自组装多肽功能化高分子/无机杂化基因和药物共传递体系的研究

Peptide functionalized polymer/inorganic hybrid gene and drug co-delivery systems will be prepared by supermolecular self-assembly. To incorporate different functions including tumor cell targeting, cell-penetrating, endosomal escaping and nuclear localization, various functional peptides will be introduced to the polymer/inorganic hybrid gene and drug co-delivery systems through electrostatic forces and biotin-avidin interactions in aqueous media. p53 plasmid and doxorubicin, an anti-tumor drug, will be loaded in the co-delivery systems. In these co-delivery systems, both the inorganic components for the drug and gene loading (CaCO3 and Ca-P) and the polymer components (natural polymers and their derivatives) for hydrophilic decoration and electrical charge decoration have very good biocompatibilities. Since the functional peptides are introduced through the self-assembly, different types of peptides with different amounts can be introduced to the same delivery system conveniently to overcome different delivery barriers subsequently and to delivery the gene and the drug to particular cells and cell nuclei. In addition, since the functional peptides are introduced through the self-assembly in the aqueous media, the bioactivities of the peptides can be well maintained. The gene transfection activity, drug delivery property and the synergistic therapeutic effect of the co-delivery systems will be investigated. This study will provide theoretical knowledge on the functional drug and gene co-delivery systems.

通过超分子组装制备多肽功能化高分子/无机杂化基因和药物共传递系统，在水溶液中通过静电力、生物素－亲和素作用等分子间力将功能化多肽引入高分子/无机杂化基因和药物共传递系统，赋予其肿瘤细胞靶向、穿膜、内涵体逃逸、核定位功能。共传递系统负载p53基因质粒和抗癌药阿霉素。系统中起负载基因和药物作用的无机组份（CaCO3及Ca-P）以及起亲水修饰、电荷修饰作用的高分子组份（天然高分子及其衍生物）均具有很好的生物相容性。由于功能化多肽组份通过自组装引入，因此可以便利地在同一体系中引入不同种类、数量的功能多肽，克服各种传递屏障，将基因和药物高效传递到特定的细胞及细胞核中。自组装在水溶液中进行，因此能充分保持多肽的生物活性。研究这些功能化共传递系统的基因转染性能、药物传递性能、药物和基因的协同作用，为此类基因和药物共传递系统的研制提供理论依据。

本项目通过超分子自组装制备了系列多肽功能化纳米高分子/无机杂化基因传递系统、药物传递系统、基因与药物共传递系统。在水溶液中通过静电力等分子间力将多种功能多肽引入高分子/无机杂化基因和药物传递系统，赋予其肿瘤细胞靶向、穿膜、内涵体逃逸、核转运功能。研究了这些功能化传递系统的基因转染性能、药物传递性能、药物和基因的协同作用、不同药物的联合及协同作用。系统中无机组份（CaCO3及Ca-P）以及高分子组份（多糖、蛋白质及其衍生物）均具有很好的生物相容性。自组装在水溶液中进行，因此能充分保持多肽的生物活性。由于功能化多肽的引入，传递系统能克服各种传递屏障，将基因和药物高效传递到特定的细胞及细胞核中。传递系统对肿瘤细胞及耐药肿瘤细胞具有良好的抑制效果，部分传递系统通过抑制细胞内P-糖蛋白的功能或表达、下调谷胱甘肽等途径能有效地克服肿瘤多药耐药，在肿瘤治疗方面具有应用前景。此研究为此类基因和药物传递系统的研制提供了理论依据。