DPP-PEG/BSA-MnO2的光声/近红外二区荧光双模成像及光疗/化学动力学治疗协同效应研究

doi:10.6023/A25050141

化学学报 ›› 2025, Vol. 83 ›› Issue (11): 1324-1334.DOI: 10.6023/A25050141 上一篇下一篇

研究论文

DPP-PEG/BSA-MnO₂的光声/近红外二区荧光双模成像及光疗/化学动力学治疗协同效应研究

李佳启^a, 黄艳琴^a^,^*(), 丁桂策^a, 张瑞^b^,^*(), 刘兴奋^a, 范曲立^a, 黄维^a^,^c^,^*()

^a 南京邮电大学信息材料与纳米技术研究院柔性电子全国重点实验室南京 210023
^b 东南大学附属中大医院眼科南京 210009
^c 西北工业大学柔性电子前沿科学中心工信部柔性电子重点实验室西安 710072

投稿日期:2025-05-05 发布日期:2025-07-04
通讯作者: 黄艳琴, 张瑞, 黄维
基金资助:
江苏省基础研究计划(BK20243057); 江苏高校优势学科建设工程(YX03001); 以及东南大学附属中大医院江苏省高水平医院建设经费(YKK24271)

Photoacoustic/Near-infrared Ⅱ Fluorescence Dual-mode Imaging and Photo/Chemodynamic Synergistic Therapy Effects of DPP-PEG/BSA-MnO₂

Li Jiaqi^a, Huang Yanqin^a^,^*(), Ding Guice^a, Zhang Rui^b^,^*(), Liu Xingfen^a, Fan Quli^a, Huang Wei^a^,^c^,^*()

^a State Key Laboratory of Flexible Electronics (LoFE), Institute of Advanced Materials (IAM), Nanjing University of Posts & Telecommunications, Nanjing 210023, China
^b Department of Ophthalmology, Zhongda Hospital, Southeast University, Nanjing 210009, China
^c Frontiers Science Center for Flexible Electronics (FSCFE), MIIT Key Laboratory of Flexible Electronics (KLoFE), Northwestern Polytechnical University, Xi'an 710072, China

Received:2025-05-05 Published:2025-07-04
Contact: Huang Yanqin, Zhang Rui, Huang Wei
Supported by:
Basic Research Program of Jiangsu(BK20243057); Priority Academic Program Development of Jiangsu Higher Education Institutions(YX03001); Zhongda Hospital Affiliated to Southeast University, Jiangsu Province High-Level Hospital Construction Funds(YKK24271)

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1. Supporting Information-A25050141.pdf(1375KB)

摘要/Abstract

构建了一种多功能纳米诊疗剂DPP-PEG/BSA-MnO₂, 用于光声/近红外二区(NIR Ⅱ)荧光双模成像以及光动力(PDT)/光热(PTT)/化学动力学(CDT)治疗协同效应研究. 通过直接(杂)芳基化聚合反应合成聚乙二醇(PEG)亲水侧链修饰的吡咯并吡咯二酮(DPP)基两亲性共轭聚合物DPP-PEG, 其纳米粒子在1000~1400 nm的NIR Ⅱ区域有较强的荧光发射, 荧光量子产率为0.374%, 能在2 min内快速点亮小鼠的全身血管网络, 实现脑部和腿部血管的清晰荧光成像. 将DPP-PEG与牛血清蛋白(BSA)-二氧化锰(MnO₂)复合, 构建了水溶性良好的复合纳米材料DPP-PEG/BSA-MnO₂(简写为DPP-PEG/B-M). 与DPP-PEG/B、B-M的对比研究表明, DPP-PEG/B-M在肿瘤微环境(TME)中具有明显的PDT/PTT/CDT协同治疗效果. 这归因于DPP-PEG优良的PDT/PTT协同效应, 以及MnO₂与TME中过表达的谷胱甘肽、H₂O₂反应生成•OH和O₂, 产生CDT效应, 并增强了PDT效应. 并且, DPP-PEG/B-M对4T1荷瘤小鼠的肿瘤呈现良好的肿瘤靶向光声成像和NIR-II荧光成像性能, 因此有望应用于光声/NIR-II荧光双模成像指导的PDT/PTT/CDT协同治疗, 在肿瘤精准高效治疗中发挥作用.

