CN115490846B - 一种水溶性近红外二区聚集诱导发光材料及其制备方法、应用 - Google Patents
一种水溶性近红外二区聚集诱导发光材料及其制备方法、应用 Download PDFInfo
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Abstract
本发明公开了一种水溶性近红外二区聚集诱导发光材料制备方法、应用，其化学结构式为：其中，A＝:单甲氧基聚乙二醇(mPEG)的分子量可以为550，1000，2000。其具有D‑π‑A‑π‑D结构，分子结构中的三苯胺作为电子给体和转子结构基元保证其聚集诱导发光特性，强电子受体的选用可以降低分子的能隙，延长吸收/发射波长至近红外二区。本发明开发的水溶性近红外二区聚集诱导分子合成路线简单，成本低，生物相容性好。其水溶性可通过改变单甲氧基聚乙二醇的分子量进行调控。所开发的材料具有不错的荧光量子产率和良好的光动力/光热效果。
Description
技术领域
本发明涉及荧光分子探针技术领域，尤其涉及一种水溶性近红外二区激发聚集诱导发光材料及其制备方法、应用。
背景技术
目前研究最广泛的荧光材料发射波长大多在可见光区（400-700 nm）和近红外一区（700-900 nm）。而此波段下光能量强度高、光散射程度高、对生物组织穿透深度浅，难以到达深层组织。相比之下，近红外二区（NIR-II, 1000-1700 nm）发射光学诊疗材料的开发可以有效弥补以上不足，最大程度地展现出光学诊疗材料的优点。
与无机和聚合物材料相比，有机小分子材料因其易于修饰、结构/纯度确切且生物相容性好而成为构建光诊疗材料的优良选择。然而，在生理环境中，疏水性的稠芳环类化合物不可避免地会形成团簇，并伴随着强烈的分子间π-π相互作用，促进聚集导致荧光淬灭（ACQ）现象的发生。幸运的是，唐本忠院士于2001年提出聚集诱导发光（AIE）概念，为解决ACQ提供了有效方法。与传统的染料分子相比，具有螺旋桨状构象的AIE分子在聚集状态下由于分子内运动受限使得激发态能量主要通过辐射跃迁途径耗散，从而发出明亮的荧光；与此同时，扭曲的AIE分子在聚集状态下仍可以通过多转子基元的局部运动使得激发态能量经由非辐射跃迁途径消散，进而用于PAI、PTI和PTT。因此，通过合理的分子设计，可以实现NIR-II AIE分子激发态能量中辐射跃迁与非辐射跃迁之间的可控调节。
然而目前报道的NIR-II AIE绝大多数是疏水性的，不能直接进行生物学的应用，通常需要使用两亲性载体将材料包封成纳米粒子以赋予其良好的水分散性。然而，这种纳米制备方法程序繁琐且重复性差。
因此，设计可直接溶解于水中进行使用的NIR-II AIE材料具备广阔的应用前景。
发明内容
本发明要解决的技术问题在于，针对现有水溶性NIR-II AIE材料缺少通用的合成方法的问题，旨在开发水溶性NIR-II AIE材料制备新方法，扩展新应用。
本发明解决该技术问题所采用的技术方案是：通过调节单甲氧基聚乙二醇分子量的大小，构筑不同分子量的新型水溶性NIR-II AIE材料，所构筑的新型水溶性NIR-II AIE材料化学结构式为：。
其中，A选自、/>、/>、/>、/>中的一种；mPEG为单甲氧基聚乙二醇；mPEG的分子量可以为550，1000，2000，5000等。
基于相同的发明构思，本发明还提供了水溶性NIR-II AIE材料的制备方法，所述方法包括如下步骤：
将化合物AIE-4COOH、mPEG-NH2、缩合剂、有机碱依次加入超干溶剂中，在惰性气体保护下进行室温搅拌，得到反应溶液；将反应溶液加入到透析袋中，经过透析、冻干后得到产物；
可选地，所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其中，所述化合物mPEG-NH2与AIE-4COOH的物质的量比为6-10：1。
可选地，所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其中，所述反应溶液中AIE-4COOH的物质的量浓度为1-2 mol/L。
可选地，所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其中，所述有机碱与AIE-4COOH的物质的量比为6-10：1。
可选地，所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其中，mPEG-NH2的分子量可以为550，1000，2000，5000等。
可选地，所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其中，所使用的缩合剂组合可以为2- (1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯（HBTU），或碳二亚胺盐酸盐（EDCI）和4-二甲氨基吡啶（DMAP），或碳二亚胺盐酸盐（EDCI）和1-羟基苯并三氮唑（HOBt）。
