多功能环肽纳米管体系的制备及其药物跨膜转运、抗肿瘤活性研究

The limition of chemotherapy is due to the trans-membrane drug transportation and multiple drug resistance(MDR). In order to solve these problems, we combine the advantages of cell-permeable cyclic peptides and cyclic peptides nanotubes, Trypsin inhibitor STFI-1 and p53 tumor suppressor activation sequence PMI were used as the template, a series of cyclic D,L-α; α, β-; γ-; δ-; ε-peptide will be synthesized, the β-sheet-like hydrogen-boned tubular architecture of the self-assembled cyclic peptides will be fabricated, boric acid will be used to label and target the tumor cells and tissues, cell experiments and animals experiments will be used to screen out some valuable sequences which have the anti-tumor activities. The combination effect of anti-tumor drug and cyclic peptide nanotubes will be selected to investigate the membrane transportation and anti-tumor effect. Based on the results, new type of multi-functional peptide nanotubes will be developed for medical treatment.

受限于小分子药物在跨膜转运、多药耐药性等方面的问题，使化学疗法在对肿瘤的治疗上受到了很大的限制。为了解决以上问题，我们结合穿膜环肽和环肽纳米管在作为新型抑癌药物及转运载体方面的优势，以蛋白抑制酶STFI-1环肽和p53肿瘤抑制激活序列PMI为模板，构建系列交替D，L-α、交替α，β-、γ-、δ-、ε-氨基酸序列的环肽分子，调控氨基酸种类，利用分子间氢键、π-π作用及范德华力自组装形成环肽纳米管；硼酸修饰来标记和靶向肿瘤细胞和组织；通过体外细胞和动物实验筛选出具有优异穿膜、自组装和抑制肿瘤细胞能力的序列。我们还将结合现有的小分子药物，系统、深入地研究这些小分子环肽/环肽纳米管对于药物快速转运的能力；深入探讨不同环境下的环肽纳米管释放药物的性能，开发出兼具抗肿瘤和转运药物分子的协同治疗功能的环肽纳米管靶向药物/功能载体来用于医学治疗。

设计、合成了系列基于功能多肽序列的纳米材料，构建了用于靶向肿瘤细胞及其亚细胞器、以及肿瘤微环境的多功能药物和基因递送载体。通过表面的可修饰化位点调控了材料的结构与性能，实现对肿瘤细胞和组织的特异性结合，筛选出了多种低毒高效、性能优良的靶向材料，并进一步构建了可进行光疗、化疗的协同肿瘤治疗系统，结合实时成像等影像学手段研究了这些纳米复合体系对于肿瘤组织的治疗效果。细胞及动物模型实验表明复合体系兼具良好的诊断和治疗功能。在未来的纳米医学和精准医疗等方向具有广阔的应用前景。