关键词: 共轭聚合物, 二氧化锰, 双模成像, 光动力治疗, 光热治疗, 化学动力学治疗, 协同治疗

In this paper, a multifunctional nanotheranostic agent DPP-PEG/BSA-MnO₂ was constructed for photoacoustic (PA)/near-infrared fluorescence (NIR Ⅱ FL) dual-mode imaging and photodynamic (PDT)/photothermal (PTT)/chemodynamic (CDT) synergistic therapy effects. A diketopyrrolopyrrole (DPP)-based amphiphilic conjugated polymer, DPP-PEG, was synthesized by direct (hetero) arylation polymerization (DHAP) of a DPP derivative monomer modified with polyethylene glycol (PEG) hydrophilic side chains and another DPP derivative monomer substituted with 2-ethylhexyl side chains. DPP-PEG nanoparticles (NPs) exhibited strong fluorescence emission in the NIR II region of 1000~1400 nm with a fluorescence quantum yield of 0.374%, which can quickly light up the mouse's systemic vascular network within 2 min, achieving clear fluorescence imaging of brain and leg blood vessels. DPP-PEG was complexed with bovine serum albumin (BSA)-manganese dioxide (MnO₂) to construct a water-soluble composite nanomaterial DPP-PEG/BSA-MnO₂ (abbreviated as DPP-PEG/B-M). Comparative studies with DPP-PEG/B and B-M showed that DPP-PEG/B-M exhibited evident PDT/PTT/CDT synergistic effect in the tumor microenvironment (TME). Both DPP-PEG/B and DPP-PEG/B-M can effect-tively inhibit the proliferation effect in the tumor microenvironment (TME). Both DPP-PEG/B and DPP-PEG/B-M can effectively inhibit the proliferation of 4T1 tumor cells under 808 nm laser irradiation, as DPP-PEG produced excellent PDT/PTT synergistic effects. Compared with DPP-PEG/B, DPP-PEG/B-M showed a significant increase in cytotoxicity under the same conditions. The overexpressed glutathione (GSH) and H₂O₂ in TME can effectively convert MnO₂ into Mn^2＋, which further underwent a Fenton-like reaction with H₂O₂ to generate •OH, thereby producing additional CDT therapeutic effects. Furthermore, MnO₂ reacted with H₂O₂ to produce O₂, promoting the generation of ¹O₂ and enhancing the PDT effect. The consumption of MnO₂ weakened the scavenging effect of GSH on •OH and ¹O₂, further synergistically enhancing the PDT/CDT effect. Moreover, DPP-PEG/B-M was injected into 4T1 tumor-bearing mice via the tail vein. 24 h post-injection, the photoacoustic and NIR-II fluorescence signals at the tumor site reached their highest intensity, indicating that DPP-PEG/B-M can be enriched to the tumor site through the enhanced permeation and retention (EPR) effect. Therefore, DPP-PEG/B-M exhibited excellent tumor-targeting photoacoustic imaging and NIR-II fluorescence imaging performance in 4T1 tumor-bearing mice, and was expected to be applied in PDT/PTT/CDT synergistic therapy guided by photoacoustic/NIR-II fluorescence dual-mode imaging, playing a role in precise and efficient tumor therapy.

Key words: conjugated polymers, manganese dioxide, dual-mode imaging, photodynamic therapy, photothermal therapy, chemodynamic therapy, synergistic therapy

引用此文

李佳启, 黄艳琴, 丁桂策, 张瑞, 刘兴奋, 范曲立, 黄维. DPP-PEG/BSA-MnO₂的光声/近红外二区荧光双模成像及光疗/化学动力学治疗协同效应研究[J]. 化学学报, 2025, 83(11): 1324-1334.

Li Jiaqi, Huang Yanqin, Ding Guice, Zhang Rui, Liu Xingfen, Fan Quli, Huang Wei. Photoacoustic/Near-infrared Ⅱ Fluorescence Dual-mode Imaging and Photo/Chemodynamic Synergistic Therapy Effects of DPP-PEG/BSA-MnO₂[J]. Acta Chimica Sinica, 2025, 83(11): 1324-1334.

