主-被动协同靶向纳米高分子载体的自组装制备及其抗肿瘤作用机制研究

临床证实Allovectin-7等纳米基因药物能有效提高抗肿瘤效果，但靶向性差及转染效率低导致其预后仍不理想。因此，构建抗特异体靶向和高转染效率药物输送体系是基因治疗关键。前期,我们设计合成系列不同嵌段高分子；依据Flory参数（χ）调控嵌段组成及包装因子（β）,研究了组装体维度与组成的标度关系；系统研究发现温敏被动靶向促进药物瘤内富集高达4倍，肿瘤杀伤显著增强。基于上述研究，本课题将进一步针对肿瘤微环境特点，运用可控聚合设计合成抗体Her2偶联温敏篏段聚合物Fab-PNIPAM/PEG/PLA；通过可控自组装技术包裹SiRNA,构建主被动协同靶向泡囊载体；并精细裁剪载体，实现抗体主动靶向、温敏被动靶向及胞内可控释放等性能；系统探讨自组装行为与载体的维度、性能、核酸药物负载率、协同靶向性、体内外基因沉默效率的关系；阐明协同靶向及抗Her2高表达肿瘤机制，为临床基因治疗提供新思路和理论依据。

Clinical reports showed that nano gene medicine such as Allovectin-7 has improved the therapeutic effects. However, its low targeting and low transfection efficiency resluted in unfavourable prognosis. Thus, construction an antibody specifically targeted and high transfection efficient drug delivery system is the key for tumor gene therapy. Previously, we have prepared series of narrow distributed block copolymers by controlled polymerization and sellfassembly.Referring to the Flory parameter (χ) and tuning the composition and packing parameter (β),we investigated the scaling law between the assembly dimension and its composition. The systemically showed that increase temperature enhanced the drug intratumor accumulation with 4 times with obviously enhanced tumor killing. Based on these observation, in this proposal, a Her2 antibody targeted temperature sensitive block copolymer Fab-PNIPAM/PEG/PLA will be further synthesized firstly. Then the SiRNA will be entapped into the vesicle. And the intelligent active/passive cooperative targeting nanocarries will be constructed by the controlled selfassembly technology and referring to the tumor microenvironmen. The virus-like properties including the antibody active targeting, temperature promoted endocytosis, endosomal controlled release will be realized by finely carrier's structural tailoring. And the including mophology, We will systemically investigate the correlations between the selfassembly behavior and carrier's dimension, the carrier's properties, the nucleic acid drug loading efficiency, the active and passive cooperative targeting efficiency, in vitro/vivo gene silencing efficincy. Then we will further reveal the targeting and anti-Her2 over-expression tumor mechnism. The successful accomplish of this project could provid a new idea and theory for clinical gene therapy.