创新纳米靶向诊断治疗载体-Pdcd4-RNA激活系统在肺癌脑转移瘤中的研究

Programmed cell death 4(Pdcd4) is connected with the metastasis of lung cancer. Hereby, we want to observe the effects of Pdcd4 activation by RNAa on lung cancer cell migration and invasion，and by the introduction of double-stranded RNA (dsRNA) which leads to gene silencing in a sequence-specific manner. Using this advanced technology, we will make a novel class of positive electrical charge magnetic nanoparticle, PMAL grafted with PEI loaded with aptamer will be prepared through direct ligand-exchange reactions and surface modifications as multifunctional complexes for Pdcd4-saRNA delivery and real-time intracellular imaging for the development of therapeutics in the near future. Currently, however, studies on the correlation between Pdcd4 expression and tumor metastasis-mediated signaling pathway are scarce in the world, not only are we credited with first discovering the tumor suppression function of Pdcd4, we also discovered that, by binding with translation initiation factor 4A, Pdcd4 functions as a protein translation inhibitor. These contributions led to a new avenue of research into suppression of tumorigenesis and understanding of protein translational regulation. To deliver of small activating RNA by novel nano particles to stimulate Pdcd4 expression in the lung cancer tissues, which is highly novel and provides important new insights and could thus reveal a new strategy for the brain metastasis of tlung cancer therapeutics.

肺癌转移侵袭尤其肺癌脑转移瘤在当下的发病率和死亡率极高。目前RNA激活技术这一发现正在开拓性用于治疗包括肿瘤、代谢及遗传性疾病等。本项目即应用纳米技术以及反义核酸基因治疗技术深入探索肺癌脑转移瘤更具特异靶向性的诊断和治疗途径。我们结合电荷靶向及荧光磁性纳米材料研发新型纳米诊疗载体，通过结合FITC、生物素标记的Pdcd4- saRNA穿透血脑屏障模型从而抑制肺癌脑转移瘤，实现载体自带红色荧光、FITC绿色荧光多模态成像，可动态观察Pdcd4- saRNA的精确释放和有效给药。故本研究将对此纳米载体的靶向性和RNA激活的机制，以及两者在抗肿瘤运用中结合的可行性和应用方面进行基础研究，并有利于寻找防治肺癌脑转移的新方法，对肺癌脑转移患者的早期诊断、提高靶向治疗疗效等有着重要的临床意义和理论价值。

我课题组构建新型电荷靶向荧光显像诊断载体系统并高效负载荧光标记的saRNA，并对其生物学改变和对肺癌脑转移动物模型的影响进行进一步研究。我们已成功建立体外模拟血脑屏障模型和动物体内肺癌脑转移模型（高潜力脑转移肺腺癌细胞株等），这对明确肺癌脑转移 的机制打下重要的理论研究基础。本项目研发的靶向纳米载体通过结合 FITC 绿 色荧光蛋白标记的saRNA，实现载体自身红色荧光、FITC 绿色荧光多模态成像，可更好的动态观察 Pdcd4-saRNA 的精确释放和有效给药抑制肺癌转移。 这对于阐明saRNA 抑制肺癌脑转移瘤增殖转移的作用机制以及开发新型激活抗肺癌转移瘤药物亦具有一定的理论价值和应用前景。