基于肿瘤细胞及细胞外基质构建协同抗肿瘤效应的聚苹果酸纳米释药体系

构建肿瘤细胞和细胞外基质双重靶向的纳米释药体系，以期达到杀灭肿瘤细胞、抑制肿瘤转移的目的。以β-聚苹果酸（PMLA）及其疏水衍生物β-聚苹果酸苄基酯（PMLABz）为原料，将分子修饰穿膜肽（DMA-TAT）、抗肿瘤药物（DOX）、肿瘤转移抑制剂赖氨酰氧化酶单克隆抗体（LOXab）、酸敏聚合物分别设计在PEG化接枝或嵌段共聚物中，溶剂诱导自组装法制备功能化纳米胶束，通过穿膜肽特异性实现载体高效靶向入胞作用，利用载体酶敏、酸敏特性实现药物在特定靶位的释放。核磁、质谱等表征嵌段、接枝共聚物结构，荧光探针法研究聚合物的自组装行为，探讨PEG、疏水性药物取代度与聚合物配比等对胶束稳定性的影响；评价分子修饰对穿膜肽特异性介导作用、功能化胶束与肿瘤细胞的相互作用、体内分布及各功能分子协同抗肿瘤作用；体内外药效学研究双重靶向对抑制肿瘤生长与转移的作用与机制，为肿瘤靶向纳米释药体系提供新的协同靶向设计策略。

This project is to develop a multifunctional nano-drug delivery system targeting both tumor cells and extracellular matrix (ECM), in order to kill tumor cells and inhibit tumor metastasis simultaneously. Poly(β-L-malic acid) (PMLA) and its’ hydrophobic derivatives, Poly(β-benzyl malate) (PMLABz) as carrier, molecular modified-penetrating peptide (transactivator of transcription (TAT) peptide, TAT-DMA), antitumor drug(doxorubicin, DOX et al), lysyloxidase monoclonal antibody(LOXab) and acid-sensitive polymer poly(L-histidine)-b-poly(ethylene glycol) (pHis-PEG) are designed in two groups of PEGlyated block or graft copolymers. Functional self-assembled drug delivery systems (SADDS) are prepared by a solvent-induced self-assembly method. The targeting and membrane-penetrating effects of drug delivery system will be further realized by endowing cell-penetrating peptides with specificity. Payload drugs will be released by enzyme and pH triggered drug release mechanism in the specific targeting site. The structure of the block or graft copolymers will be confirmed by NMR and MS. The self-assembly behavior of the polymers will be observed by pyrene or DPH as a fluorescent probe. The influence of the substitution degree of PEG, hydrophobic drug and the ratio of the copolymers on the stability of the micelle will be discussed. Flow cytoMetry, confocal fluorescence microscopy and in vivo imaging system will be employed to evaluate molecular modification approach for the specific mediated role of cell penetrating peptide, the interaction between the nanomicelle and tumor cells, drug distribution and synergistic antitumor effects and mechanisms of different functional molecular. Pharmacodynamics studies in vivo and in vitro will be performed to investigate the inhibition of the tumor growth and metastasis. This research would provide a new synergistic targeted strategy for tumor targeted nano-drug release systems.