调控供电子策略简易制备近红外二区有机小分子光学诊疗试剂

doi:10.6023/A22060267

摘要/Abstract

有机小分子凭借着明确的化学结构、出色的生物相容性、优异的可重复性等诸多优势被广泛应用于光学诊疗领域. 然而, 目前报道的有机小分子存在合成步骤复杂、成像波长位于近红外一区(NIR-I)、光热转换效率及单线态氧产率低等缺陷, 严重限制了其诊疗效果. 基于此, 本工作以吡咯并吡咯二酮作为缺电子单元、分别以苯、苯胺、邻苯二胺作为供电子单元, 通过一步偶联反应简易制备得到三种有机小分子DPP-0、DPP-2、DPP-4, 进一步利用纳米沉淀法制备得到对应的水溶性纳米粒子DPP-0 NPs、DPP-2 NPs和DPP-4 NPs. 研究发现, 随着氨基数量的增加, 纳米粒子吸收/发射均发生了红移, 其中DPP-4 NPs具有良好的NIR-I吸收能力且其最大荧光发射达到了近红外二区(NIR-II)区域, 表明可以通过改变供电子单元策略实现光学性能的调控. 在单一激光照射下, DPP-4 NPs可以同时产生NIR-II荧光信号、过高热及单线态氧, 其光热转换效率和单线态氧产率分别高达40.2%及34.3%, 可成功应用于肿瘤深层次NIR-II荧光成像诊断及高效光热/光动力联合治疗.

关键词: 有机小分子, 光学诊疗, 近红外二区荧光成像, 光动力治疗, 光热治疗

Organic small molecules hold great promise in the field of phototheranostics by virtue of their clear chemical structure, outstanding biocompatibility, and distinguished repeatability. Whereas the synthetic process of them suffers from multi-step and complex reactions. Meanwhile, most of small molecules employed near-infrared-I (NIR-I) fluorescence imaging, which could not effectively provide comprehensive tumor information with high resolution. In addition, the reported small molecules showed unsatisfactory singlet oxygen yield and photothermal conversion eﬃciency, limiting their extensive application in cancer theranostics. Herein, by conjugating diketopyrrolopyrrole (an electron-withdrawing unit) with benzene, aniline, or 1,2-diaminobenzene (electron-donating units), respectively, three novel small molecules DPP-0, DPP-2 and DPP-4 were designed and synthesized by one-step reaction. DPP-0 NPs, DPP-2 NPs and DPP-4 NPs as phototheranostics were further obtained through nanoprecipitation method by self-assembling with Pluronic F127. It was found that with the increase of amino groups, the absorption/emission peaks of NPs were red-shifted. Especially, DPP-4 NPs exhibited strong absorption in the NIR-I region, and the maximum emission peak of DPP-4 NPs was located in the near-infrared-II (NIR-II) region, suggesting that the optical properties of small molecules can be regulated by changing the electron-donating unit. After irradiation of DPP-4 NPs with a single laser, excellent NIR-II fluorescence signal can be obtained for efficient imaging of tumor with high resolution. Moreover, abundant reactive oxygen species (singlet oxygen yield 34.3%) and hyperthermia (photothermal conversion efficiency 40.2%) can also be produced by irradiation of DPP-4 NPs, realizing the combined photodynamic/photothermal therapy guided by NIR-II fluorescence imaging.

Key words: organic small molecule, phototheranostics, near-infrared-II fluorescence imaging, photodynamic therapy, photothermal therapy

引用此文

王其, 夏辉, 熊炎威, 张新敏, 蔡杰, 陈冲, 高逸聪, 陆峰, 范曲立. 调控供电子策略简易制备近红外二区有机小分子光学诊疗试剂[J]. 化学学报, 2022, 80(11): 1485-1493.

Qi Wang, Hui Xia, Yanwei Xiong, Xinmin Zhang, Jie Cai, Chong Chen, Yicong Gao, Feng Lu, Quli Fan. Simple Preparation of Near-infrared-II Organic Small Molecule-based Phototheranostics by Manipulation of the Electron-donating Unit[J]. Acta Chimica Sinica, 2022, 80(11): 1485-1493.