可选地，所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其中，所使用的超干溶剂可以为四氢呋喃和N,N-二甲基甲酰胺的组合。
可选地，所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其中，所使用的有机碱可以为三乙胺（Et3N）或N,N-二异丙基乙胺（DIPEA）。
所述对所述反应溶液进行纯化，得到所述水溶性近红外二区激发聚集诱导发光材料的步骤包括：
将反应溶液以1：10的比例加入水并转移至透析袋中。透析初始的12 h内每两个小时换一次透析水，随后的24 h内每12 h换一次水，然后使用真空冻干机将水溶液中的水分除去得到所述新型水溶性NIR-II AIE材料。
有益效果：本发明提供的水溶性近红外二区激发聚集诱导发光材料具有D-π-A-π-D（D为电子给体，A为电子受体）结构，其中mPEG分子量的不同赋予材料可调控的亲水性。所得到的水溶性材料在水相中可以自组装成超小的纳米粒子，通过NIR-II荧光成像可以观察到材料能被肾脏功能正常的小鼠排出体外；而发生肾脏纤维化的小鼠，材料则会持续积累在肾脏部位。此外，本发明所提供的新型水溶性NIR-II AIE材料还具有良好的光热产生能力和光动力治疗效果，可用于多种细菌的光学杀伤。
附图说明
图1是本发明实施例1和2中制备的水溶性NIR-II AIE材料的合成路线图。
图2是本发明实施例1中制备的AIE-DPTQ-4PEG550材料的MALDI-TOF-MS图。
图3是本发明实施例2中制备的AIE-DPTQ-4PEG1000材料的MALDI-TOF-MS图。
图4是本发明实施例1中制备的AIE-DPTQ-4PEG550材料的紫外吸收和荧光发射光谱图。
图5为实施例1中制备的AIE-DPTQ-4PEG550材料在DMSO/水混合溶剂中的荧光发射增强倍数图。
图6是本发明实施例1中制备的AIE-DPTQ-4PEG550材料与吲哚菁绿在0.3 W cm-1的660 nm激光照射下的荧光稳定下对比图。
图7是本发明实施例1中制备的AIE-DPTQ-4PEG550材料与人肾皮质近曲小管上皮细胞共孵育的细胞存活率图。
图8是本发明实施例1中制备的AIE-DPTQ-4PEG550材料注射到叶酸诱导的肾纤维化的C57BL/6小鼠后，肾脏的荧光成像和光声成像图。
图9是本发明实施例中制备的AIE-DPTQ-4PEG1000用于光热/光动力协同抗MRSA实验。
具体实施方式
本发明提供的新型水溶性近红外二区聚集诱导发光材料制备方法、应用，为使本发明的目的、技术方案及优点更加清楚、明确，以下对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
随着荧光分子共轭骨架的延展，分子的疏水性也随着增强，需要通过纳米包载的途径才能赋予材料生物学应用的条件。而纳米包载过程步骤冗长且重现性差，极大的限制了材料的进一步推广。
本发明实施例提供了一种水溶性近红外二区激发聚集诱导发光材料，其化学结构式为：。其中，A= :/>；单甲氧基聚乙二醇（mPEG）的分子量可以为550，1000，2000，5000等。其具有D-π-A-π-D结构，分子结构中的三苯胺作为电子给体和转子结构基元保证其聚集诱导发光特性，强电子受体的选用可以降低分子的能隙，延长吸收/发射波长至近红外二区。不同受体基元的选择可以调控所得材料的波长和性能，mPEG作为亲水性调控基元，用于调控材料的水溶性。
发明提供了一种上述水溶性近红外二区激发聚集诱导发光材料的制备方法，包括步骤：
实施例1
化合物AIE-4PEG550的制备方法具体包括以下步骤：
步骤一）：化合物II的合成
将化合物I（14.7g，35 mmol）加入N,N-二(4-甲酰苯基)苯胺（4.5 g，15 mmol）的无水甲苯溶液中（100 mL）中，并用干燥氮气吹扫三次。将溶液在室温下搅拌48小时。通过TLC检测反应完成后，除去溶剂，用硅胶柱纯化得到亮黄色油状物II（8.35g，95%产率）。1H NMR(600 MHz, Chloroform-d) δ 7.60 (d,J= 15.9 Hz, 2H), 7.35 (d,J= 8.4 Hz, 4H),7.26 (t,J= 7.7 Hz, 2H), 7.09 (t,J= 8.0 Hz, 3H), 7.01 (d,J= 8.4 Hz, 4H), 6.28(d,J= 15.9 Hz, 2H), 4.34 – 4.20 (m, 4H), 1.14 – 0.97 (m, 4H), 0.06 (s, 18H).13C NMR (150 MHz, Chloroform-d) δ 166.57, 148.18, 145.71, 143.02, 129.09,128.64, 128.30, 125.28, 124.15, 122.69, 115.97, 61.86, 16.79, -2.00.
