更多的烷基链和转子结构，在获得高PCE基础上仍能保持可观的QY，从而获得发光在NIR-II区乃至NIR-IIb区，集高热转化系数、可观的吸光能力和荧光量子产率的于一体的纳米粒子荧光探针。在此基础上，本发明利用该荧光探针实现对血栓的诊疗一体化。
本发明的目的通过以下技术方案实现：
一种含苯并噻二唑大共轭受体衍生物，结构式如下：
其中，R1和R1’是相同或者不同的烷基链；
R2和R2’分别为以下结构式中的一种：
优选的，R1和R1’为C4-C20烷基链(碳数为4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20的烷基链)。
进一步优选的，R1和R1’为己基，十二烷基。
优选的，R2和R2’的结构式为：
优选的，结构式如下：
一种纳米粒子荧光探针，包括上述的含苯并噻二唑大共轭受体衍生物和两亲性聚合物；所述两亲性聚合物包裹含苯并噻二唑大共轭受体衍生物。
优选的，所述两亲性聚合物为二硬脂酰基磷脂酰乙醇胺-聚乙二醇1000-3000。
进一步优选的，所述两亲性聚合物为二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000。
优选的，所述含苯并噻二唑大共轭受体衍生物、两亲性聚合物的质量比为1：3-8。
优选的，所述纳米粒子荧光探针的颗粒尺寸为50纳米至180纳米；
进一步优选的，所述纳米粒子荧光探针的颗粒尺寸为60纳米至160纳米。
优选的，所述纳米粒子荧光探针的发光区间为900纳米至1700纳米的近红外II区域。同时具有优异的光热转化能力。
上述的纳米粒子荧光探针的制备方法，包括以下步骤：
(1)将含苯并噻二唑大共轭受体衍生物、两亲性聚合物、有机溶剂混合后，再加入水中，得到混合溶液；
(2)将混合溶液进行超声、搅拌去除有机溶剂，再过滤得到纳米粒子荧光探针。
优选的，步骤(1)所述含苯并噻二唑大共轭受体衍生物、两亲性聚合物、有机溶剂、水的质量体积比为1mg：3-8mg：0.5-1.5mL：12-20mL；
进一步优选的，所述含苯并噻二唑大共轭受体衍生物、两亲性聚合物、有机溶剂、水的用量比为1mg：5mg：1mL：16mL。
优选的，所述有机溶剂为四氢呋喃。
上述的含苯并噻二唑大共轭受体衍生物和上述的纳米粒子荧光探针在制备成像试剂和光热治疗试剂中的应用。
优选的，所述成像试剂的成像是近红外二区成像。具体的是1000nm-1700nm区域成像或者1500nm-1700nm区域成像。
优选的，所述成像试剂用于对血管和肿瘤成像。
优选的，所述光热治疗试剂用于对血栓和肿瘤光热诊疗。
本发明含苯并噻二唑大共轭受体衍生物、纳米粒子荧光探针、成像试剂和光热治疗试剂通过口服或者静脉内注射方式施用于受试者。
本发明提供了一种进行血栓诊疗的方法，所述方法包括：将本发明的纳米粒子荧光探针施用于受试者，通过成像判断血栓位置，再通过光照生热来消融血栓。
本发明相比于现有技术，具有的有益效果在于：
(1)本发明的含苯并噻二唑大共轭受体衍生物具有近红外发光、高热转化系数、高吸光能力和高荧光量子产率；同时具有聚集诱导发光性质。
(2)本发明提供了发光在NIR-II区乃至NIR-IIb区，集高热转化系数、可观的吸光能力和高荧光量子产率的于一体的纳米粒子荧光探针，相比于现有的NIR-II区荧光探针具有更高的光热转化能力和光致发光强度。
(3)本发明所述的纳米粒子荧光探针具有在NIR-II区乃至NIR-IIb区发光的特性，实现了高分辨的生物NIR-II区脑血管成像、全身血管成像乃至NIR-IIb区全身血管成像。
(4)本发明所述的纳米粒子荧光探针具有高NIR-II发光特性，通过血管成像实现了对血栓的诊断，同时具有高光热转化能力可以使光高效转化为热来消融治疗血栓。这为荧光探针的诊疗一体化提供了设计灵感。
附图说明
