近红外光在体诱导形成的基因工程蛋白质水凝胶用于肿瘤的光热治疗-长程化疗联用及其光声/荧光的实时监测研究

Tumor recurrence is a very serious problem in the treatment of clinical oncology. To prevent the recurrence of tumor, it is urgent to develop new systems for sustained tumor treatment. In this project, a system of near-infrared light-induced protein-engineered hydrogel will be developed for sustained tumor therapy. The thermo-sensitive nanogel particles will be prepared simply with the complex of the thermo-sensitive polymer and the genetically engineered proteins containing targeting ligands. The chemotherapeutics and silver sulfide quantum dots will be loaded into the nanogels. Silver sulfide quantum dots possess ideal photothermal effect, near-infrared fluorescence, and photoacoustic effects. After the hybrid nanogels accumulation in the targeted tumor tissue, silver sulfide quantum dots will convert near-infrared light into heat by the photothermal effect for tumor photothermal therapy, and the heat will also cause aggregate of thermo-sensitive polymer, which will lead to an increase in the genetically engineering protein concentration. The concentrated hybrid nanogels will form a macro-size hydrogel by self-assembly of gene engineering protein. Upon gelation, the drug loaded in hybrid nanogels will be enclosed in the macro-size protein hydrogel and will release through the erosion of the protein-engineered hydrogel for sustained chemotherapy. In addition, in vivo photoacoutic/fluorescence real-time imaging will be employed for monitoring the tumor treatment. The study will quest and develop a new target system based on the genetically engineered proteins for sustained chemo-photothermal therapy and therapeutic monitoring. This study is expected to provide some new ideas and approaches for understanding the basic law of cancer occurrence and realizing high resolution tumor imaging for cancer therapy.

肿瘤复发是临床肿瘤治疗中面临的一个非常严重的问题，因此发展持续的肿瘤治疗体系非常重要。本项目拟发展一种采用近红外光在体诱导形成基因工程蛋白质水凝胶体系用于肿瘤的持续治疗。其基本研究思路是利用表达有靶向配体的基因工程蛋白质偶联热敏性高分子制备纳米水凝胶颗粒，在其中装载化疗药物和硫化银量子点；靶向到达肿瘤部位的硫化银量子点通过吸收近红外光产生热用于热疗及引起偶联在基因工程蛋白质上的热敏性高分子聚集；促使基因工程蛋白质浓度增大而在肿瘤周围自组装形成宏观水凝胶；包被在水凝胶内的化疗药物缓慢释放用于长程化疗，从而实现光热和长程释放化疗药物对肿瘤进行联合治疗，并对治疗响应进行光声/荧光成像实时在体监测。该研究将探索和发展基于基因工程蛋白质的新型持续治疗系统，实现肿瘤的光热治疗和长程化疗联用及其治疗响应可视化监测，从而为研究癌症发生发展的基本规律、恶性肿瘤高分辨成像的精准诊疗提供新的思路和方法。

恶性肿瘤是一种严重威胁人类健康的多发疾病，其发病率逐年上升。因恶性肿瘤引起的死亡率一直居各种疾病前列，因此发展新的肿瘤诊断和治疗手段和方法具有十分重要的意义。在本项目中，我们设计和制备了几种用于肿瘤的长程化疗/光热治疗/免疫治疗/声动力治疗/化学动力学治疗的可注射性基因工程蛋白质水凝胶的探针，并且采用近红外II区的荧光成像/光声成像对治疗过程进行了监测。结果表明，设计的探针都具有较好的抗肿瘤效果，并且能够防止肿瘤的复发及减少肿瘤的转移。例如，我们采用Ag2S QD同时作为荧光成像、光声成像探针及光热试剂于一体体系用于NIR II荧光/光声成像监测肿瘤的长程化疗和光热治疗的研究。首先将疏水性Ag2S QD和化疗药物紫杉醇PTX通过超声处理封装在PC10A多肽形成的纳米凝胶中制备PC10A/Ag2S QD/PTX纳米水凝胶，Ag2S QD和PTX具有较好载药率和包封率，将该纳米水凝胶分散在多肽PC10A中制备多功能PC10A/Ag2S QD/PTX可注射水凝胶用于肿瘤的长程化疗和光热联合治疗。细胞毒性实验结果表明，PC10A/Ag2S QD/PTX水凝胶具有良好的生物相容性。体外和体内实验结果均表明PC10A/Ag2S QD/PTX水凝胶具有良好的长程化疗和光热治疗效果。此外，通过近红外荧光成像和光声成像监测了可注射PC10A/Ag2S QD/PTX水凝胶的体内降解。因此，采用基于基因工程蛋白质的水凝胶修饰的探针将为肿瘤的治疗提供一种新的思路和方法，具有较好的应用前景。项目原预期发表SCI论文6-8篇，申请专利1 项，其中影响因子大于5的3-4；实际发表SCI论文20篇，影响因子大于10的7篇，授权国家发明专利3项，超出了申请书中的初始计划。