靶向载HSV-TK基因的纳米超声分子探针治疗HIFU消融后残留肝癌的实验研究

High intensity focused ultrasound (HIFU) treating liver cancer have a defect of the residual tumor. in the previous experiment study of united parcel HSV-TK gene ultrasound lipid of microbubble kill HIFU treating liver cancer residual lesions , we completed the HSV-TK suicide gene and the bubble of connection, Proof of suicide gene targeting damage in the cell can improve target genes in the cancer tissue of the transfection and expressed and has an obvious effect to kill. It also found that the existing lipid microbubble size is larger, Can't directly through the blood capillary endothelial cells, No active target of identification residual carcinoma, Limit its clinical application.. According to these shortcomings, This project will be the first to preparation nanometer level ultrasound molecular probe which can pass through vascular endothelial cells and active identification liver cancer cell membrane protein GPC3 specificity through the surface of the antibody, to achieve Target recognition Residual cancer.Ultrasound molecular probe and HSV-TK suicide gene connection, Use low-frequency ultrasonic targeted damage probe and Cavitation effect functions etc, To further improve the suicide gene targeting and transfection rate, With more fully after the treatment of HIFU kill the residual cancer cells, Improve HIFU curative effect, In HIFU and the gene combination to targeted therapy liver cancer has the new breakthrough.

高强度聚焦超声（HIFU）治疗肝癌有癌组织残存的缺陷，目前尚无较好的解决方案。我们前期研究发现载HSV-TK基因的超声脂质微泡对治疗HIFU消融后残留肝癌有较好的疗效，但同时发现现有脂质微泡粒径较大，无法直接穿过肿瘤血管内皮细胞且缺乏主动靶向性，不能主动识别残癌等缺点，限制其临床应用前景。.针对以上缺点，本项目在前期研究基础上，制备载HSV-TK基因的纳米超声分子探针，并导入HIFU消融后残癌的裸鼠，使其能穿过肿瘤血管内皮细胞，通过其表面包被的抗GPC3单抗，主动识别GPC3阳性残留肝癌细胞，达到主动靶向识别残癌的目的。随后以低频超声辐照残癌区，破坏超声分子探针，释放自杀基因转染残癌细胞。同时作用于超声分子探针产生的空化效应及机械效应使肿瘤血管通透性增加，进一步提高自杀基因转染率，更充分地杀灭HIFU消融后的残癌细胞，提高HIFU疗效，力图在HIFU和基因联合靶向治疗肝癌方面取得新的突破。

高强度聚焦超声（HIFU）治疗肝癌有癌组织残存的缺陷，目前尚无较好的解决方案。我们前期研究发现载HSV-TK基因的超声脂质微泡对HIFU治疗后残留肝癌有较明显的疗效，但同时也发现现有脂质微泡粒径较大，无法直接穿过肿瘤血管内皮细胞且缺乏主动靶向性，不能主动识别残留肝癌等缺点，限制了其临床应用前景。 针对以上这些缺点，本项目在前期研究基础上首先制备纳米级超声分子探针，使其能穿过肿瘤血管内皮细胞，通过其表面包被抗GPC3单抗，主动识别GPC3阳性肝癌细胞，达到主动靶向识别残癌的目的。然后将超声分子探针与HSV-TK自杀基因连接，利用低频超声辐照靶向破坏探针，在释放自杀基因的同时，超声波作用于探针产生的空化效应及机械效应使肿瘤血管通透性增加，进一步提高自杀基因的靶向性及转染率，更充分地杀灭HIFU消融后的残癌细胞，提高HIFU疗效，力图在HIFU和基因联合靶向治疗肝癌方面取得新的突破