【作者】 李斌；

【导师】 李占先；

【作者基本信息】 郑州大学 ， 物理化学， 2025， 硕士

【摘要】 作为危害人类健康的首要疾病之一,癌症治疗方案的探索与开发始终是医学研究领域的核心焦点。焦亡作为一种重要的程序性细胞死亡方式,在癌症治疗中引发强烈的炎症反应,并且在肿瘤生物学中具有双重作用:适度的焦亡可增强抗肿瘤免疫反应,而过度激活则可能导致严重的炎症和组织损伤。活性氧物质（如过氧亚硝酸盐（ONOO^-））和细胞极性的变化在焦亡调控中起着关键作用,其水平异常变化会加剧疾病进展。博来霉素则是一种广泛应用的抗癌药物,其作用机制可通过引发内质网应激影响癌细胞存活。内质网应激能够触发未折叠蛋白反应（UPR）的活化,并进一步通过内质网与线粒体的相互作用机制,诱导线粒体功能发生异常。然而,博来霉素在发挥抗癌作用的同时,也会导致肺部损伤,这严重限制了其临床应用。1、本论文第二章利用三苯胺衍生物和四甲基喹啉衍生物为原料,成功构建了一种新型的聚集诱导发光效应（AIE）型双通道近红外荧光探针PBQI,该探针能够同时检测极性和ONOO^-。在探针结构设计中,丙酸基团作为ONOO^-的特异性响应位点,而噻吩单元的引入则实现了荧光发射的红移,使探针能够在700nm和520 nm处分别对极性和ONOO^-产生特异性响应。试验结果表明,PBQI在生理条件下表现出高灵敏度、优异的选择性和抗干扰能力。生物成像实验进一步证实,PBQI能够精准定位线粒体和脂滴,并通过检测细胞中极性和ONOO^-水平的差异,有效区分正常细胞与癌细胞。此外,PBQI被成功应用于药物诱导的肝癌小鼠模型,并能够有效监测细胞焦亡过程中极性和ONOO^-的动态变化。研究还揭示了脂多糖、抗癌药物顺铂及二甲双胍触发肿瘤细胞焦亡的作用机制,并验证了双硫仑作为焦亡抑制剂在减轻炎症反应中的关键作用。2、本论文第三章以对甲基苯磺酰胺、吲哚盐和三苯胺衍生物等为原料,构建了一种具有D–π–A构架的新型近红外荧光探针BDSTI,该探针展现出了对极性与粘度变化的高度敏感性和响应特性。光谱数据结果显示,当探针体系极性降低,探针BDSTI在450 nm和730 nm处的荧光信号显著增强。在粘度系数介于0.83至2.94的溶液环境中,观察探针在730 nm处的荧光强度对数值(lg I₇₃₀)与体系粘度对数值（logη）之间存在着显著的线性相关性（R²=0.982）,这一结果表明,BDSTI在粘度检测方面展现出了高度的准确性。此外,探针BDSTI还展现出良好的热稳定性、选择性、生物相容性和显著的近红外荧光发射等特点。由于BDSTI具有吲哚盐阳离子结构,该探针能够有效地定位于带负电的线粒体上,实现线粒体的准确靶向。同时,通过对甲苯磺酰胺基团的引入,赋予了BDSTI探针针对内质网进行靶向的能力。生物成像实验表明,探针BDSTI能够灵敏地监测由博来霉素引起的细胞中极性和粘度微环境的改变,并通过商用染料揭示了博来霉素通过诱导内质网应激导致线粒体损伤的机制。体内实验进一步发现,博来霉素在治疗肿瘤过程中会引起肺部纤维化,而内质网应激抑制剂（如TUDCA和4-PBA）能够有效改善肺部纤维化损伤。更多还原

【Abstract】 As one of the most dangerous diseases to human health,the exploration and development of cancer treatment options has always been a central focus of medical research.Pyroptosis,as a critical programmed cell death modality,triggers robust inflammatory responses in cancer therapy and exhibits a dual role in tumor biology:moderate pyroptosis may enhance antitumor immune responses,whereas excessive activation can result in severe inflammation and tissue damage.Reactive oxygen species,such as peroxynitrite（ONOO^–）,and cell polarity play a critical regulators role in pyroptosis,and their dysregulated levels can exacerbate disease progression.Bleomycin,a widely used anticancer drug,exerts its therapeutic effects by inducing endoplasmic reticulum（ER）stress to modulate cancer cell survival.Endoplasmic reticulum stress can initiate activation of the unfolded protein response（UPR）and further induce aberrant mitochondrial function through the mechanism of endoplasmic reticulum-mitochondrial interactions.However,bleomycin-induced pulmonary injury during treatment severely limits its clinical application.1.In Chapter 2 of this thesis,a novel aggregation-induced emission（AIE）-type dual-channel near-infrared fluorescent probe PBQI was successfully constructed using derivatives of triphenylamine and tetramethylquinoline as raw materials.The probe is capable of simultaneously detecting polarity and ONOO^–.In the probe structure design,the propionic acid group serves as the specific response site for ONOO^–,while the introduction of the thiophene unit enables red-shifted fluorescence emission,allowing the probe to specifically respond to polarity and ONOO^–at 700 nm and 520 nm,respectively.Experimental results indicate that PBQI exhibits high sensitivity,excellent selectivity,and strong anti-interference ability under physiological conditions.Biological imaging experiments further confirm that PBQI can precisely target mitochondria and lipid droplets and effectively distinguish normal cells from cancer cells by detecting differences in the levels of polarity and ONOO^–in cells.Additionally,PBQI was successfully applied to a drug-induced hepatocellular carcinoma mouse model,where it can effectively monitor the dynamic changes of polarity and ONOO^–during pyroptosis.The study also elucidates the mechanisms by which lipopolysaccharide（LPS）,the anti-cancer drug cisplatin,and metformin trigger pyroptosis in tumor cells and verifies the key role of disulfiram as a pyroptosis inhibitor in alleviating inflammatory responses.2.In Chapter 3,a novel near-infrared fluorescent probe BDSTI with a D-π-A architecture was constructed from p-methylbenzenesulfonamide,indole salts,and triphenylamine derivatives,which demonstrated a high degree of sensitivity and responsiveness to changes in polarity and viscosity.The results of the spectral data show that the fluorescence signals of the probe BDSTI at 450 nm and 730 nm are significantly enhanced when the polarity of the probe system is decreased.In a solution environment with viscosity coefficients ranging from 0.83 to 2.94,there is a significant linear correlation（R²=0.982）between the logarithm of the fluorescence intensity at730 nm(lg I₇₃₀)of the observation probe and the logarithm of the system viscosity（logη）.This result indicates that BDSTI demonstrates high accuracy in viscosity detection.In addition,the probe BDSTI exhibits good thermal stability and selectivity,excellent biocompatibility,and remarkable near-infrared fluorescence emission.Due to the indole salt cationic structure of BDSTI,it can effectively aggregate on negatively charged mitochondria,thus achieving mitochondrial targeting.Meanwhile,the introduction of the p-toluenesulfonamide moiety endows the BDSTI probe with the ability to target the endoplasmic reticulum.Biological imaging experiments indicate that probe BDSTI can sensitively monitor changes in the polarity and viscosity microenvironment of cells induced by bleomycin and elucidate the mechanism by which bleomycin induces mitochondrial damage through endoplasmic reticulum stress.In vivo experiments further reveal that bleomycin can cause pulmonary fibrosis during tumor treatment,while endoplasmic reticulum stress inhibitors（such as TUDCA and4-PBA）can effectively mitigate pulmonary fibrosis damage.更多还原