图1为实施例3的4THTPB NPs的吸收光谱和荧光光谱。
图2为实施例4的4THTPB，4THTPB NPs和IR-26的荧光积分强度图。
图3为实施例5用808nm激光照射(1W cm-2,照射面积0.32cm2)4THTPB纳米粒子的光热响应曲线(a)；和从冷却期间获得的-Lnθ与时间之间的线性关系曲线(b)。
图4为实施例6在808nm激光照射下不同浓度4THTPB纳米粒子溶液的光热响应曲线。
图5为实施例7注射4THTPB NPs后在不同LP滤光片对活体小鼠全身血管区域NIR-II荧光信号的比较以及在不同深度对小鼠脑血管进行NIR-II成像。a)1200nm LP,40ms,79mW/cm2；b)1300nm LP,100ms,79mW/cm2；c)1500nm LP,400ms,100mW/cm2。比例尺10mm。d-f)沿红线对应的截面荧光强度分布图。高斯拟合的轮廓为红色虚线。g-i)不同深度(540 -840μm)小鼠脑血管NIR-II荧光显微成像，808nm激发，1100nm LP；j)为g)图的沿红线对应的截面荧光强度分布图。高斯拟合的轮廓为红色虚线。
图6为实施例8体外血栓治疗的效果图。a)PBS缓冲液(pH＝7.4)为母液，不同浓度的4THTPB NPs在808nm激光照射(0.3W/cm2)下的体外溶栓实验。b)pH＝7.4的PBS缓冲液为母液，808nm激光照射(0.3W/cm2)不同浓度4THTPB NPs，游离血液在540nm处吸光度的动力学痕迹。
图7为实施例9体内血栓诊断和治疗的效果图。治疗前后小鼠的左右腿NIR-II成像图(用808nm激发，1175nm LP成像；右腿为股动脉血栓模型)。左图为未光照的NIR-II成像，右图为在808nm激光照射(0.3W/cm2,6min)后的NIR-II成像(静脉注射4THTPB NPs)。
具体实施方式
下面将联系实例来对本发明具体实施来进一步说明如何实现，但是本发明的实施和保护并不局限于这些。需要注意的是，如果下面的步骤没有具体地被描述，那么这些步骤将被所属领域的技术人员参考已有技术实施或了解。对于所使用的试剂和仪器，如果没有标明制造商，则是可通过市场来购买的常规商品。
实施例1：化合物4THTPB的合成
合成路线如下：
(1)将化合物1(0.922g，2.4mmol)和Pd(PPh3)4(0.167g，0.144mmol)加入250mL反应瓶，在N2保护下，加入化合物2(5.381g，7.68mmol)和90mL二氧六环，90℃加热搅拌24小时。反应结束冷却后用KF水溶液猝灭，用DCM萃取，将萃取液浓缩，硅胶柱纯化，得到紫色固体3(产率79.1％)；
(2)将化合物3(0.209g，0.2mmol)，锌粉(0.785g，12mmol)和NH4Cl(0.193g，3.6mmol)加入反应瓶，加入18mL DCM和29mL 90％甲醇，常温搅拌4小时。用硅藻土垫过滤，DCM洗涤，用水饱和NaHCO3水溶液洗涤滤液，将有机相蒸发得粗产物4，无需进一步提纯，可直接进行下一步；
将上一步得到的粗产物4和化合物5(0.020g，0.076mmol)加入反应瓶中，加入12mL氯仿和12mL冰醋酸，75℃加热搅拌12小时。冷却至室温，用水和DCM萃取，有机相用NaHCO3水溶液洗涤，将有机相浓缩，硅胶柱纯化，得到藏青色固体4THTPB(产率82.8％)。
1H NMR(400MHz,CDCl3)δ(ppm)＝9.49-9.40(4H,d),8.06-8.00(2H,m),7.74-7.62(8H,d),7.55-7.41(4H,s),7.38-7.27(16H,m),7.24-6.85(32H,m),2.68-2.47(8H,m),1.66-1.55(8H,m),1.13-0.84(24H,m),0.64-0.49(12H,m).
