大分子自组装形成高效抗菌肽囊泡的研究

Resistance of microbial pathogens to antibiotics is an increasingly serious problem, which result in urgency for new type antibiotics development. In this proposal,two designed routes were used to synthesis peptide-amphiphilic- copolymers:(1) PCL-b-PAMA were used as macroinitiator to copolymerize lysine-NCA with hydrophobic amino acid-NCA monomers to prepare antimicrobial peptides(PCL-b-PAMA-g-AMP);(2)4-(hydroxymethyl) phenyl acetic acid were used as initiator to prepare ploy(ε-caprolactone)with end group -COOH (PCL-COOH),and n-propylamine were used to initiate lysine-NCA and hydrophobic amino-acid-NCA random copolymerize to prepare antimicrobial peptide, the two polymers can form the amphiphilic copolymer(after deprotected)with DCC/HOSu as the condensation agent. The two kinds of amphiphilic copolymers can dissolve in water and self-assemble to antimicrobial- peptide-vesicles which the peptides disperse on the surface of the vesicles. Due to the antimicrobial peptides have the different mechanism from traditional antibiotics, so the antimicrobial peptides have low propensity to induce resistance in pathogens. Antimicrobial-peptide-vesicles embedded with traditional antibiotics, have two kind of acting mechanism to pathogens at same time, which will decrease the resistance to the new antibiotic in pathogens. The relationship between the ratio of antimicrobial peptide/PCL, composition of amino acid in peptide and length of peptide to the antimicrobial ability of the antimicrobial-peptide-vesicles were studied.

传统抗生素的长期使用导致细菌耐药性增加，故开发新型抗菌剂迫在眉睫。本项目拟用两条路线合成含抗菌肽的两亲性聚合物：1.PCL-b-PAMA为大分子引发剂，引发赖氨酸-NCA与疏水氨基酸无规共聚制备抗菌肽；2.以羟甲基苯基乙酸为引发剂，制备一端含羧基的PCL，另外以正丙胺为引发剂，赖氨酸-NCA与疏水氨基酸无规共聚合成末端为氨基的多肽，两种聚合物缩合成两亲性聚合物。所得嵌段共聚物在水中都能够自组装形成抗菌肽囊泡,抗菌肽舒展在囊泡表面。抗菌肽的杀菌机理与传统抗生素不同, 病原微生物对抗菌肽难以产生耐药性。包埋了适量传统抗生素的多肽囊泡具有两种杀菌机制，它们的协同作用有望降低病原微生物对抗菌药的耐药性。本课题将研究多肽与高分子链段的比例、多肽组分及长度对囊泡抗菌性能的影响。同时研究细菌对抗菌肽囊泡的耐药性，有利于开发新的高效抗菌剂体系。

细菌感染诱导多类疾病是长期困扰人类社会的问题，诸如癌症在内多种疾病都会在病变处由于细菌感染产生并发症，为疾病的治疗增加很高难度。抗生素是一种高效的杀菌药物，但随着受众人群的增加以及治疗过程中给药制度的不严谨，会诱导细菌产生耐药性，为持续性治疗带来很大挑战。为此，在治疗癌症的过程中，赋予药物载体一定的抗菌功能，能在不诱导耐药性细菌的前提下进行杀菌和药物运输是一种很好的治疗手段。遗憾的是，传统药物载体不具有抗菌功能，因此，如何将不引起耐药性产生的杀菌功能与药物载体结合起来，设计并合成兼具抗菌和抗癌药物输送功能的抗菌载体材料，具有重要的科学意义和临床意义。在癌症治疗过程中，囊泡是一类高效的药物载体。但癌症病人往往在长时间的治疗周期中，由于免疫理的下降而受到细菌感染。抗菌肽囊泡可以解决这一难题。另外，在抗菌肽囊泡上修饰上叶酸，使抗菌肽囊泡具有靶向作用。另外我们设计并合成了类抗菌肽聚合物，即用疏水的有机小分子替代疏水氨基酸，与赖氨酸共聚合成交替共聚类抗菌肽。该类肽共聚物在水溶液中能组装形成抗菌肽囊泡。该囊泡在骨修复过程中，不仅能替代抗生素防止感染，同时还可以包载生长因子促进骨头生长。所合成的抗菌肽均具有较好的抗菌性和生物相容性，更重要的是，通过抗菌机理的研究，我们发现这些抗菌肽共聚物具有与天然抗菌肽相似的抗菌机理，即膜破坏机理。这种抗菌机理使得细菌对这些抗菌肽共聚物难以产生耐药性，因此抗菌肽共聚物在抗感染治疗领域有着潜在的应用价值。