探索肿瘤诊断治疗一体化的新方法对于肿瘤的治疗具有重要意义。本课题拟研究一种基于二氧化锰纳米层的多功能肿瘤靶向诊断治疗系统。首先将具有肿瘤微环境响应特性的二氧化锰纳米层与靶向肿瘤血管CD14受体的NGR短肽(N：天冬酰氨酸, G：氨基乙酸, R：精氨酸)通过生物相容性高分子材料相连，然后装载化疗药物顺铂(CDDP)和新型基因药物CRISPR/Cas9技术介导的hEGFR sgRNA (small guide RNA)，制备诊断治疗一体化肿瘤靶向给药系统，实现肿瘤微环境响应下的MRI成像和联合治疗。CRISPR/Cas9技术介导的目标基因的sgRNA是一种新的基因沉默技术，具有效率高，作用时间长的优点。该系统借助 NGR 的肿瘤靶向性高效转递至肿瘤部位，实现基于二氧化锰纳米层降解为Mn+2的MRI成像，协同发挥CDDP细胞毒作用和CRISPR/Cas9依赖的EGFR sgRNA基因治疗作用。

It is of great importance to explore the new methods for cancer diagnosis and therapy simultaneously. This project aims to establish a multifunctional tumor-targeting drug delivery system for tumor diagnosis and therapy based on manganese dioxide nanosheets. The tumor-targeting peptide NGR against CD14 was conjugated with the tumor microenvironment sensitive manganese dioxide nanosheets through the polymer materials with outstanding biocompatibility. Due to the low pH and high concentration of reduced glutathione in the tumor microenvironment, manganese dioxide nanosheets will be degraded to Mn2+, which enables magnetic resonance imaging (MRI). Both chemotheraputic agent cis-platinum and the CRISPR/Cas9 system based human EGFR sgRNA (small guide RNA) are loaded into the system for tumor MRI as well as combination of chemotherapy and gene therapy. The CRISPS/Cas9 system is a newly developed gene silencing technology mediated by sgRNA targeting the target gene, which has the advantages of high efficiency and long effect. In this study, we will firstly investigate the CD14 receptor-mediated endocytosis of this system，the tumor inhibitory effect, the MRI property under the condition that mimics the in vivo tumor microenvironment in vitro. In addition, the pharmacokinetics and biodistribution, drug release profile and anti-tumor activity as well as MRI in vivo will also be studied for evaluating the tumor-targeting potential, MRI property and combinational treatment effect.