金基纳米材料功能化厌氧菌在恶性肿瘤可控性治疗和成像中的应用研究

The nationwide high incidence and mortality of cancer and its continued increase in China have attracted extensive attention for the development of new effective cancer treatment strategy. The majority of solid tumors in patients have shown, irrespective of their size, to contain hypoxic and/or necrotic regions. It has been shown anaerobic bacteria have excellent tumor colonizing property and oncolytic performance, which is highly specific for tumors’ hypoxic and/or necrotic regions. However, the potential risk of infection has restricted their application. Our previous studies have demonstrated that, with the high photothermal conversion efficiency under NIR, gold nanomaterials can effectively control the activity of bacteria, which is expected to solve the problem of anaerobic bacteria infection. Hereby, this present project aims to give a controllable “time bomb” to anaerobic bacteria by loading gold nanomaterials onto their surface, thus constructing the functional anaerobic bacteria as novel controlled therapeutic agent. We plan to study the performance of gold nanomaterials to control the biological activity, the adhesive and invasive ability of functionalized anaerobic bacteria. And then we will study the performance of gold nanomaterials to control the survival status of anaerobic bacteria inside tumor and adjust the oncolytic effect of anaerobic bacteria. We look forward to use the loaded gold nanomaterials to improve the safety and therapeutic efficiency based on anaerobic bacteria, meanwhile, to realize the in vivo tracing of functional anaerobic bacteria. This project provides a new strategy based on controlled-anaerobic bacteria for cancer therapy in clinical, which has important theoretical and clinical value.

我国癌症高发率和死亡率的持续攀升，使发展安全高效的癌症治疗新策略成为当今社会的迫切需要。研究表明大多数实体肿瘤都存在缺氧/坏死的区域，厌氧菌具有在缺氧区域靶向繁殖的特性、溶瘤效果显著，却因潜在的感染风险在肿瘤治疗中受到限制。而金基纳米材料的近红外光热作用能够有效控制细菌的生物活性，有望解决厌氧菌感染的问题。.据此，本项目提出将金基纳米材料与厌氧菌相结合，为厌氧菌带上可控性“定时炸弹”，构建功能化厌氧菌作为新型肿瘤治疗剂。研究在近红外光的远程控制下，负载后的金基纳米材料对功能化厌氧菌的生长周期、繁殖、侵袭肿瘤细胞能力的可控性调节；对肿瘤内功能化厌氧菌的活性和溶瘤速度与效果的可控性调节；对肿瘤的协同治疗作用；对功能化厌氧菌的体内示踪作用。以期利用金基纳米材料控制厌氧菌活性，调节肿瘤治疗的进程，提高安全性和治疗效果，建立在体肿瘤的高度靶向、高效可控的安全治疗新策略，具有重要的理论意义和临床价值。

实体肿瘤特异性微环境如乏氧、低pH及高浓度过氧化氢等，为纳米材料辅助的靶向诊断、治疗和药物运输提供了靶点。本研究证实：具有光热转换性能的纳米材料能够通过静电吸附（Ag-CDs荧光纳米材料）、共价化学修饰-戊二醛交联（Spore@AuNRs/NCs）以及与细菌细胞壁成分磷壁酸的特异性相互作用（GO-Zr-Au纳米复合材料）等方式，稳定的修饰于细菌（营养体或芽胞）表面，构建纳米材料功能化细菌。修饰后纳米材料的光热转换性能和被修饰细菌的生物活性不受影响。在近红外光（NIR）照射下，修饰在细菌表面的纳米材料可产生过高热，有效地调控修饰后细菌的活性和感染肿瘤细胞的能力，进而实现纳米材料功能化细菌对肿瘤细胞的可控性治疗，并且具有细菌和光热纳米材料协同治疗的效果。这种光热纳米材料稳定功能化的细菌为肿瘤的高度靶向、高效可控的安全治疗提供了新策略。