基于多肽骨架的肿瘤靶向双靶点药物Janus型树枝状化合物的研究

Based on our previous work about dendrimers and target drug delivery, the latest study from other scholars, and the strategy of dendritic drug system design, we first present to study the novel amphiphilic Janus peptide dendrimers as the model "(tumor-targeting peptide)m-dendritic carrier-(dual target drug)n", which are cutting-edge research in dendrimer field. Tumor targeting peptide (based on αvβ3-intergrin ligand) and dual-target anti-tumor drugs (target TS and DNA TodoⅠ) are grafted on dendritic peptide carrier, and the ratio of targeting moieties/ drugs can be controlled by the dendrimer carrier. This project will establish the methodology of the synthesis of this type of dendrimers, study the conformational behavior of the peptide dendrimers as artificial protein. Moreover, the relationship between targeting effect and anti-tumor activity, the dendritic approach, the micelles self-assembled from Janus dendrimers, and the degradation of dendrimers as domino also intersete us. Summarily, the designed dendrimers, which are totally different from conventional tumor targeting drugs, are promissing to exhibit extraordinary properties such as tumor targeting effect, drug delivery and drug release. This project may solve the problems of the shortcoming of current studies, and provide groundbreaking approach for drug delivery system.

在课题组长期从事树枝状化合物和靶向药物研究基础上，结合国外目前的研究成果，首次提出运用树枝状化合物设计理念，研究具有精确结构的两亲性Janus型"(肿瘤靶向肽片段)m-肽型树枝状载体-(双靶点药物)n"分子的研究设想，研究内容是Dendrimers领域的前沿工作。将αvβ3受体识别功能的肿瘤亲和性靶向多肽载体以及TS及DNA Todo Ⅰ双靶点的抗肿瘤治疗药物相偶联，并通过多肽型树枝状载体调节靶向肽与药物的偶联比例，建立方法学，研究空间结构拟球形的"蛋白"型分子独特的性质、靶向性和生物活性的关系，探明靶向特征、树枝状效应、胶束形成及"多米诺骨牌"降解等特性。本项目研究的Janus型分子将与传统研究的肿瘤靶向分子完全不同，在靶向性、体内转运、药物缓释等方面具有特殊性质，有助于解决传统设计的弊端并突破现有研究瓶颈，为突破性结构靶向药物的研制创立新思路和新方法。

在课题组长期从事树枝状化合物和靶向药物研究基础上，结合国外目前的研究成果，首次提出运用树枝状化合物设计理念，研究具有精确结构的两亲性Janus型“(肿瘤靶向肽片段)m-肽型树枝状载体-(双靶点药物)n”分子。设计并合成了一系列双靶向抗肿瘤5-FU前药和双靶向抗炎萘普生前药、基于RGD的树枝状5-氟尿嘧啶前药、Janus型树枝状酸性氨基酸-树枝状前药、Janus型抗菌性树枝分子和亲脂性树枝状抗氧化分子、基于谷氨酸寡肽的骨靶向前药、葡萄糖和RGD肽双重修饰的脑肿瘤靶向脂质体、双分枝生物素修饰的乳腺癌靶向脂质体配体等，并通过多肽型树枝状载体调节靶向肽与药物的偶联比例，建立方法学，研究空间结构拟球形分子独特的性质、靶向性和生物活性的关系，探明靶向特征、树枝状效应、胶束形成及“多米诺骨牌”降解等特性。本项目研究的Janus型分子将与传统在靶向性、体内转运、药物缓释等方面具有特殊性质，有助于解决传统设计的弊端并突破现有研究瓶颈，为突破性结构靶向药物的研制创立新思路和新方法。