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图/表 7

图1. (a) DPP-0、DPP-2及DPP-4结构式及纳米粒子示意图; (b) DPP-4 NPs光学诊疗示意图

Figure 1. (a) Chemical structures of DPP-0, DPP-2 and DPP-4, as well as schematic illustration of nanoparticles; (b) schematic illustration of DPP-4 NPs for phototheranostics

图2. DPP-0、DPP-2和DPP-4在THF中的(a)吸收及(b)荧光发射光谱; DPP-0 NPs、DPP-2 NPs和DPP-4 NPs在水中的(c)吸收及(d)荧光发射光谱; (e) DPP-4 NPs的DLS及TEM结果, 比例尺: 100 nm; (f) DPP-4 NPs的稳定性测试

Figure 2. (a) Absorption and (b) fluorescence emission spectra of DPP-0, DPP-2 and DPP-4 in THF; (c) absorption and (d) fluorescence emission spectra of DPP-0 NPs, DPP-2 NPs and DPP-4 NPs in water; (e) DLS and TEM data of DPP-4 NPs, scale bar: 100 nm; (f) stability of DPP-4 NPs

图3. (a) DPP-4 NPs在不同激光功率密度照射下的升温曲线; (b) 不同浓度的DPP-4 NPs在同一功率密度激光照射下的升温曲线; (c) 不同浓度DPP-4 NPs激光照射下的红外热图像; (d) DPP-4 NPs的光热稳定性测试

Figure 3. (a) The heating curves of DPP-4 NPs under laser irradiation with different power densities; (b) the heating curves of DPP-4 NPs at different concentrations under laser irradiation with the same power density; (c) infrared thermal images of DPP-4 NPs at various concentrations under laser irradiation; (d) photothermal stability of DPP-4 NPs

图4. DPP-4 NPs和DPBF混合溶液在具有不同功率密度660 nm激光照射下的吸收光谱: (a) 0.5 W?cm?2, (b) 0.75 W?cm?2, (c) 1.0 W?cm?2; (d) 不同功率密度激光照射下DPBF吸收峰的强度变化; (e) Hela细胞中ROS的检测

Figure 4. Absorption spectra of mixed aqueous solutions of DPP-4 NPs and DPBF under 660 nm laser irradiation at different power densities: (a) 0.5 W?cm?2, (b) 0.75 W?cm?2, (c) 1.0 W?cm?2; (d) the intensity changes of the absorption peak of DPBF under laser irradiation with different power densities; (e) the detection of ROS in Hela cells

图5. (a) FITC NPs孵育6 h、12 h后的Hela细胞共聚焦图片; (b) 流式细胞仪定量FITC NPs孵育6 h、12 h后的Hela细胞的荧光强度; (c) DPP-4 NPs对NIH3T3正常细胞的生物相容性测试; (d) DPP-4 NPs对Hela细胞的光毒性测试; (e) 活/死细胞染色分析

Figure 5. (a) Confocal images of Hela cells incubated with FITC NPs for 6 h and 12 h; (b) flow cytometric analysis of fluorescence intensity of Hela cells incubated with FITC NPs for 6 h and 12 h; (c) determination of the biosafety of DPP-4 NPs against NIH3T3 normal cells; (d) determination of the phototoxicity of DPP-4 NPs to Hela cells; (e) live/dead cell staining analysis

图6. (a) 不同浓度DPP-4 NPs NIR-II荧光强度; (b) 覆盖不同厚度鸡胸肉后NIR-II荧光成像; (c) Hela荷瘤小鼠注射DPP-4 NPs后NIR-II荧光成像; (d) 不同时间点肿瘤位置NIR-II荧光信号强度

Figure 6. (a) NIR-II intensity of DPP-4 NPs at different concentrations; (b) NIR-II images of DPP-4 NPs after covered chicken-breast tissue; (c) NIR-II imaging of Hela-tumor-bearing mice after injection of DPP-4 NPs; (d) NIR-II signal intensities of the tumor site at different post-injection times

图7. (a) 相对肿瘤体积变化曲线; (b) 治疗结束后肿瘤重量; (c) 小鼠体重变化曲线; (d) 治疗结束后主要器官H&E染色图片, 比例尺: 100 μm

Figure 7. (a) Relative tumor volume changes of mice during therapy; (b) tumor weight changes of mice after therapy; (c) body weight changes of mice during therapy; (d) H&E staining of major organs after therapy, scale bars: 100 μm

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