靶向炎性脑水肿的诊疗一体化近红外荧光探针的构建与评价

doi:10.12300/j.issn.1674-5817.2023.166

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (3): 243-250.DOI: 10.12300/j.issn.1674-5817.2023.166

• 人类疾病动物模型 • 下一篇

靶向炎性脑水肿的诊疗一体化近红外荧光探针的构建与评价

秦靖, 赵勇, 张彩勤, 白冰, 师长宏()()

空军军医大学实验动物中心, 西安 710032

收稿日期:2023-11-21 修回日期:2024-04-14 出版日期:2024-06-25 发布日期:2024-06-25
通讯作者: 师长宏（1973—），男，博士，教授，博士生导师，研究方向：人类疾病动物模型。E-mail： changhong@fmmu.edu.cn。ORCID： 0000-0001-7490-3593
作者简介:秦靖（1994—），女，硕士研究生，助理实验师，研究方向：分子影像研究。E-mail： qinjingjd@fmmu.edu.cn
基金资助:
军队实验动物专项科研课题“靶向性近红外荧光探针在损伤性脑水肿模型评估与治疗中的应用”(SYDW〔2020〕21号);陕西省创新能力支撑计划“创伤性脑水肿模型的制备及影像学实时监测评估”(2022PT-45)

Construction and Evaluation of Theranostic Near-infrared Fluorescent Probe for Targeting Inflammatory Brain Edema

Jing QIN, Yong ZHAO, Caiqin ZHANG, Bing BAI, Changhong SHI()()

Laboratory Animal Center, Air Force Medical University, Xi'an 710032, China

Received:2023-11-21 Revised:2024-04-14 Published:2024-06-25 Online:2024-06-25
Correspondence to: SHI Changhong (ORCID: 0000-0001-7490-3593), E-mail: changhong@fmmu.edu.cn

摘要/Abstract

摘要：

目的制备基于近红外荧光（near-infrared fluorescence，NIRF）探针的新型化合物，通过活体成像实现对炎性脑水肿小鼠模型的动态监测，以及对治疗效果的实时评估。方法选择NIRF探针IR-783与临床脑水肿治疗药物呋塞米（furosemide，FSM）进行化学连接，获得新的化合物IR-783-FSM。通过紫外分光光度计评价该化合物的紫外荧光特性；体外细胞学实验检测小鼠巨噬细胞RAW 264.7对该化合物的摄取情况；CCK8实验评价该化合物的细胞毒性。BALB/c小鼠腹腔注射脂多糖构建炎性脑水肿模型，通过HE染色和测量脑组织干湿重法确认建模成功；将脑水肿模型小鼠分为对照组、IR-783和IR-783-FSM治疗组，分别给予PBS、IR-783和IR-783-FSM腹腔注射后进行实时活体荧光成像，并在10 h后处死各组小鼠，进行脑部离体成像和干湿重测量，观察IR-783-FSM对炎性脑水肿模型的NIRF成像特性和治疗效果。结果新合成的化合物IR-783-FSM保留了IR-783优良的近红外荧光特征，可以靶向小鼠巨噬细胞，IC₅₀为48.82 μmol/L。腹腔注射脂多糖可以成功构建炎性脑水肿模型，且其脑组织含水量较空白对照组小鼠明显升高（P<0.01）；小鼠活体成像显示，与IR-783相比，IR-783-FSM在脑水肿模型中具有明显较强的荧光信号；与对照组相比，2、5和8 mmol/L IR-783-FSM治疗组小鼠的脑含水量均明显减少（P<0.01）。结论合成的新型NIRF探针IR-783-FSM可以实现对脑水肿的动态监测和对治疗效果的实时评估。

关键词: 脑水肿, 脂多糖, 近红外荧光, 呋塞米, 诊疗一体化, 小鼠

Abstract:

Objective A novel compound based on near-infrared fluorescence (NIRF) probe was prepared to achieve dynamic monitoring of an inflammatory brain edema model in mice and real-time evaluation of therapeutic effects through in vivo imaging. Methods The NIRF probe IR-783 was chemically linked with clinical brain edema therapeutic drug furosemide (FSM) to obtain the new compound, IR-783-FSM. The ultraviolet fluorescence properties of the compound were evaluated using an ultraviolet spectrophotometer. The uptake of the compound by mouse macrophage cells RAW 264.7 was detected with in vitro cellular experiments. Its cytotoxicity was evaluated through CCK8 assays. A brain edema model was established in BALB/c mice via intraperitoneal injection of lipopolysaccharide (LPS), confirmed by HE staining and dry-wet weight methods for brain tissues. The mice in the brain edema model were divided into control group, IR-783, and IR-783-FSM treatment groups, receiving intraperitoneal injections of PBS, IR-783, and IR-783-FSM, respectively. Real-time in vivo fluorescence imaging was then performed. The mice in each group were euthanized after 10 hours. Ex vivo brain imaging and dry-wet weight measurements were performed to observe the NIRF imaging characteristics and therapeutic effects of IR-783-FSM on brain edema model. Results The newly synthesized compound, IR-783-FSM, retained the excellent near-infrared fluorescence characteristics of IR-783. It could target mouse macrophages with an IC₅₀ of 48.82 μmol/L. A brain edema model could be successfully constructed with intraperitoneal injection of LPS, with significantly higher brain tissue water content compared to the control group (P<0.01). In vivo imaging showed that IR-783-FSM had a significantly stronger fluorescence signal in the brain edema model than IR-783. Compared to the control group, the brain water content was significantly reduced in the 2, 5, and 8 mmol/L IR-783-FSM treatment groups (P<0.01). Conclusion The newly synthesized NIRF probe IR-783-FSM facilitates dynamic monitoring of brain edema and real-time evaluation of therapeutic effects.

Key words: Brain edema, Lipopolysaccharide, Near-infrared fluorescence, Furosemide, Theranostics, Mice

中图分类号:

R-332

秦靖,赵勇,张彩勤,等. 靶向炎性脑水肿的诊疗一体化近红外荧光探针的构建与评价[J]. 实验动物与比较医学, 2024, 44(3): 243-250. DOI: 10.12300/j.issn.1674-5817.2023.166.

Jing QIN,Yong ZHAO,Caiqin ZHANG,et al. Construction and Evaluation of Theranostic Near-infrared Fluorescent Probe for Targeting Inflammatory Brain Edema[J]. Laboratory Animal and Comparative Medicine, 2024, 44(3): 243-250. DOI: 10.12300/j.issn.1674-5817.2023.166.

图/表 5

注：A，IR-783-FSM结构图；B，IR-783-FSM核磁共振氢谱图；C，IR-783-FSM在不同溶剂中的荧光强度（左图从左至右的溶剂分别为DMSO、H₂O、PBS，右图从左至右的溶剂分别为H₂O和PBS）；D，IR-783-FSM的荧光光谱（左）和吸光度光谱（右）。
">

图1 IR-783-FSM探针的结构与表征
注：A，IR-783-FSM结构图；B，IR-783-FSM核磁共振氢谱图；C，IR-783-FSM在不同溶剂中的荧光强度（左图从左至右的溶剂分别为DMSO、H₂O、PBS，右图从左至右的溶剂分别为H₂O和PBS）；D，IR-783-FSM的荧光光谱（左）和吸光度光谱（右）。

Figure 1 Structure and characterization of the IR-783-FSM probe
Note：A, Structure of IR-783-FSM; B, Nuclear magnetic resonance hydrogen spectrum of IR-783-FSM; C, Fluorescence intensity of IR-783-FSM in different solvents (in the left graph, the solvents from left to right are DMSO, H₂O, and PBS; in the right graph, the solvents from left to right are H₂O and PBS); D, Fluorescence spectra (left) and absorbance spectra (right) of IR-783-FSM.