步骤二）：化合物III的合成
化合物II（5.86g，10mmol）和10%Pd/C（1.06g）加入乙酸乙酯（100mL）中，抽真空后，使用H2（40atm）回填。在室温搅拌过夜后，使用垫有硅藻土的砂芯漏斗过滤反应混合液，然后用乙酸乙酯（30mL x 3）冲洗。减压旋转蒸发除去溶剂，得到粗产物，无需进一步纯化，可直接投入下一步反应。1H NMR (400 MHz, Chloroform-d) δ 7.24 – 7.19 (m, 2H), 7.09(d,J= 8.5 Hz, 4H), 7.07 – 7.04 (m, 2H), 7.03 – 7.00 (m, 4H), 6.97 (s, 1H),4.25 – 4.17 (m, 4H), 2.92 (t,J= 7.8 Hz, 4H), 2.67 – 2.56 (m, 4H), 1.07 – 0.95(m, 4H), 0.08 (s, 18H).13C NMR (101Hz, Chloroform-d) δ 172.44, 147.36, 145.45,134.32, 128.52, 128.48, 123.66, 123.00, 121.66, 61.99, 35.52, 29.76, 16.72, -2.02.
步骤三）：化合物IV的合成
将化合物III（4.71 g，8 mmol）溶解在DCM（100 mL）中并置于冰浴下。然后把NBS（2.25 g，12.61 mmol）分5份加入到反应液中。室温下搅拌过夜后，用硅胶柱纯化得到得到无色油状化合物IV（5.01g，产率94%）。1H NMR (400 MHz, Chloroform-d) δ 7.25 (d,J=8.9 Hz, 2H), 7.07 (d,J= 8.5 Hz, 4H), 6.97 (d,J= 8.5 Hz, 4H), 6.88 (d,J= 8.9Hz, 2H), 4.24 – 4.14 (m, 4H), 2.90 (t,J= 7.7 Hz, 4H), 2.59 (t,J= 7.8 Hz, 4H),1.04 – 0.95 (m, 4H), 0.06 (s, 18H).13C NMR (101 MHz, Chloroform-d) δ 172.26,146.49, 144.90, 134.95, 131.41, 128.66, 123.90, 123.88, 113.61, 61.95, 35.42,29.73, 16.72, -2.01.
步骤四）：化合物V的合成
将1，4-二氧六环（50 mL）、化合物IV（4 g，6 mmol）、双（三苯基膦）二氯化钯（II）（0.44 g，0.175 mmol）、KOAc（1.47 g，15 mmol）和联硼酸频那醇酯（1.83 g，7.2 mmol）加入到250 mL双颈圆底烧瓶中，将烧瓶抽真空后用干燥氮气吹扫三次。然后，将反应混合物在120°C的油浴中搅拌过夜。冷却至室温后，用乙酸乙酯萃取体系并用饱和NaCl溶液洗涤3次。有机相用无水Na2SO4干燥并通过减压旋转蒸发除去溶剂，用硅胶柱纯化得到无色油状物V（3.29g，76.7%产率）。1H NMR (400 MHz, Chloroform-d) δ 7.64 (d,J= 8.5 Hz, 2H),7.09 (d,J= 8.5 Hz, 4H), 7.01 (d,J= 8.5 Hz, 4H), 6.98 (d,J= 8.5 Hz, 2H), 4.23– 4.14 (m, 4H), 2.91 (t,J= 7.8 Hz, 4H), 2.60 (t,J= 7.8 Hz, 4H), 1.33 (s,12H), 1.04 – 0.93 (m, 4H), 0.05 (s, 18H).13C NMR (101 MHz, Chloroform-d) δ172.43, 150.03, 144.89, 135.18, 135.06, 128.55, 124.43, 120.59, 82.86, 62.01,35.44, 29.75, 24.41, 24.23, 16.68, -2.07.