13C NMR(125MHz,CDCl3),δ(ppm):153.38,147.52,147.43,146.21,145.41,144.00,138.86,130.20,130.07,129.37,129.30,129.07,128.72,126.61,124.62,124.50,124.44,123.74,123.18,31.44,30.37,30.28,28.92,22.37,13.88.
实施例2：纳米粒子荧光探针4THTPB NPs的制备
将1mg 4THTPB和5mg DSPEG-PEG2000加入1mL THF中，超声溶解。然后将溶液快速加入16mL超纯水中，在水中超声处理3min。然后，剧烈搅拌24h除去THF。将收集的纳米粒子通过离心浓缩，储存在4℃下，以供下一步使用。
实施例3：吸收光谱与荧光光谱测定
将实施例2中获得的4THTPB NPs稀释至10μM,测得吸收光谱和荧光光谱。吸收光谱和荧光光谱见图1，蓝线为4THTPB纳米粒子的紫外—可见光—近红外吸收谱，紫线为荧光发射谱，插图为1400nm-1700nm的荧光谱，可见吸收峰在732nm，发射峰在1058nm，发光可至1700nm。
实施例4：相对荧光量子产率的测定
将NIR-II荧光染料IR-26(QY＝0.5％)作为参考染料溶解于1，2-二氯乙烷中，然后进行稀释，制得在808nm处吸光度小于0.1的五个样(使二次光学过程如再吸收和再发射最小化)。将五个样在相同的比色皿下，测得在808nm纳米激发下的荧光光谱，将荧光光谱进行积分，绘制吸光度与荧光积分强度相关图，再进行线性拟合得斜率。4THTPB溶于THF中，4THTPB NPs在水相中进行相同程序得斜率。再依据(1)式求得QY。
其中QYs和QYr分别是样品和参照样的荧光量子产率，Slopes和Sloper分别是样品和参照样的斜率，ns和nr分别是样品和参照样所用溶剂的折射率。
4THTPB，4THTPB NPs和IR-26(一种近红外荧光团，QY＝0.5％)在五种不同浓度下的荧光积分强度结果如图2所示，用于通过比较线性拟合的斜率来计算量子产率，THTPB在THF中和4THTPB NPs在水相中的QY分别为0.64％和4.1％。
实施例5：计算光热转换效率
NPs的光热转换效率(η)由下式(2)计算：
其中η为光热转换效率，TMax和TSurr分别为平衡温度(℃)和环境温度(℃)。QDis为样品池输入的基准能量，I为808nm激光功率，A为NPs在808nm处的吸光度。
hS的值由式(3)得到：
hS为容器和溶剂相关参数(h、S分别为传热系数和容器表面积)，m为水的质量，Cp为水的热容。
τs的值由式(4)得到：
t＝τs(-lnθ) (4)
式中t为照射后的冷却时间点，T为溶液温度，TMax和TSurr分别为平衡温度和环境温度。
图3中的a为用808nm激光照射(1W cm-2,照射面积0.32cm2)4THTPB纳米粒子溶液(100μM)至不再升温后然后关闭激光的光热响应曲线；b为从冷却期间获得的-Lnθ与时间之间的线性关系曲线。
根据以上公式和图3可得4THTPB的光热转化效率为87.6％。
实施例6：不同浓度4THTPB NPs的光热性能
将4THTPB NPs母液稀释为25μM,50μM,100μM,200μM，用808nm激光(1W/cm2)照射，获得溶液随时间的温度变化曲线，如图4，可以看出，NPs表现出浓度依赖的光热效应，与浓度呈正相关。
实施例7：小鼠NIR-II荧光成像