注：A，近红外荧光显微镜观察小鼠巨噬细胞RAW 264.7对IR-783-FSM探针的摄取能力（红色荧光表示IR-783-FSM探针，蓝色荧光为DAPI标记的细胞核，Merged图提示IR-783-FSM探针进入细胞）；B，CCK8法检测IR-783-FSM探针作用后小鼠巨噬细胞RAW 264.7的活力。
">

图2 IR-783-FSM探针的体外细胞摄取能力及细胞毒性
注：A，近红外荧光显微镜观察小鼠巨噬细胞RAW 264.7对IR-783-FSM探针的摄取能力（红色荧光表示IR-783-FSM探针，蓝色荧光为DAPI标记的细胞核，Merged图提示IR-783-FSM探针进入细胞）；B，CCK8法检测IR-783-FSM探针作用后小鼠巨噬细胞RAW 264.7的活力。

Figure 2 In vitro cellular uptake ability and cytotoxicity of IR-783-FSM probe in mouse macrophages
Note：Near-infrared fluorescence microscopy was used to observe the uptake ability of mouse macrophages RAW 264.7 to IR-783-FSM probe (Red fluorescence indicated IR-783-FSM probe. Blue fluorescence indicated the nucleus marked by DAPI. Merged plots represented the entry of the IR-783-FSM probe into cells). B, The viability of mouse macrophages RAW 264.7 treated with IR-783-FSM probe was assessed by CCK8 assay.

注：A，脂多糖腹腔注射造模后小鼠精神萎靡（左）伴有腹泻（右）；B，HE染色观察脂多糖腹腔注射造模后小鼠脑组织病理切片（左为注射生理盐水的空白组小鼠，右为注射脂多糖的小鼠，箭头所指部位血管周缝明显增宽显示脑水肿）。
">

图3 脂多糖脑水肿小鼠模型构建成功
注：A，脂多糖腹腔注射造模后小鼠精神萎靡（左）伴有腹泻（右）；B，HE染色观察脂多糖腹腔注射造模后小鼠脑组织病理切片（左为注射生理盐水的空白组小鼠，右为注射脂多糖的小鼠，箭头所指部位血管周缝明显增宽显示脑水肿）。

Figure 3 The mouse model of lipopolysaccharide-induced brain edema was successfully constructed
Note：A, After intraperitoneal injection of lipopolysaccharide (LPS), mice appeared lethargic (left) with diarrhea (right). B, HE staining was used to observe the pathological sections of brain tissues in mice after model construction with LPS intraperitoneal injection (left image indicated the blank group injected with normal saline, and the right indicated the mice injected with LPS, while the arrows indicated marked widening of the perivascular spaces, indicating cerebral edema).

注：A，PBS、IR-783和IR-783-FSM腹腔注射10 h后的活体和离体成像图；B，IR-783-FSM在脑水肿小鼠模型中的近红外荧光实时成像；C，IR-783-FSM在炎性脑水肿模型小鼠中的近红外荧光成像定量分析（ROI表示感兴趣的区域）。
">

图4 脑水肿小鼠模型体内IR-783和IR-783-FSM的荧光成像结果
注：A，PBS、IR-783和IR-783-FSM腹腔注射10 h后的活体和离体成像图；B，IR-783-FSM在脑水肿小鼠模型中的近红外荧光实时成像；C，IR-783-FSM在炎性脑水肿模型小鼠中的近红外荧光成像定量分析（ROI表示感兴趣的区域）。

Figure 4 Fluorescence imaging results of IR-783 and IR-783-FSM in a mouse model of brain edema
Note： A, In vivo and ex vivo near-infrared fluorescence imaging 10 h after intraperitoneal injections of PBS, IR-783, and IR-783-FSM; B, Real-time near-infrared fluorescence imaging of IR-783-FSM in a mouse model of brain edema; C, Quantitative analysis of near-infrared fluorescence imaging of IR-783-FSM in a mouse model of brain edema (ROI represents regions of interest).

表1 脑水肿小鼠经IR-783-FSM治疗后的脑含水量变化

Table 1 Changes of brain water content in mice with brain edema treated with IR-783-FSM

给药分组（n=5） Grouping and administration (n=5)	脑组织含水量/% Brain water content/%
PBS	79.511±0.483
5 mmol/L IR-783	78.364±0.949
2 mmol/L IR-783-FSM	77.988±0.124^**
5 mmol/L IR-783-FSM	77.276±0.816^**
8 mmol/L IR-783-FSM	77.364±0.949^**

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Construction and Evaluation of Theranostic Near-infrared Fluorescent Probe for Targeting Inflammatory Brain Edema

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