步骤五）：化合物VI的合成
将1，4-二氧六环（20 mL）、4,9-二溴-6,7-二苯基-[1,2,5]噻二唑并[3,4-g]喹喔啉（简写DPTQ）（4.5g，9mmol）、化合物V（2.15g，3mmol）、Pd（PPh3）4（0.17g，0.15mmol）、K2CO3（4.14g，30mmol）加入到50mL双颈圆底烧瓶中，将烧瓶抽真空后用干燥氮气吹扫三次。将反应混合物加热至120°C过夜。冷却至室温后，用乙酸乙酯萃取体系并用饱和NaCl溶液洗涤3次。有机相用无水Na2SO4干燥并通过减压旋转蒸发除去溶剂，用硅胶柱纯化得到绿色固体化合物VI（2.86g，产率63%）。1H NMR (400 MHz, Chloroform-d) δ 7.97 (d,J= 8.7 Hz,4H), 7.68 (d,J= 7.0 Hz, 4H), 7.40 (d,J= 7.3 Hz, 2H), 7.34 (t,J= 7.4 Hz, 4H),7.30 – 7.26 (m, 4H), 7.18 (q,J= 8.7 Hz, 16H), 4.26 – 4.19 (m, 8H), 2.97 (t,J=7.8 Hz, 8H), 2.71 – 2.63 (m, 8H), 1.00 (d,J= 8.4 Hz, 8H), 0.06 (s, 40H).13CNMR (101 MHz, Chloroform-d)1δ 172.56, 152.51, 152.07, 147.48, 145.05, 137.95,135.40, 135.10, 133.33, 129.44, 128.93, 128.59, 127.88, 127.57, 127.17,124.66, 120.39, 62.10, 35.53, 29.82, 16.70, -2.07.
步骤六）：化合物AIE-4COOH的合成
将化合物VI（0.15g，0.1mmol）、DCM（2 mL）加入到10 mL的单口圆底烧瓶中，并于冰浴下缓慢滴加TFA（2 mL）。将反应混合物缓慢升温至环境温度并继续搅拌48小时。反应结束后，真空除去溶剂并重新溶解在DCM/MeOH中，加入Et2O沉淀粗产物，然后用EA洗涤，得到绿色固体化合物AIE-4COOH（0.106g，95%产率）。1H NMR (400 MHz, DMSO-d 6) δ 12.16 (s,4H), 7.88 (d,J= 8.4 Hz, 4H), 7.59 – 7.51 (m, 4H), 7.40 (d,J= 7.1 Hz, 2H),7.35 (t,J= 7.3 Hz, 4H), 7.23 (d,J= 8.3 Hz, 8H), 7.09 – 7.03 (m, 12H), 2.81(t,J= 7.6 Hz, 8H), 2.55 (t,J= 7.7 Hz, 8H).13C NMR (101 MHz, DMSO-d 6) δ 173.67,152.50, 152.21, 147.37, 144.67, 138.10, 136.20, 135.07, 133.91, 129.53,129.35, 128.82, 127.97, 127.64, 127.25, 124.74, 119.61, 34.97, 29.60.
步骤六）：化合物AIE-4PEG550的合成
将AIE-4COOH（111mg，0.1mmol）、HBTU（19mg，1mmol）和mPEG550-NH2（1mmol）溶解在DMF（5 mL）中。然后将DIPEA（180uL，1mmol）加入溶液中，并室温搅拌48小时。反应完成后，将混合物转移到透析管（MWCO 2500DA）中，初始的12 h内每两个小时换一次透析水，随后的24h内每12 h换一次水，然后使用真空冻干机将水溶液中的水分除去得到绿色半油状化合物AIE-4PEG550。MALDI-TOF-MS. Expected M.W. 3243, Measured M.W. 3262.