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图/表 6

图1. DPP-PEG/B-M的制备和肿瘤诊疗应用示意图

Figure 1. Schematic illustration of preparation and applications of DPP-PEG/B-M in tumor diagnosis and therapy

图2. (a) DPP-PEG水溶液的UV-Vis-NIR吸收光谱和808 nm激光激发的荧光光谱(插图: DPP-PEG水溶液的照片); (b) B-M, (c) DPP-PEG/B-M和(d) DPP-PEG/B的流体动力学尺寸和TEM图像; (e) B-M、DPP-PEG/B和DPP-PEG/B-M的流体动力学尺寸对比图; (f) B-M、DPP-PEG/B和DPP-PEG/B-M的Zeta电位

Figure 2. (a) UV-Vis-NIR absorption and fluorescence (λexc: 808 nm) spectra of DPP-PEG aqueous solution (inset: photograph of DPP-PEG aqueous solution); hydrodynamic sizes and TEM images of (b) B-M, (c) DPP-PEG/B-M, and (d) DPP-PEG/B; (e) comparison of hydrodynamic sizes of B-M, DPP-PEG/B, and DPP-PEG/B-M; (f) Zeta potentials of B-M, DPP-PEG/B, and DPP-PEG/B-M

图3. (a) DPP-PEG/B-M的能量色散X射线光谱图; (b) DPP-PEG/B, B-M和DPP-PEG/B-M的固态照片; (c) DPP-PEG/B, B-M和DPP-PEG/B-M在中性PBS (pH 7.4)和弱酸性PBS (pH 5.5, 100 μmol/L H2O2)中的溶液照片; (d)在酸性PBS(pH 5.5, 100 μmol/L H2O2)中的溶解氧浓度随时间变化; DPP-PEG/B、B-M和DPP-PEG/B-M在中性PBS (pH 7.4)和酸性PBS (pH 5.5, 100 μmol/L H2O2)中的(e) UV-Vis-NIR吸收光谱; (f)荧光光谱(激发波长: 808 nm)

Figure 3. (a) Energy-dispersive X-ray spectroscopy spectrum of DPP-PEG/B-M; (b) photos of DPP-PEG/B, B-M, and DPP-PEG/B-M solid state; (c) DPP-PEG/B, B-M, and DPP-PEG/B-M in the solution of neutral PBS (pH 7.4) and weakly acidic PBS (pH 5.5, 100 μmol/L H2O2); (d) time-dependent dissolved oxygen concentration of DPP-PEG/B, B-M, and DPP-PEG/B-M in acidic PBS (pH 5.5, 100 μmol/L H2O2); (e) UV-Vis-NIR absorption spectra and (f) fluorescence spectra (λexc: 808 nm) of DPP-PEG/B, B-M, and DPP-PEG/B-M in neutral PBS (pH 7.4) and acidic PBS (pH 5.5, 100 μmol/L H2O2)

图4. (a) DPBF在含有DPP-PEG/B-M或DPP-PEG/B的中性PBS (pH 7.4)或弱酸性PBS (pH 5.5, 100 μmol/L H2O2)中的吸光度变化与辐照时间(808 nm, 1 W/cm2)的线性关系; (b)在与DPP-PEG/B-M和DPP-PEG/B分别孵育后的4T1细胞内检测1 O2, 采用DCFH-DA作为荧光探针; DPP-PEG/B-M, GSH, H2O2和MB在NaHCO3缓冲溶液(25 mmol/L)中(c)混合不同时间后, MB的吸收光谱变化; (d)混合0.5 h后, MB的吸收光谱随GSH浓度(0~50 mmol/L)的变化; (e)在不同功率的激光(808 nm)激发下, DPP-PEG/B-M (400 μg/mL)的升温曲线; (f) DPP-PEG/B-M在激光(808 nm, 1.2 W/cm2)照射下的光热响应, 重复照射和关闭, 循环五次; (g) f图中的单次光热循环; (h)从图g的降温过程得到的时间与－lnθ的线性关系

