【作者】 李彤；

【导师】 逯乐慧；

【作者基本信息】 中国科学技术大学 ， 分析化学， 2024， 硕士

【摘要】 双硫仑(DSF)是一种潜在的新型广谱抗癌药物,其抗癌活性依赖于DSF的代谢产物DTC与Cu2+螯合形成的产物CuET。鉴于DSF稳定性差和体内Cu2+含量不足的特性,迫切需要设计合理的给药体系以达到DSF与Cu2+的共同递送。目前,纳米技术的快速发展为高效药物递送提供了保障,特别是能够特异性响应肿瘤微环境(TME)中pH值低、乏氧、过氧化氢(H2O2)和三磷酸腺苷(ATP)浓度高等特征的纳米探针,引起了越来越多的关注。对TME响应的纳米材料不仅可以控制药物释放,还能与其他新型癌症治疗手段联合使用,如化学动力学疗法(CDT)和光动力疗法(PDT),以克服单一治疗模式的局限性,获得更好的疗效。基于此,为了实现高效的DSF与Cu2+递送,本论文利用TME的特点,构建不同的TME响应型DSF与Cu2+共同递送纳米平台,为基于DSF的癌症治疗提供更多可选策略。主要包括以下两个部分:1.制备了 pH/ATP双响应DQ@ZIF-90@TA-Cu双硫仑前药纳米平台用于增强化疗。首先合成DSF的前药(DQ),并证明DQ响应H2O2的能力和CuET生成效果。接着利用沸石咪唑骨架-90(ZIF-90)封装DQ,并通过单宁酸(TA)和Cu2+的配位作用得到DQ@ZIF-90@TA-Cu。实验结果表明,DQ@ZIF-90@TA-Cu会响应TME的低pH和高表达ATP而分解,裂解出的前药DQ被TME中高浓度H2O2激活生成DTC,接着DTC与表面TA-Cu释放的Cu2+螯合得到CuET。DQ@ZIF-90@TA-Cu充分利用了 TME的特点,通过原位生成CuET实现细胞杀伤效果,为基于DSF的药物递送纳米平台提供了新的视角。2.构建了 pH响应型DSF/Ce6@ZIF-8@CuO2(DCZCu)纳米平台用于癌症协同治疗。首先通过一锅法合成沸石咪唑框架-8(ZIF-8)来包封DSF和光敏剂二氢卟吩e6(Ce6),接着将透明质酸(HA)修饰的CuO2负载在表面得到DCZCu纳米探针。DCZCu表面的HA赋予其靶向肿瘤细胞CD44受体的能力,加速DCZCu被内吞进肿瘤细胞。在酸性TME中,CuO2被分解为Cu2+、H2O2和O2,而ZIF-8则释放出了包封的DSF和Ce6。其中DSF与Cu2+螯合生成了抗癌活性成分CuET以增强化疗效果。同时,DCZCu自供的H2O2和O2分别促进了铜离子介导的CDT和Ce6介导的PDT以产生活性氧(ROS)。此外,细胞内的GSH还能被Cu2+所消耗,从而促进ROS诱导的肿瘤细胞死亡。体外和动物实验证实了 DCZCu能够通过增强DSF化疗、H2O2自供CDT和O2增强PDT三者的协同作用来抑制肿瘤生长,提供了一种高效的协同癌症治疗模式。更多还原

【Abstract】 Disulfiram(DSF)is a new potential broad-spectrum anticancer drug,and its anticancer activity relies on the formation of CuET,the chelation product of DSF’s metabolite DTC with Cu2+.Based on the poor stability of DSF and insufficient Cu2+content in the vivo,there is an urgent need to design the rational drug delivery system to achieve the co-delivery of DSF and Cu2+.The rapid development of nanotechnology provides a guarantee for efficient drug delivery,especially nanoprobes that can specifically respond to the characteristics of hypoxia,low pH,high H2O2 concentration and high expression of adenosine triphosphate(ATP)in the tumor microenvironment(TME)are receiving more and more attention.TME-responsive nanomaterials can not only control drug release,but can also be used in combination with other novel cancer therapies,such as chemodynamic therapy(CDT)and photodynamic therapy(PDT),to overcome the limitations of a single therapeutic modality for better efficacy.Therefore,in order to achieve efficient DSF and Cu2+delivery,we have constructed different TMEresponsive DSF and Cu2+co-delivery nanoplatforms using the characteristics of TME to provide more optional strategies for cancer therapy based on DSF.The research mainly consists of the following two parts:1.A pH/ATP dual-responsive DQ@ZIF-90@TA-Cu disulfiram prodrug nanoplatform was prepared for enhanced chemotherapy.Firstly,the prodrug(DQ)of DSF was synthesised and its ability to respond to H2O2 and the efficacy of CuET generation was demonstrated.Then,we encapsulated the DQ using zeolite imidazole backbone-90(ZIF-90)and obtained DQ@ZIF-90@TA-Cu nanoparticles through the coordination of tannic acid(TA)and Cu2+.The experimental results showed that DQ@ZIF-90@TA-Cu decomposed in response to the low pH and high expression of ATP in TME.The cleaved prodrug DQ was activated by the high concentration of H2O2 in TME to generate DTC,and then DTC chelated with Cu2+released from surface TACu to obtain CuET.The DQ@ZIF-90@TA-Cu fully exploited the characteristics of the TME to achieve the cell killing effect by generating CuET in situ,which provides a new perspective for the drug delivery nanoplatforms based on DSF.2.A pH-responsive DSF/Ce6@ZIF-8@CuO2(DCZCu)nanoplatform was constructed for multimodal cancer synergistic therapy.Firstly,zeolite imidazole framework-8(ZIF-8)was synthesized by a one-pot method to encapsulate DSF and photosensitizer chlorin e6(Ce6),and then hyaluronic acid(HA)-modified CuO2 was loaded on the surface to obtain DCZCu nanoparticles.HA on the surface of DCZCu endowed it with the ability to target CD44 receptor on the tumor cells,accelerating the endocytosis of DCZCu into the tumor cells.In the acidic TME,CuO2 was decomposed into Cu2+,H2O2 and O2,while ZIF-8 released encapsulated DSF and Ce6.DSF could be chelated with Cu2+to generate CuET,an anticancer active ingredient,to enhance the chemotherapeutic effect.Meanwhile,the self-supplied H2O2 and O2 from DCZCu promoted copper ion-mediated CDT and Ce6-mediated PDT to generate reactive oxygen species(ROS),respectively.In addition,Cu2+effectively consumed intracellular GSH,thereby promoting ROS-induced tumor cell death.The in vitro and animal experiments confirmed the ability of DCZCu to inhibit tumour growth through the synergistic triple action of enhanced DSF chemotherapy,H2O2 self-supplied CDT and O2-enhanced PDT,providing a highly effective and synergistic cancer treatment modality.更多还原