特异性识别胰导管腺癌核酸适配体的筛选及其诊治应用的初步研究

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with difficulty for early diagnosis and exhibiting profound resistance to existing therapies. Thus, it is very important to develop sensitive detection techniques and effective therapy methods for PDAC management. The project will focus on selecting aptamers differentiating the molecular differences between PDAC cells and normal pancreatic ductal cells by using cell-SELEX. Then, we will perform systematic studies on mapping the different pancreatic cancer cell lines and clinic samples with the selected aptamers to obtain the molecular profiles of pancreatic cancer, laying the foundations for molecular typing of pancreatic cancer. Furthermore, we will develop novel upconversion fluorescence/MRI targeted bimodality by integrating the specificity of aptamers with the upconversion fluorescence, mangnetic resonance signal and biocompatibility of upconversion nanoparticles (UCN), providing a method with high-sensitive, high-revolution and low-background for incipient PDAC diagnosis. Then, we will also develop targeted theranostic nanosystem based on aptamer and upconversion nanoparticles, providing a new strategy for personalized therapy of PDAC. The project may have great potential in providing new research platform for early diagnosis, targeted therapy and progonosis evaluation of PDAC.

胰导管腺癌由于早期诊断难和对治疗易产生抗性，而预后极差。因此，发展高灵敏度的早期诊断技术和有效的治疗方法是胰导管腺癌研究的迫切需要。本项目拟通过cell-SELEX技术，筛选能区分胰导管腺癌细胞与正常胰导管细胞之间分子差异的核酸适配体，系统研究核酸适配体对胰腺癌不同细胞系和临床组织样品的识别能力，建立胰腺癌核酸适配体分子图谱，为胰腺癌的分子分型提供依据。在此基础上，本项目拟利用核酸适配体的高特异性结合上转换纳米颗粒的良好生物兼容性、核磁及上转换荧光信号，发展可用于早期胰导管腺癌检测的上转换荧光/核磁双模靶向纳米探针，为胰导管腺癌的早期诊断提供高灵敏、高分辨率和低背景的检测技术；同时拟发展基于核酸适配体与上转换纳米颗粒、集早期诊断和靶向治疗于一体的纳米诊治探针，为胰导管腺癌的个体化治疗提供新技术。本项目的实施有望为胰导管腺癌早期诊断、靶向治疗和预后评估提供新的探针和技术平台。

由于在早期易转移和对治疗易产生抗性，胰腺癌的预后性极差。因此，发展高灵敏度的早期诊断技术和有效的治疗方法是胰腺癌研究的迫切需要。本项目通过cell－SELEX技术，以人hTERT-HPNE细胞为反筛细胞，胰腺癌PL45细胞为靶标，筛选获得了能区分胰腺癌细胞与正常胰腺细胞之间分子差异的核酸适体XQ-2d。系统研究表明XQ-2d对胰腺癌临床组织样品具有很好的识别能力，同时能富集在小鼠体内肿瘤。在此基础上，本项目利用核酸探针的高特异性结合二氧化锰纳米片，发展了可激活式荧光/核磁双模影像靶向纳米诊疗探针，有望为胰腺癌的早期诊断提供高灵敏、高分辨率和低背景的检测技术。同时本项目发展了两种基于人血清蛋白为载体的纳米药物。本项目的实施有望为胰腺癌早期诊断、靶向治疗和预后评估提供新的技术平台。