实施例2
化合物AIE-4PEG1000的制备方法具体包括以下步骤：
将AIE-4COOH（111mg，0.1mmol）、HBTU（19mg，1mmol）和mPEG1000-NH2（1mmol）溶解在DMF（5 mL）中。然后将DIPEA（180uL，1mmol）加入溶液中，并室温搅拌48小时。反应完成后，将混合物转移到透析管（MWCO 5000DA）中，初始的12 h内每两个小时换一次透析水，随后的24 h内每12 h换一次水，然后使用真空冻干机将水溶液中的水分除去得到绿色半油状化合物AIE-4PEG1000。MALDI-TOF-MS. Expected M.W. 5043, Measured M.W. 5065.
由图4可知，本发明实施例1中制备的AIE-DPTQ-4PEG550材料具有近红外二区的长波长发射效果。
由图5可知，本发明实施例1中制备的AIE-DPTQ-4PEG550材料具备聚集诱导发光的性质。
由图6可知，本发明实施例1中制备的AIE-DPTQ-4PEG550材料具备比吲哚菁绿更好的荧光稳定性。
由图7可知，本发明实施例1中制备的AIE-DPTQ-4PEG550材料具有优良的细胞相容性。
由图9可知，本发明实施例2中制备的AIE-DPTQ-4PEG1000材料介导的光热/光动力联合协同替考拉宁可以更有效的杀灭MRSA。
综上所述，本发明实施例提供了一种新型水溶性NIR-II AIE材料，其化学结构式为：。其中，A= :/>；单甲氧基聚乙二醇（mPEG）的分子量可以为550，1000，2000，5000等。其具有D-π-A-π-D结构，分子结构中的三苯胺作为电子给体和转子结构基元保证其聚集诱导发光特性，强电子受体的选用可以降低分子的能隙，延长吸收/发射波长至近红外二区。不同受体基元的选择可以调控所得材料的波长和性能，mPEG作为亲水性调控基元，用于调控材料的亲水性。本专利所开发的新型水溶性NIR-II AIE材料在近红外二区仍具有良好的荧光量子产率，可通过近红外二区荧光成像和光声成像实现对肾纤维化小鼠肾脏的双模态成像；此外，材料还具有不错的活性氧和光热产生能力，可用于光热/光动力协同杀菌。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (8)
1.一种水溶性近红外二区聚集诱导发光材料，其特征在于，其化学结构式如下：
，
其中，mPEG为单甲氧基聚乙二醇；
所述的mPEG的分子量为550；
所述的水溶性近红外二区激发聚集诱导发光材料应用于肾脏疾病荧光成像。
2.一种如权利要求1所述的水溶性近红外二区激发聚集诱导发光材料的制备方法，其特征在于，包括：
将化合物AIE-4COOH、mPEG550-NH2、缩合剂以及有机碱加入超干溶剂中，得到反应溶液；
将反应溶液加入到透析袋中，经过透析、冻干后得到水溶性近红外二区激发聚集诱导发光材料；其中，所述化合物AIE-4COOH的结构式如下：。
3.根据权利要求2所述水溶性近红外二区激发聚集诱导发光材料的制备方法，其特征在于，所述化合物mPEG550-NH2与AIE-4COOH的物质的量比为6-10：1。
4.根据权利要求2所述水溶性近红外二区激发聚集诱导发光材料的制备方法，其特征在于，所述反应溶液中AIE-4COOH的物质的量浓度为1-2mol/L。
5.根据权利要求2所述水溶性近红外二区激发聚集诱导发光材料的制备方法，其特征在于，所述有机碱与AIE-4COOH的物质的量比为6-10：1。
6.根据权利要求2所述水溶性近红外二区激发聚集诱导发光材料的制备方法，其特征在于，所述缩合剂组合为2-(1H-苯并三氮唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯，或苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐或碳二亚胺盐酸盐和4-二甲氨基吡啶，或碳二亚胺盐酸盐和1-羟基苯并三氮唑。
7.根据权利要求2所述水溶性近红外二区激发聚集诱导发光材料的制备方法，其特征在于，所述超干溶剂为四氢呋喃与N,N-二甲基甲酰胺的混合溶液。
8.根据权利要求2所述水溶性近红外二区激发聚集诱导发光材料的制备方法，其特征在于，所述有机碱为三乙胺或N,N-二异丙基乙胺。
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