实体瘤组织的低渗透性使得常规纳米载体难以进入肿瘤内部，严重影响抗肿瘤纳米制剂的功效。纳米载体的粒径和实体瘤细胞间坚实的细胞外基质、较高的内流体压力是影响药物瘤内渗透的关键因素。在前期研究基础上，本课题拟构建一种肿瘤组织高渗透性的多级纳米载体系统（MGNPs），由聚己内酯-缩酮聚氨基酯（PCL-KPAE）胶束、iRGD修饰的明胶纳米粒（iRGD-GNPs）和透明质酸酶（HAase）通过静电作用组装构成。其优势特点是：HAase可降解肿瘤细胞外基质从而降低内流体压力；GNPs在血液中稳定且可被肿瘤组织丰富的MMP-2降解，释放出小粒径的PCL-KPAE胶束易于进入实体瘤内部；KPAE遇酸降解导致溶酶体胀破使得表柔比星释放，发挥治疗功效。本课题将在分子、细胞和动物水平上，系统研究MGNPs肿瘤渗透作用的影响因素，探索促进纳米载体肿瘤渗透性的有效途径，为抗肿瘤靶向纳米制剂研究提供实验和理论依据。

The main obstacle for cancer chemotherapy is the poor solid tumor permeability which blocks the penetration of the conventional nanocarrier into the internal tumor. The smaller size nanocarrier and penetration promoting factor of tumor is a promising approach to overcome the barrier. However, the smaller nanocarrier tends to be cleared in the blood circulation. Our research team previously prepared a gelatin nanoparticle that is degraded by matrix metalloproteinase (MMP-2) in the tumor tissue. Based on this observation, we plan to construct a tumor-microenvironment-responsive multistage nanocarrier, which allows us to prepare the gelatin nanoparticles (GNPs) loading epirubicin micelles and penetration promoting factor hyaluronidase (HAase) and gelatin modified with iRGD for enhancement of the permeability of tumor vessel as the polymer carrier. The larger size GNPs will have better stability in the blood circulation, and the smaller size epirubicin micelles and HAase will be released to easily penetrate into the internal tumor following the degradation of gelatin by the MMP-2 in the tumor tissue. KPAE will be degraded into small molecules at pH5 in lysosome, and the high osmotic pressure in lysosome caused by small molecules will lead to the burst of lysosome, thus the epirubicin will be released from the micelles and lysosome to cytoplasm. The influence of the multistage nanocarrier on the penetration promoting effects and histophysiological characters of tumor will be investigated at the levels of molecular, cellular and animal model. We will focus on the mechanism of the nanocarrier for the enhancement of tumor penetration ability and targeting to internal tumor cells. It is expected to establish an experimental and theoretical basis for the exploitation of nano-delivery system and the clinical therapy of cancer with high efficiency.