兰州大学机构库 >化学化工学院
Alternative TitleDesign, synthesis and biological application of fluorescent probes based on self-destruct structure
Thesis Advisor张海霞
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name理学博士
Degree Discipline化学
Keyword硫化氢,荧光探针,自毁化学,毒性评价,诊疗一体,活体成像,可视化 Hydrogen sulfide fluorescent probe self-destruct chemistry toxicity evaluation integrated diagnosis and treatment in vivo imaging visualization


(1)硫化氢(H2S)作为一种参与自噬的信号分子,被认为在疾病的发生和治疗中至关重要。为了阐明H2S在疾病过程中的作用,迫切需要H2S的动态可视化检测。我们构建了一种水溶性近红外(发射波长为695 nm)自毁型荧光探针CySO3N3,用于H2S的检测。探针与H2S反应后能够发生结构的裂解,不仅能够释放荧光团,而且脂水分布系数大幅改变,这种设计自毁设计策略能够提高探针的代谢能力,进而降低探针的毒性。该探针不仅可用于活细胞和小鼠体内H2S的检测,可以检测炎症和心肌损伤时H2S的变化,也可以通过监测H2S的变化监测细胞自我修复过程。




Other Abstract

In the development of fluorescence imaging technology, fluorescent probes have the advantages of high sensitivity, high accuracy, strong selectivity, convenient and fast detection, etc., and are mostly used in the field of life sciences. A large number of studies have explored various types of fluorescent probes and used them to detect biomarkers to achieve disease monitoring, but in fact only a few fluorescent probes can be commercialized and widely used in clinical medicine. The research of fluorescent probes Still in the stage of broadening the use of fluorescent probes and perfecting practical applications. Self-destruct chemistry enables the release of moiety structures in response to stimuli, often containing specific self-destruct spacers, which covalently link moiety-triggering molecules to substrates of interest, such as fluorophores, drugs, and other compounds. In this thesis, based on the self-destruct reaction, the fluorescent probe not only achieves the purpose of detection, but also adds other functions by modifying the self-destruct spacer. The research work carried out is as follows:

(1) Hydrogen sulfide (H2S), as a signaling molecule involved in autophagy, is considered to be crucial in the occurrence and treatment of diseases. To elucidate the role of H2S in disease processes, the dynamic visual detection of H2S is urgently needed. We constructed a water-soluble near-infrared (emission wavelength of 695 nm) self-destructing fluorescent probe CySO3N3 for the detection of H2S. It not only verified the ability of the probe to detect H2S, but also improved the metabolic ability of the probe and reduced the toxicity of the probe. The probe can not only be used to detect H2S in living cells and mice, but also detect changes in H2S during inflammation and myocardial injury, and monitor cell self-repair processes by monitoring changes in H2S.

(2) In biological detection, the toxicity of the probe itself to the detected organism is often ignored, and it is urgent to reduce the toxicity of the probe under the premise of ensuring the detection performance. We constructed an analyte-compensated fluorescent probe (NP-SN3) based on the structure of 1,8-naphthoimide for the detection of H2S. Through the experimental results of HepG2 cells, zebrafish embryos and juvenile images, it was found that there was no significant difference in imaging performance between the new probe and the traditional probe (NP-N3). After imaging activated HSC-T6 cells, the new probe showed lower detection-induced toxicity. During zebrafish embryo development and continuous dosing in rats, the new probe showed low embryonic mortality, high hatchability, and low malformation rates in zebrafish embryos. Stained tissue sections of rats also showed less pathological symptoms caused by the new probe.

(3) In order to better understand and monitor the anticancer effect of H2S in real time, a near-infrared fluorescent diagnostic probe YH-NO2 based on the self-destruct reaction to release H2S was designed and synthesized. After the probe is activated by the overexpressed nitroreductase in the tumor, it releases near-infrared fluorophore and H2S simultaneously to realize the function of diagnosis and treatment of cancer. YH-NO2 can not only distinguish nitroreductase activity under different degrees of hypoxia, but also identify normal cells and cancer cells by imaging. After verifying that YH-NO2 can stably release H2S in cells, it was found that YH-NO2 can not only selectively eliminate cancer cells, but also accurately identify and eliminate tumor tissues in vivo. These results indicate that the diagnosis and treatment mechanism of YH-NO2 can not only monitor the anticancer effect of H2S in vivo, but also play an important role in promoting the relationship between H2S and cancer.

(4) According to the self-destruct structure, a novel diagnostic probe Nap-NP-NSB combining fluorescent probe, H2S and non-steroidal anti-inflammatory drug (NSAIDs) naproxen was developed, which can be associated with inflammation Moreover, the overexpressed ROS releases H2S, naproxen and fluorophores at the same time after activation to achieve the purpose of diagnosis and treatment. Through fluorescence analysis of cell and tissue supernatants, Nap-NP-NSB enables the visual detection of synergy between H2S and NSAIDs. In cells and in vivo, Nap-NP-NSB showed stronger anti-inflammatory effect and lower gastric mucosal damage side effects than naproxen. Combining fluorescent probes, H2S, and NSAIDs demonstrates atom economy, provides a new way to study drug synergy, and expands the application prospects of fluorescent probes.

Subject Area荧光分析
MOST Discipline Catalogue理学 - 化学 - 分析化学
Other Code262010_120200904701
Document Type学位论文
Recommended Citation
GB/T 7714
张金龙. 基于自毁结构的荧光探针设计合成及其生物应用[D]. 兰州. 兰州大学,2023.
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