基于构象工程的脂质体载药系统肿瘤主动靶向新策略研究

随着基于化学键的分子工程的成熟，化学下一个重大挑战将是构象工程，即像蛋白质那样对分子构象进行精确控制来实现更复杂的功能。前期我们经过近十年的探索，成功通过构象工程方法，在金纳米粒子上实现了对柔性多肽构象的控制，制备出了全新的人工抗体：金抗体。在此基础上，本项目拟在更具挑战性且更具医学应用前景的脂质体上，探索通过构象工程方法赋予脂质体特异性识别表皮生长因子受体(EGFR)的功能，发展载药脂质体主动靶向肿瘤组织的全新策略，提高药物靶向效率及肿瘤治疗效果。项目前期探索表明，这种新型靶向脂质体可提高肿瘤组织药物富集率至临床应用的脂质体药物Doxil的5倍左右，显示了良好的前景。本项目将在此初步探索成功的基础上，进一步优化靶向载药脂质体的制备方法，在分子水平上测定其与EGFR的特异性结合常数，在细胞水平上评估其细胞毒性及与细胞表面EGFR结合的特异性，并在动物水平上验证药物的靶向性和抗肿瘤活性。

As the chemical bond-engineering becoming a mature technology, the next era of chemistry would be "conformational engineering", pursuing creating special functions through precise control of the conformation of large molecules as natural proteins fold. Previously, we had successfully achieved precise control of the conformation of flexible peptides on gold nanoparticles through conformation engineering, and created a novel type of artificial antibody based on gold nanoparticles, denoted as Goldbody. Based on the success of Goldbody, the current project is to create an EGFR-recognizing function through conformational engineering on liposomal drug delivery system, a more challenging system with huge potential for medical applications, towards a significantly increased active-targeting efficiency and drug enrichment for tumor therapy. Our preliminary exploration has already demonstrated that the enrichment rate of this new targeted liposome in tumor tissue is about 5 times as high as that of Doxil, a widely used clinical drug. This project intends to further optimize the synthesis and formulation of the tumor-targeting Doxorubicin-loaded liposome, as well as to characterize the specific binding affinity of the liposomes with EGFR at the molecular level, to evaluate the cytotoxicity and the specificity of the liposomes with EGFR at the cell level, and to verify the targeting and antitumor activity of the drugs at the animal level.