肺癌早期诊断用高精准靶向型磁共振造影复合纳米粒子的研究

This project aims to develop novel high-specifically-targetable composite nanoparticles with magnetic resonance imaging (MRI) contrast agents inside for detection of lung cancer in early stage, including preparation of sub-200 nm biodegradable nanoparticles, encapsulation of MRI contrast agents inside the nanoparticles, conjugation of ligand folic acid and graft of pH-sensitive polymers on the surface of the nanoparticles. In surroundings of normal cells, the ligand folic acid on the surface of the composite nanoparticles is always hidden in the pH-sensitive polymers. However, after arriving at lung tumour site, the folic acid will be exposed to recognize and bind to folate receptors on the surface of lung cancer cells due to shrinkage of the pH-sensitive polymers. This smart system is high selective and able to distinguish the molecular signatures of lung cancer cells without non-specific uptake by trillions of healthy cells in the body. This project will also investigate the MRI signal enhancement mechanism of the composite nanoparticles in the lung tumour site; optimize the length and density of the grafted pH-sensitive polymers on the surface of the composite nanoparticles by analysing the in vivo MRI efficacies, improve the lung tumor targetability of the composite nanoparticles. The expected results of this project will be that the developed composite nanoparticles could be high specifically delivered to lung tumour cells, and a future specific and sensitive detection technique for early lung cancer would be promising based on the composite nanoparticles.

为实现对肺癌的早期诊断，本课题拟开发一种高精准靶向型磁共振造影复合纳米粒子，研究思路如下：构建并制备出尺寸小于200 nm、内部包埋有磁共振造影剂、表面偶联有配体叶酸并接枝有pH敏感型高分子的可生物降解磁共振造影复合纳米粒子，使复合纳米粒子表面的叶酸在正常生理条件下隐藏在高分子之中、在肺癌组织环境下由于高分子收缩而暴露出来与肺癌细胞表面的叶酸受体发生特异性相互作用，达到降低正常细胞对复合纳米粒子非特异性摄取的目的；通过医学磁共振成像技术，研究该复合纳米粒子在肺癌组织内的磁共振造影信号增强机制；研究复合纳米粒子表面pH敏感型高分子的接枝密度和链长长度对靶向造影效果的影响，优化高分子的接枝密度和链长长度，有效提高磁共振造影复合纳米粒子对肺癌组织的靶向效果。通过本项目的研究，有望制备出一种能高精准靶向肺癌组织的磁共振造影复合纳米粒子，为将来发展一套特异、灵敏的肺癌早期诊断技术打下基础。

肺癌的早期诊断将大大增加彻底手术治疗的成功机率，磁共振成像（MRI）造影剂可提高MRI技术检测早期肺癌的灵敏度，但传统的MRI造影剂存在细胞毒性和低靶向性等缺点。为实现对肺癌的早期诊断，本研究开发了一种高精准靶向型磁共振造影复合纳米粒子，即构建并制备出了尺寸小于200 nm、内部包埋有MRI造影剂、表面偶联有配体叶酸并接枝有pH敏感型高分子的可生物降解MRI造影复合纳米粒子。本研究考察了复合纳米粒子表面pH敏感型高分子的接枝密度和链长长度对靶向造影效果的影响，优化了高分子的接枝密度和链长长度，有效提高了磁共振造影复合纳米粒子靶向肺癌细胞的效果。根据pH7.4和5.5下细胞摄取纳米粒子的结果，pH敏感型高分子与复合纳米粒子的重量比（即接枝密度）和pH敏感型高分子的分子量（即接枝长度）分别优化为1.32和5.7 kDa。在最优条件下，复合纳米粒子表面的配体叶酸在pH7.4下隐藏在高分子之中，但在pH5.5时，靶分子叶酸因高分子收缩而暴露出来，与肺癌细胞表面的叶酸受体发生特异性相互作用，从而实现了对肺癌细胞的精准靶向。本项目制备出了一种能精准靶向肺癌细胞的MRI造影复合纳米粒子，为将来发展一套特异、灵敏的肺癌早期诊断技术打下了基础。