通常纳米释药体系在肿瘤中的分布并不均匀，不充分的药物递送不仅削弱了治疗效果，还会引起未充分摄取药物的肿瘤细胞（特别是深部肿瘤组织）产生耐药性。本课题从粒径转换、联合给药两个方面构建兼具长循环、高渗透特性的靶向多级纳米释药体系，以期实现纳米载体在肿瘤组织中充分的药物递送及序贯释药。采用无机-有机复合纳米材料组成小粒径纳米载体（SN），姜黄素、阿霉素分别以吸附、键合的方式包载于SN，进而通过3或4-arm PEG共价连接组装成较大粒径释药体系（LN），在肿瘤组织利用酶促断裂反应释放小的纳米载药库SN，研究载体粒径及粒径转换对肿瘤组织渗透、入胞的影响；考察序贯释药协同抗肿瘤作用，评价有效杀死肿瘤细胞（表层及深部）并抑制肿瘤耐药的靶向治疗效果。体内外生物学实验探讨运用粒径转换及序贯释药方式充分杀伤肿瘤细胞的可行性，为构建高效靶向纳米释药体系提供新的多模式设计策略。

Despite the great achievements that nanomedicines have obtained so far, deep penetration of nanomedicines into tumors is still a major challenge in tumor treatment. Inadequate drug delivery not only weakens the therapeutic effect, but also causes drug resistance of tumor cells, especially for deep tumor tissue. So，based on variable particle size and drug combination therapy, a multistage nano-drug delivery system with multi-functional properties, including long circulation time, high permeability and cellular uptake, is constructed to realize abundant drug delivery and sequential drug release in the tumor tissue. Inorganic-organic composite nanomaterial is used to synthesize small-size nano-carriers (SN, MSNs@PMLA-iRGD). Curcumin and doxorubicin were encapsulated in SN by adsorption and bonding. Then, SN units are covalently linked via 3- or 4-armed polyethylene glycol (PEG) to form large-size nano-carriers (LN). When the LN reach to the tumor site by the enhanced permeability and retention (EPR) effect, they would be cleaved into SN in the presence of high-expression enzyme, resulting in high tumor penetration and retention. Besides, sequential release of curcumin and doxorubicin is utilized to enhance the chemotherapy effect, thus improving the anticancer activity. In vivo and in vivo experiments would be performed to investigate the effects of size-tunable property and sequential drug release on anti-tumor activity and the inhibition of drug resistance of tumor cells, providing a new multi-mode strategy for designing ideal tumor targeting nano-drug delivery systems of high efficiency.