将小鼠麻醉，尾静脉注射4THTPB NPs(850μM，150μL)，选用不同长通对小鼠进行血管进行成像，成像结果如图5所示。在1200LP，1300LP和1500LP成像，血管的表观宽度分别为0.43mm，0.36mm和0.33nm(图5中的a-f),显示出NIR-II b成像具有更小的散射信号，分辨率更高。对小鼠脑血管显微成像如图5中的g-i所示，其在540μm处可以清晰看到表观宽度为3.4μm的脑血管，同时最深可以成像到840μm。
实施例8：体外血栓治疗
将已经凝固的血块置于容器中，分别加入相同体积的空白PBS、15μM和30μM的4THTPB NPs溶液，用0.3W/cm2的808nm激光照射，每隔10min对溶液测试UV-Vis吸收光谱，得游离血液在540nm处吸光度的动力学痕迹，如图6所示。可观察到，含有4THTPB NPs的溶液在808nm光照下对血块溶解具有大幅提升效果。
实施例9：小鼠体内血栓诊疗
将小鼠麻醉，对小鼠右腿血管用(10％FeCl3溶液)来浸润制作血栓模型，尾静脉注射4THTPB NPs(150μL,850μM)，用1175LP进行NIR-II成像，可以明显看到右腿血管血栓的形成，如图7。用808nm(0.3W/cm2)激光照射右腿血栓处6min，再进行NIR-II区成像，可以明显看到血块溶解血管连通。
上述实例仅是本发明的较优实现形式，这些例子只是对本发明进行说明，并不是对本发明的限制。本领域技术人员在不背离本发明的精神范围的情况下做出的改变、替代、修改等都应当属于本发明的保护。
Claims (10)
1.一种含苯并噻二唑大共轭受体衍生物，其特征在于，结构式如下：
其中，R1和R1’是相同或者不同的烷基链；
R2和R2’分别为以下结构式中的一种：
2.根据权利要求1所述的含苯并噻二唑大共轭受体衍生物，其特征在于，R1和R1’为C4-C20烷基链。
3.根据权利要求1所述的含苯并噻二唑大共轭受体衍生物，其特征在于，结构式如下：
4.一种纳米粒子荧光探针，其特征在于，包括权利要求1-3任一项所述的含苯并噻二唑大共轭受体衍生物和两亲性聚合物；所述两亲性聚合物包裹含苯并噻二唑大共轭受体衍生物。
5.根据权利要求4所述的纳米粒子荧光探针，其特征在于，所述两亲性聚合物为二硬脂酰基磷脂酰乙醇胺-聚乙二醇1000-3000；
所述含苯并噻二唑大共轭受体衍生物、两亲性聚合物的质量比为1：3-8。
6.根据权利要求4所述的纳米粒子荧光探针，其特征在于，所述纳米粒子荧光探针的颗粒尺寸为50纳米至180纳米；
所述纳米粒子荧光探针的发光区间为900纳米至1700纳米。
7.权利要求4-6任一项所述的纳米粒子荧光探针的制备方法，其特征在于，包括以下步骤：
(1)将含苯并噻二唑大共轭受体衍生物、两亲性聚合物、有机溶剂混合后，再加入水中，得到混合溶液；
(2)将混合溶液进行超声、搅拌去除有机溶剂，再过滤得到纳米粒子荧光探针。
8.根据权利要求7所述的制备方法，其特征在于，步骤(1)所述含苯并噻二唑大共轭受体衍生物、两亲性聚合物、有机溶剂、水的质量体积比为1mg：3-8mg：0.5-1.5mL：12-20mL；
所述有机溶剂为四氢呋喃。
9.权利要求1-3任一项所述的含苯并噻二唑大共轭受体衍生物和权利要求4-6任一项所述的纳米粒子荧光探针在制备成像试剂和光热治疗试剂中的应用。
10.根据权利要求9所述的应用，其特征在于，所述成像试剂的成像是近红外二区成像。
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| CN117659054B (zh) * | 2024-01-18 | 2024-03-29 | 电子科技大学 | 一种多臂有机光电小分子及其制备方法和应用 |
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