超屏蔽磁感靶向声释氧微聚体的构建及多模态分子影像引导精准声动力治疗肝癌的能效研究

Sonodynamic therapy (SDT) is a new non-invasive approach that shows remarkable potential in the treatment of therioma. SDT would irradiate the sound sensitizers by low frequency and low-intensity ultrasound (US) to kill tumor cells. Conventional sound sensitizers could not be specifically clustered in tumor tissues, which could not achieve the precise SDT. A single imaging technology cannot meet the needs of precise tumor therapy any longer. Our previous studies suggested that SDT could induce apoptosis of tumor cells; furthermore, with the aid of low frequency ultrasound, nanobubbles can be used as a high efficient NET-1 siRNA vehicle, which can achieve efficient transfection into hepatocellular carcinoma. IR-780 iodide used as a new sound sensitizer, its therapeutic and fluorescent imaging effects have been proved preliminarily. The research team envisaged to apply nanobubbles as the vehicle, O2 as the gas core to improve the anoxic microenvironment of tumor, IR-780 iodide as the sound sensitizer and Fe3O4-PEG-2000 as the USR magnetic imaging agent. The magnetic IR-780@Fe3O4-O2 nanopolymers, which could be apply to US-MRI- Fluorescence Imaging and precise SDT, were prepared innovatively. With the aid of low frequency and low-intensity ultrasound, the IR-780 iodide and O2 were delivered precisely to make the SDT visible,precise and effective in hepatocellular carcinoma.

声动力治疗（SDT）是一种新型非侵入性恶性肿瘤治疗技术，通过超声激活声敏剂而杀伤肿瘤细胞。然而常见声敏剂无法特异性聚集在肿瘤组织内，且因肿瘤缺氧微环境，无法实现高效声动力治疗。此外，单一的影像技术也无法满足肿瘤精准治疗的需求。我们前期研究发现，声动力治疗可诱导肿瘤细胞凋亡；同时，低频超声联合靶向纳米微泡可实现NET-1siRNA基因在肝癌细胞的高效转染。IR-780碘化物作为新兴的声敏剂，其治疗及荧光显像作用已得到初步证实。课题组设想以纳米微泡为载体，以O2为内核改善肿瘤缺氧微环境，IR-780为核心，Fe3O4-PEG-2000纳米粒子为超屏蔽磁感显像剂，创新性提出制备携载IR-780的超屏蔽磁感靶向声释氧纳米微聚体，使其兼具精准声动力疗法介导剂和超声-磁共振-荧光多模态分子成像的功能。联合低频低强度超声辐照，进行IR-780和O2靶向递送，以实现肝癌声动力治疗的可视化、精准化和高效性。

HCC为高度血管化的肿瘤,但肿瘤血管功能存在异常, 细胞外基质的沉积以及纤维化进程中的解剖学改变也可使血管阻力增加, 从而影响氧气的交换导致组织缺氧。.本项目拟设计制备包裹氧气的纳米微聚体(nanopolymer，NP)，通过声动力控制纳米微聚体在HCC肿瘤周围释放氧气，改善肿瘤缺氧微环境，提高声动力诱导ROS产生的能力。.课题组通过采用氧气与全氟丙烷混合气体作为核心，多种磷脂复合物为原料，以IR-780碘化物为声敏剂，制备靶向声释氧纳米微聚体。通过相关表征实验，证明靶向声释氧纳米微聚体制备成功。课题组成员再通过细胞学实验、活体动物实验，证明靶向声释氧纳米微聚体可实现HCC的多模态分子成像，在低频低强度超声介导下，其可提高肿瘤组织局部氧含量，进一步增强声动力疗法抗肿瘤疗效。.此外、课题组还采用了多种新兴的生物信息技术，如RNA-seq测序技术、单细胞测序、蛋白质组学等技术，在基因组、蛋白质组层面，探索声动力疗法治疗肝细胞癌的机制。.本项目聚焦于肝细胞癌的超声-荧光多模态分子影像诊断与声动力疗法，联合低频低强度超声，实现肝细胞癌的的分子影像诊断与精准声动力治疗一体化，为肝癌的诊疗一体化提出了一种崭新的方法。.截止目前，本项目已超额完成预期研究目标。依托本项目，项目负责人程文教授课题组已申请本项目直接相关国家发明专利一项，并已获得授权。课题组成员发表与本项目直接相关的SCI期刊文章8篇，其中单篇影响因子大于10.0一篇。发表国家级核心期刊论文5篇。本项目相关科研论文总计他引30余次。依托本项目，程文教授已培养毕业博士研究生1名，毕业硕士研究生2名，在读博士研究生1名。