基于光热和光致相变技术的靶向超声微泡对肝细胞癌的治疗作用及机制研究

Occult and residual lesions may still exist after normalized treatment of Hepatocellular carcinoma. Earlier detection together with targeted therapy of the lesions and decrease of recurrence and metastasis are key issues for improvement of the survival rate of patients with hepatocellular carcinoma. Previous studies have demonstrated that thermo-chemotherapy can inhibit the growth, recurrence and metastasis of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition and Treg cell-mediated immune escape. Based on these, brand new targeted ultrasound microbubble (PFH@PLGA/MNPs/PD-GPC3) with the ability of multimodality imaging and thermo-chemotherapy is intended to be developed. GPC3 antibody is able to target hepatocellular carcinoma cells, and multimodality imaging including magnetic resonance imaging, ultrasound imaging, photoacoustic imaging can improve the detection of occult and residual lesions for further guiding the treatment of hepatocellular carcinoma. After stimulating microbubbles with near-infrared light, hyperthermia caused by melanin nanoparticles and the chemotherapeutic effect of polydatin are capable to synergistically inhibit the growth, invasion and metastasis of hepatocellular carcinoma, and the mechanisms involving epithelial-mesenchymal transition and tumor immune microenvironment will be meticulously discussed. This study provides new methods and theoretical basis for improving the prognosis, reducing the recurrence and metastasis of hepatocellular carcinoma.

肝细胞癌规范化治疗后仍可能存在隐匿及残余病灶，如何早期检出并靶向治疗这些病灶、减少肝细胞癌的复发和转移是提高患者生存率的关键问题。本课题组前期研究表明热化疗可以通过抑制上皮间质转化和Treg细胞介导的免疫逃逸，从而抑制肝细胞癌的生长、复发和转移。在此研究基础上，拟研制一种具有多模态成像及热化疗功能的靶向超声微泡（PFH@PLGA/MNPs/PD-GPC3），通过GPC3抗体靶向肝癌细胞，利用该靶向微泡的磁共振、超声、光声多模态成像功能提高隐匿及残余病灶的检出率，引导肝细胞癌的治疗。该靶向微泡在近红外光激发下, 利用其壳上黑色素纳米粒的热疗作用联合虎杖苷的化疗作用协同抑制肝细胞癌的生长、侵袭和转移，并从上皮间质转化和肿瘤免疫微环境调节两方面揭示其作用机制。本研究为减少肝细胞癌的复发和转移，改善预后，提供新的方法和理论依据。

研究背景：肝细胞癌复发转移率高，早期检出并靶向治疗肝细胞癌病灶，有效抑制肝细胞癌的复发和转移是提高患者生存率的关键问题。超声造影是临床上高效诊断肝细胞癌的影像学技术之一，纳米技术的迅猛发展更为肿瘤的精准诊断及靶向治疗提供了新思路。因此将超声造影剂与药物或光热治疗剂整合于纳米载体中，能在定位肿瘤基础上实现精准治疗，从而有效抑制肝细胞癌的生长、复发和转移。.研究内容：本项目已验证多种抗肿瘤药物、抗纤维化药物对肝细胞癌生长转移特性及肝细胞癌肿瘤微环境的作用效果及机制，在此基础上制备相应载药及光热型诊疗一体化纳米颗粒对肝细胞癌进行定位及靶向治疗，利用体内外实验揭示上述纳米治疗剂抑制肝细胞癌生长进展的治疗机制。.研究结果：环维黄杨星D、高三尖杉酯碱、虎杖苷、荷叶碱、吡非尼酮、尼达尼布及相应诊疗一体化超声微泡或纳米颗粒联合超声靶向爆破效应分别通过抑制EGFR-FAK-AKT/ERK1/2-Slug及PI3K/AKT/GSK-3β/Slug信号通路、促进肿瘤细胞自噬或凋亡、抑制肝细胞癌肿瘤微环境纤维基质细胞活性从而抑制肝细胞癌生长转移。此外，PFP@PLGA/Cu12Sb4S13纳米囊泡及Melanin@PLGA/Nuciferine纳米颗粒在定位肿瘤后能对肝细胞癌进行有效光热治疗，并通过抑制RAS/MAPK/MT-CO1通路引起线粒体代谢改变、诱导肿瘤细胞自噬性死亡抑制肝细胞癌生长转移。.意义：本研究制备的多种诊疗一体化载药纳米颗粒或超声微泡、光热型纳米颗粒能在定位肿瘤基础上联合低强度聚焦超声或近红外光，实现肝细胞癌靶向药物及光热治疗，并通过抑制肝细胞癌细胞上皮-间质转化或调节肝细胞癌肿瘤微环境等多种机制有效抑制肝细胞癌生长转移，为减少肝细胞癌的复发转移提供新依据。.