载PD-L1肽磁性外泌体分子显像、增效HIFU及协同免疫治疗肝癌的研究

高强度聚焦超声（HIFU）是最有前途的肝癌辅助治疗手段之一，而且还具有激活免疫系统的潜力，然而面临以下挑战：①以超声引导、监控及判断消融程度存在不足；②对于深部、血供丰富的病灶消融困难；③HIFU消融后肿瘤残余导致的复发和转移仍是亟待解决的难题。本课题基于肝癌HIFU消融及分子影像学前期研究工作，结合内源性纳米载体外泌体及肿瘤免疫治疗研究进展，以外泌体为基础载体，携载Fe3O4颗粒研制一种具有高生物相容性、体内稳定性和肿瘤靶向性的磁性纳米分子探针，再运用磁导航技术提高其肿瘤富集，增强光声/磁共振成像并引导、监控及增效肝癌HIFU消融，减少残余癌。然后在HIFU激活机体免疫功能基础上，以磁性外泌体载入PD-L1肽进行协同免疫治疗，防止肿瘤复发和转移。通过新型的磁性外泌体纳米分子探针，将多模态分子影像、HIFU消融、磁导航及肿瘤免疫治疗有机结合，协同增效，为肝癌靶向治疗探索一种新策略。

High intensity focused ultrasound (HIFU) is one of the promising adjuvant therapy for hepatocellular carcinoma (HCC) and endowed with the potential to acitivate immune system. However, HIFU treatment is challenged by several limitations. Firstly, there are some defects in guiding, monitoring and estimating the degree of HIFU ablation by ultrasonography. Secondly, it is difficult to completely ablate the lesions located in deep region or characterized with rich blood supply. Thirdly, the relapse and metastasis resulted from the residual tumor after HIFU ablation remains an urgent problem. Therefore, this project is designed to solve the above problems based on our previous studies including HIFU mechanisms and molecular imaging. Also, the research progress on endogenous exosomes and tumor immunotherapy are introduced and combined. In this study, a novel magnetic nanoprobe will be constructed by loading Fe3O4 into tumor-derived exosomes with high biocompatibility, in vivo stability and tumor targeting ability. Then the magnetic-guidance technology will be applied to increase the nanoproble accumulation in tumor area, which facilitates it to enhance photoacoustic imaging (PA) and MRI. Meantime, the nanoprobe can also guide, monitor and synergize HIFU ablation, which improve the therapeutic efficiency of HIFU treatment and minimize the size of residual tumor. Moreover, on the basis of the HIFU-activated immune response, the magnetic exosomes loaded with PD-L1 peptide are then administrated to obtain synergistic effect on tumor immunotherapy preventing tumor recurrence and metastasis. In short, this project integrates the multi-modal molecular imaging, HIFU treatment, magnetic guidance and tumor immunotherapy technologies using the fabricated magnetic exosomes as novel nanoprobe, which will explore a new strategy for non-invasive hepatocarcinomar treatment.