兼具主动靶向性和程序式环境响应的仿生纳米载体的研究

In the study of cancer-targeting carriers, to improve the selectivity of the carrier during the process of transportation, absorption and release is very important. Although in recent years, the research of enhancing tumor cell absorption through targeted ligands modification have made some progress, the nano-carrier system combining receptor mediated active targeting and programmed reaction of the micro environment in and out of the tumor cells is scarce to date..This subject is inspired by natural lipoprotein, using electrostatic and hydrophobic interactions, combining lipids structure unit together with peptide and polyaminoacid, to design and build up a multi-layer nano structure: PEG, targeting peptide and poly histidine form the periphery to avoid the elimination of RES system and achieve the receptor mediated absorption selectivity, tumor microenvironment pH response and enzyme response; the middle layer was composed by poly amino acid and lipid structure, mainly support the nano carrier structure and assist endosome escape; The inner layer composing hydrophobic drugs and dendritic peptide-gene conjugates can help the nucleus location and expression of a gene. Based on the systematic research of the synthesis and structure-activity relationship of such type of nanomaterials, further studies concerning about the absorption, transportation and targeting mechanism of this nanomaterial will be carried out, and providing novel ideas, important experiment and theoretical basis for the research of novel nanocarriers.

在肿瘤靶向载体研究中，提高载体在转运、摄取、释放等过程中的选择性至关重要。尽管近年来通过靶向配体修饰等手段增强肿瘤细胞摄取的研究已取得一定进展，但将受体介导的主动靶向性与针对肿瘤细胞内外微环境的程序式响应性结合起来的纳米载体系统却少有报道。本课题受天然脂蛋白的启发，巧妙地利用静电和疏水相互作用，将脂质结构单元与多肽和聚氨基酸结合，设计并构建了多层次的纳米复合结构：外层由PEG、靶向多肽和聚组氨酸构成，可以避免RES系统清除、实现受体介导选择性摄取、肿瘤微环境pH响应和酶响应；中间层由聚氨基酸和脂质构成，主要支撑纳米载体的结构和辅助内涵体逃逸；内层由疏水性药物和分枝状多肽-基因复合物等构成，可以协助基因的细胞核定位。本课题将在系统研究该类纳米材料的合成及构效关系的基础上；进一步深入研究其在多种不同肿瘤模型中的转运、摄取及靶向机制等。为新型纳米载体的研究提供新的思路和重要的实验与理论依据。

在肿瘤靶向载体研究中，提高载体在转运、摄取、释放等过程中的选择性至关重要。尽管近年来通过靶向配体修饰等手段增强肿瘤细胞摄取的研究已取得一定进展，但将受体介导的主动靶向性与针对肿瘤细胞内外微环境的程序式响应性结合起来的纳米载体系统却少有报道。本项目将脂质结构单元与多肽和聚氨基酸结合，设计并构建了多层次的纳米复合结构：外层由PEG、靶向多肽和聚组氨酸构成，可以避免RES系统清除、实现受体介导选择性摄取和肿瘤微环境pH响应；中间层由聚氨基酸和脂质构成，主要支撑纳米载体的结构和辅助内涵体逃逸；内层包裹了疏水性药物，可以协助基因的细胞核定位。本课题在系统研究该类纳米材料的合成及构效关系的基础上；进一步深入研究其在多种不同肿瘤模型中的转运、摄取及靶向机制等。本项目的研究为后续靶向抗肿瘤药物制剂研发打下了很好的基础。在本项目的资助下，共发表研究论文20余篇，全部为SCI收录论文；申请了2项国家发明专利，1项PCT专利，其中1项已经授权。