携载ILKsiRNA多功能纳米粒子在甲状腺癌基因/光热联合治疗及成像监控中的研究

The thyroidectomy of PTC treatment can lead to endocrine dysfunction, and therefore research about targeted therapy of thyroid cancer plays an important role. The results of our previous study have shown that tall cell variant of papillary thyroid carcinoma appears the up-regulation characteristics of molecular signaling of mesenchymal epithelial transiton, including MMPs, integrin α3 and fibronectin. Based on our previous research work on molecular markers, we synthesize the polypyrrole-ILK siRNA-gelatin nanoparticles with photosensitivity by self-assembly technique. Once reaching the tumor microenvironment with MMPs by the EPR effect , the gelatin shell will be removed under the action of MMPs to trigger the release of siNRA and avoid the degradation of siRNA by nucleases in the bloodstream. Under the excitation of pulsed laser, the nanoparticles produce transient high temperature, which leads to the increase of cell membrane permeability and promotes ILK siRNA to enter into tumor cells efficiently. After ILK siRNA and ILK mRNA in the cytoplasm bind specifically and silencing of the ILK gene, the up-regulation of integrin is inhibited, which can inhibit tumor proliferation and metastasis. Then with continuous irradiation by near-infrared laser, polypyrrole can produce high temperature and have the potential to therapentil efficiency. At the same time, photoacoustic tomography will be performed to obtain tumor microvascular information and achieve integral strategy of imaging and treatment.

甲状腺癌手术治疗会导致人体内分泌功能受损，因此甲状腺癌靶向治疗的研究具有重要作用。本课题前期研究结果显示乳头状癌高细胞亚型出现了大量上皮间质转化相关的分子信号，其中包括MMPs、整合素α3和纤维粘连蛋白等。在前期分子标记物研究的基础上，通过自组装技术形成具有光敏特性的聚吡咯-ILK siRNA-明胶纳米粒子，通过EPR效应到达具有MMPs的肿瘤微环境后，在MMPs作用下脱去明胶外壳，触发siNRA的释放，避免siRNA在体内循环中被核酸酶降解。在脉冲激光的激发下，纳米粒子产生瞬间升温，致使细胞膜通透性增加，促进ILK-siRNA高效进入肿瘤细胞, 待其与细胞质中的ILK mRNA特异性结合并使其沉默后，整合素的上调被抑制, 从而抑制肿瘤增值及转移，然后进行连续近红外激光的照射，聚吡咯产生高温，将肿瘤组织彻底消融,同时产生光声断层成像获取肿瘤内微血管信息实现治疗成像一体化策略。

目前手术切除仍然是甲状腺乳头状癌（PTC）治疗的常规手段，但手术切除甲状腺之后的患者生活质量下降，同时也不能避免甲状腺癌的复发和转移。热消融是一种可以代替手术的微创治疗手段，纳米光热材料在这方面得到了广泛应用。整合素连接酶（ILK）已被多项研究证实可促进PTC的淋巴转移，肿瘤增殖及复发。基于以上背景，我们制备了基于聚吡咯-聚乙烯亚胺（PEI）-整合素连接酶（ILK）小干扰基因[PPRILK] 的纳米系统，来进行PTC的微创热消融同时抑制其淋巴转移。明胶稳定的聚吡咯在近红外光区具有良好的光敏性质，可以作为光热和光声成像材料；其表面的明胶作为一种两性物质可以提供电荷反转功能，在生理pH值(7.35~7.45) 下吸附PEI和siILK,在溶酶体的酸性 (pH 4.0~5.5)环境中可以促进基因的溶酶体逃逸释放siILK使其在胞质中发挥作用抑制肿瘤增殖和淋巴转移。荧光和光声双模态成像的可指导基因递送和聚吡咯的肿瘤内定位。最后，肿瘤被光热治疗完全消融且其复发和淋巴转移被显著抑制。