由于血脑屏障的存在，脑肿瘤的非伤害性治疗一直是一个国际性的大难题。本课题创新性地采用GFAP启动子，构建针对EGFR的具有脑特异表达功能的shRNA表达质粒；同时合成和修饰"PEG修饰的免疫脂质复合体"，使它能同时装载shRNA质粒 和化疗药DOX，连接起靶向作用的单抗，使之能通过血脑屏障, 对实验性脑肿瘤进行脑靶向性联合治疗，以期增强治疗效果，降低毒副作用。我们将首先优化制备免疫脂质复合体的条件，然后在体外U87神经胶质瘤细胞上研究比较单一及联合治疗对肿瘤细胞生长的抑制作用，并探讨可能的增强抑制作用机制，然后再同样体内研究脑内接种的U87肿瘤的治疗效果及其毒副作用。本课题研究的免疫脂质复合体可以同时装载各样的shRNA和各样的带正电荷的化疗药物，因而具有广谱性。所以本课题对于探索肿瘤，尤其是脑肿瘤的治疗新策略具有重要理论意义和实际应用价值。

Noninvasive therapy of brain cancer remains to be a big chalenge due to the blood-brain barrier. Based on our experience, a new therapeutic strategy for targeting experimental brain cancer is proposed, which involves construction of a brain-specifc shRNA expression plasmid (anti-EGFR shRNA) against EGFR under the control of GFAP promoter as well as synthesis and modification of pegylated immuno-lipopolyplexes (PILP). More importantly, the PILP will be made possible to encapsulate both anti-EGFR shRNA and the chemotherapeutic DOX at the same time. A targeting monoclonal antibody will be conjugated to PILP, which will facilitate the transcytosis of the therapeutics across the blood-brain barrier and tumor cell membrane. With all these efforts, we are aiming at an enhanced therapeutic effect for barin cancer, and less side effects. We will first test the new drug system's cytotoxicity and growth inhibitory effect on U87 glioma cells, and then move to in vivo efficacy study in U87 orthotopic brain tumor model. Furthermore, the mechanism of possibly enhanced therapeutic effect and toxicicty will also be investigated. This new PILP system could be a universal system to encapsulate any kinds of shRNA and any positively charged chemotheraputics. Therefore, this project is of grest significance to cancer therapy, espeially brain cancer therapy.