Figure 4. (a) Linear relationship between absorbance changes of DPBF and irradiation time (808 nm, 1 W/cm²) in neutral PBS (pH 7.4) or weakly acidic PBS (pH 5.5, 100 μmol/L H₂O₂) containing DPP-PEG/B-M or DPP-PEG/B; (b) intracellular detection of ¹O₂ in 4T1 cells incubated with DPP-PEG/B-M and DPP-PEG/B using DCFH-DA as a fluorescent probe; (c) absorption spectral changes of MB in NaHCO₃ buffer (25 mmol/L) after mixing DPP-PEG/B-M, GSH, H₂O₂, and MB for different durations; (d) absorption spectra of MB at varying GSH concentrations (0~50 mmol/L) after mixing DPP-PEG/B-M, GSH, H₂O₂, and MB for 0.5 h; (e) temperature elevation curves of DPP-PEG/B-M (400 μg/mL) under 808 nm laser irradiation at different power densities; (f) photothermal response of DPP-PEG/B-M during five on/off cycles under 808 nm laser irradiation (1.2 W/cm²); (g) single photothermal cycle from (f); (h) linear relationship between time and −lnθ derived from the cooling phase in (g)

图5. 黑暗条件下(a)与DPP-PEG/B共孵育的3T3和4T1细胞存活率; (b)黑暗条件下与DPP-PEG/B-M共孵育的3T3和4T1细胞存活率; (c)经过DPP-PEG/B光动力、光热和光动力/光热联合治疗后的4T1细胞存活率, 经过DPP-PEG/B-M光动力/光热联合治疗后的4T1细胞存活率(808 nm激光照射8 min, 0.8 W/cm2); (d)与DPP-PEG/B-M共孵育的4T1细胞在(1)黑暗和(2)光照(808 nm, 0.8 W/cm2) 8 min条件下的AM/PI染色; 与DPP-PEG/B共孵育的4T1细胞在(3)黑暗和(4)光照(808 nm, 0.8 W/cm2)8 min 条件下的AM/PI染色

Figure 5. Cell viability of 3T3 and 4T1 cells coincubated with (a) DPP-PEG/B or (b) DPP-PEG/B-M under dark conditions; (c) cell viability of 4T1 cells after PDT, PTT and PDT/PTT treatment with DPP-PEG/B, and cell viability of 4T1 cells after PTT/PDT treatment with DPP-PEG/B-M (808 nm laser irradiation, 8 min, 0.8 W/cm²); (d) AM/PI staining of 4T1 cells coincubated with DPP-PEG/B-M: (1) under dark condition and (2) under laser irradiation (808 nm, 0.8 W/cm², 8 min); AM/PI staining of 4T1 cells coincubated with DPP-PEG/B: (3) under dark condition and (4) under laser irradiation (808 nm, 0.8 W/cm², 8 min)

图6. (a)静脉注射DPP-PEG NPs的PBS溶液后不同时间点的小鼠全身血管NIR-II荧光成像; (b) DPP-PEG/B-M的PBS溶液浓度与NIR-II荧光强度的线性关系; (c) DPP-PEG/B-M的PBS溶液浓度与光声强度的线性关系; 静脉注射DPP-PEG/B-M的PBS溶液后不同时间点的4T1荷瘤小鼠(d)体内NIR-II荧光成像; (e)体内光声成像(激发波长均为808 nm, 红色圆圈代表肿瘤区域)

Figure 6. (a) NIR-II fluorescence imaging of systemic vasculature in mice at various time points post intravenous injection of DPP-PEG NPs in PBS; (b) linear relationship between the concentration of DPP-PEG/B-M in PBS and NIR-II fluorescence intensity; (c) linear relationship between the concentration of DPP-PEG/B-M in PBS and photoacoustic intensity; (d) in vivo NIR-II fluorescence imaging and (e) in vivo photoacoustic imaging of 4T1 tumor-bearing mice at different time points after intravenous injection of DPP-PEG/B-M in PBS (λexc: 808 nm; red circles indicate tumor regions)

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DPP-PEG/BSA-MnO₂的光声/近红外二区荧光双模成像及光疗/化学动力学治疗协同效应研究

Photoacoustic/Near-infrared Ⅱ Fluorescence Dual-mode Imaging and Photo/Chemodynamic Synergistic Therapy Effects of DPP-PEG/BSA-MnO₂

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