阿霉素联合调控DNA损伤反应的miRNA靶向治疗脑胶质瘤多功能纳米粒子构建

Enrichment of brain-targeting doxorubicin in the brain will improve the curative effect of treating brain glioma. While the evasion of a part of the brain glioma in the process of DNA damage will lead to the tumor recurrence. In order to further study the mechanism of DNA damage caused by doxorubicin ,we constructed multifunction brain-targeting doxorubicin nanoparticles (NPs). We plan to study the DNA damage response of brain glioma induced by brain-targeting doxorubicin NPs. In the DNA damage process, we will analysis the change of miRNA via gene chip technique and forecast the effect of miRNA by bioinformatics techniques. Also, we will seek for the miRNA that restrain the repair of the damaged DNA, synthesis this miRNA, and construct the co-dilivery of doxorubicin and miRNA multifuctional targeting nano-carrier system. Use the way of brain-targeting of NPs to realize the miRNA transfection on brain glioma and verify the effect on passing through the blood brain barrier. We will detect the enrichment and the localization of drug-loaded NPs in glioma, analysis the effect of drug-loaded NPs on restrain the repair of the damaged DNA, and the efficacy of arousing glioma cell apoptosis. We will preliminary clarify the regulatory role of miRNA played in the DNA damage response aroused by doxorubicin and achieve the teatment of the glioma by the co-delivery of chemotherapy drug and gene brain-targeting NPs, which will provide new targets and ideas for the treatment of glioma .

脑靶向阿霉素能在脑内富集，提高了对脑胶质瘤的治疗疗效，但阿霉素在引起脑胶质瘤DNA损伤的过程中，有部分肿瘤细胞会逃避DNA损伤，导致肿瘤复发。为了进一步研究阿霉素引起DNA损伤的机制，我们成功构建了多功能脑靶向阿霉素纳米粒子，拟研究阿霉素纳米粒子引起的脑胶质瘤DNA损伤反应，利用基因芯片分析miRNA的变化，利用生物信息学等技术预测miRNA的作用，寻找抑制DNA损伤修复的miRNA,合成miRNA并构建能同时携载阿霉素和miRNA的多功能靶向纳米载药系统，以纳米粒子脑靶向的方式实现miRNA转染脑胶质瘤，验证其透过血脑屏障作用，检测其在脑胶质瘤内的富集与定位，分析其抑制脑胶质瘤DNA损伤修复作用、引起脑胶质瘤细胞凋亡药效，初步阐明miRNA在阿霉素导致的脑胶质瘤DNA损伤反应中的调控作用，并实现了化疗药物与基因药物联合构建脑靶向纳米粒子治疗脑胶质瘤，为脑胶质瘤的的治疗提供新的靶点和思路。

脑靶向阿霉素能在脑内富集，提高了对脑胶质瘤的治疗疗效，但阿霉素在引起脑胶质瘤DNA损伤的过程中，有部分肿瘤细胞会逃避DNA损伤，导致肿瘤复发。我们成功构建了能同时携载阿霉素和miRNA的β-环糊精-聚乙烯亚胺-磷脂(β-CD-PEI-PE)多功能脑靶向阿霉素纳米粒子，研究了阿霉素纳米粒子引起的脑胶质瘤DNA损伤反应，利用基因芯片分析miRNA的变化，利用生物信息学技术研究了miRNA的作用，寻找抑制DNA损伤修复的miRNA，以纳米粒子脑靶向的方式实现miRNA转染脑胶质瘤，验证其透过血脑屏障作用，检测其在脑胶质瘤内的富集与定位，分析了其抑制脑胶质瘤DNA损伤修复作用、引起脑胶质瘤细胞凋亡药效， 体内外研究揭示这些靶向的纳米粒子具有卓越的生物相容性、提高了阿霉素和miRNA对C6细胞的吸收和主动靶向性, 转铁蛋白修饰的纳米粒子有利于肿瘤的特异性治疗，这种靶向药物递送系统对于脑胶质瘤治疗具有显著的先进性。我们的研究表明miRNA在阿霉素导致的脑胶质瘤DNA损伤反应中的调控作用，并实现了化疗药物与基因药物联合构建脑靶向纳米粒子治疗脑胶质瘤，为脑胶质瘤的的治疗提供新的靶点和思路。