软物质纳米颗粒在肿瘤间质孔隙网络结构中的扩散机理研究

As nanomedicine for cancer diagnosis and treatment, nanoparticles should pass through many physical barriers and internalized by tumor cells to achieve their function. However, the experimental results in vivo show that the distribution of nanoparticles in the cancer tissue is mainly focused on the perivascular space, because the interstitial matrix is an important physical barrier for the nanoparticle diffusion, which is a pore network made of collagens, laminins, proteoglycans and so on. Thus nanoparticle diffusion in the interstitial matrix is very difficult. The cancer cells can change their cell shape to pass through narrow space in the metastasis process. Inspired by cancer cell metastasis, we purposed this project to improve the nanoparticles diffusion in the interstitial matrix through soft nanoparticle design innovatively. In this study, we investigate the nanoparticle diffusion mechanism in the porous network structure through experiments and molecular dynamics simulation. We study the effect of nanoparticle shapes, rigidity, pore network structures on the diffusion coefficient, and obtain the optimum properties of nanoparticle and network structure. The results can provide significant suggestions for the cancer diagnostic and treatment.

作为肿瘤诊疗药剂的纳米颗粒需经复杂体内传输到达肿瘤细胞才能实现其功能。但众多活体实验发现，纳米颗粒在肿瘤组织内的分布主要集中在血管壁周围，原因为肿瘤间隙基质由胶原蛋白、层粘连蛋白、蛋白聚糖等组成了高度粘连的孔隙网络结构，构成了纳米颗粒传输的重要物理屏障。针对纳米颗粒在肿瘤间隙基质中传质困难的问题，基于癌细胞转移过程会通过自身的形状变化来通过一些狭小空间的启发，本项目创新性地提出通过软物质纳米颗粒的形变效应来提高其在复杂孔隙网络中的扩散效率。拟通过实验观测及分子模拟，从微纳尺度研究软物质纳米颗粒在间隙基质孔隙网络结构中的动力学行为，揭示其扩散的本质机理；阐明粒子的动态形变特性、软硬结构设计、孔隙网络结构参数对扩散的影响规律，获得最优扩散系数。研究结果可为纳米医药的设计提供理论指导及数据支撑，具有重要的学术价值及临床医用价值。

纳米药物在肿瘤诊疗领域广泛应用，但纳米颗粒需要经过复杂的体内输运到达肿瘤细胞以实现其诊疗功能，然而肿瘤组织因其间隙基质合成/降解的紊乱，形成高度粘连的孔隙网络结构，构成了纳米颗粒体内传输的重要物理屏障。本项目通过实验观测及分子模拟，针对纳米颗粒在肿瘤间隙基质中传输困难的问题开展研究：表征临床胃癌肿瘤组织，获得肿瘤间隙基质密度、硬度、纤维排列有序度增加的病理学及物理学特征，通过肿瘤组织去细胞实验获得纳米颗粒在肿瘤间隙基质中的分布特性；构建了纳米颗粒和肿瘤间隙基质网络结构的分子模型，阐明纳米颗粒在孔隙网络结构中的动力学行为，揭示其扩散的本质机理；构建了网络结构及硬度可控的体外水凝胶体系，通过单粒子追踪实验验证分子模型的有效性，并明晰了纳米颗粒性质及网络结构参数对扩散的影响规律；综合分析多参数的协同作用，提出了纳米粒子扩散能力的评估模型，对癌症的个性化诊疗具有重要的指导意义。