磁靶向抗菌肽的设计、合成以及抗肿瘤研究

Development of antitumor drugs with high selectivity and low toxicity remains a considerable challenge in the field of pharmaceutical research and development. Recently,antimicrobial peptides are gaining more and more attentions due to their unique action mode. However, low enzymatic stability, low tumor accumulation and potent toxicity hinder the in vivo application of natural antimicrobial peptides. Based on our previous studies, we improve the stability and antitumor activity of antimicrobial peptides SPA-1 by peptide modification in this project. Then, we construct a novel type of magnetic targeting antimicrobial peptides by attaching the antimicrobial peptide analogs to the Fe3O4 magnetic nanoparticles. We hope that this magnetic targeting strategy can improve the tumor treatment efficiency of antimicrobial peptides by enhancing tumor selectivity, increasing tumor accumulation and decreasing toxicity to normal tissues. In short, we hope that this construction of the magnetic targeting antimicrobial peptides will contribute to the useful exploration for clinical applications of antimicrobial peptides.

开发高效低毒的抗肿瘤药物在医药研发领域极富挑战性。近些年，抗菌肽由于其独特的作用机制而逐渐引起药学界的广泛关注。然而酶解稳定性差、肿瘤组织蓄积能力低以及潜在的毒性限制了天然抗菌肽的体内应用。在原有工作基础上，本项目拟首先通过结构改造以提高抗菌肽SPA-1的酶解稳定性和抗肿瘤活性。然后将筛选出的抗菌肽与Fe3O4磁纳米颗粒相连而构建一类新型的磁靶向抗菌肽，以提高抗菌肽的肿瘤组织选择性和肿瘤组织蓄积能力，降低抗菌肽对正常组织的毒性，最终提高抗菌肽的肿瘤治疗效率。总之，我们希望通过这种磁靶向抗菌肽的设计为提高抗菌肽的临床应用进行有益的探索。

开发高效低毒的抗肿瘤药物在医药研发领域极富挑战性。抗菌肽由于具有一定的肿瘤选择性以及独特的作用机制而受到广泛关注。但是获得具有临床应用价值的抗肿瘤抗菌肽候选药物面临诸多难题，例如体内毒性，抗肿瘤活性需要提高，体内半衰期短等。本项目对抗菌肽进行改造修饰合成了一系列的类似物，并对这些类似物的抗肿瘤活性、毒性、酶解稳定性以及作用机制进行了研究和筛选工作。在项目执行期间，我们筛选出了具有高抗肿瘤活性、低毒性以及高稳定性的抗菌肽类似物SPA-5，AH-15。得到了具有多重作用机制的吖啶-NLS偶联物。我们还发现了具有高抗肿瘤活性的自组装抗菌肽C16-camel。另外，还发展了一类具有肿瘤靶向性的抗菌肽bombesin-2，将其连接到磁纳米颗粒之后，其抗肿瘤活性显著提高。我们的工作为发展高效低毒的抗菌肽类抗肿瘤药物进行了较为系统的研究，为抗菌肽类抗肿瘤药物的研发提供了丰富的理论支持。