基于炎症微环境响应的多糖缀合物高效抗感染研究

Antibiotics are highly specific to prevent and treat bacterial infections, while most of them are effective only at a very high dose due to a lack of selective targeting towards pathological site. Previous studies revealed that polysaccharides such as chitosan or hyaluronan can be a efficient Trojan horse for the delivery of aminoglycoside antibiotics to treat intracellular bacterial infections. This proposal is designed to construct a selective targeting delivery system to treat infectious deseases. In detail, two antibiotics, vancomycin and levofloxacin are conjugated to hyaluronan via a reactive oxygen species (ROS)-responsive or nitric oxide (NO)-responsive linker. One Gram-positive pathogen, Staphylococcus aureus and one Gram-negative pathogen, Pseudomonas aeruginosa, are used to set up two mouse infection models.The accumulation and release of antibiotics in pathological sites are examined. The efficacy of this strategy is evaluated. In this proposal, we hypothesize that the receptor of hyaluronan, CD44 rich in inflammatory conditions will make selective accumulation of hyaluronan-antibiotic conjugates at infectious sites. Excess amount of ROS or NO will be generated during inflammation which break down ROS or NO responsive linker between hyaluronan and antibiotics.The proposal above will open up a new avenue to combat infectious deseases and will be helpful to build up a multidisciplinary cross connection between glycobiology and other fields.

抗生素是治疗各种细菌性疾病的特效药，然而，大多数抗生素进入体内后仅极少一部分作用于病灶部位，是制约其疗效并增加毒副反应风险的根本原因。前期研究表明多糖接枝策略能增加亲水性抗生素在细胞中累积而利于胞内病原菌的清除。本申请拟构建一种基于炎症微环境响应的多糖靶向型抗感染体系：即通过活泼自由基（ROS/NO）响应型连接臂在透明质酸上分别负载万古霉素或左氧氟沙星；建立金色葡萄球菌和铜绿假单胞菌感染肺炎模型，明确炎性部位透明质酸受体CD44高表达与抗生素富集的对应关系，弄清楚活泼自由基的消耗对炎性组织损伤程度及对抗生素释放的影响，阐明上述多糖复合物对细菌性感染肺炎的实际疗效。本申请利用多糖与受体的相互作用实现抗生素在炎性组织富集，通过消耗局部有害的活泼自由基来释放抗生素而不影响药物在局部的弥散与分布，从而为实现抗生素的高效抗感染提供一种新的思路，对促进多糖生物学与其它学科的交叉融合具有一定的指导意义。

抗生素是治疗各种细菌性疾病的特效药，然而，大多数抗生素进入体内后仅极少一部分作用于病灶部位，是制约其疗效并增加毒副反应风险的根本原因。前期研究表明多糖接枝策略能增加亲水性抗生素在细胞中累积而利于胞内病原菌的清除。本项目通过邻苯二胺和酮缩硫醇键作为桥键分子，成功合成了多个多糖复合物，用以负载抗生素；阐明了上述化合物对活泼氮/氧（ROS/NO）的响应及药物释放情况；弄清楚了上述化合物在动物体内的富集、释放及抗感染能力。在该项目的资助下，以通讯作者SCI论文10篇，培养了3名博士、4名硕士，参加了4次国内学术会议，并做了大会报告。该项目利用多糖与受体的相互作用实现抗生素在炎性组织富集，通过消耗局部有害的活泼自由基来释放抗生素而不影响药物在局部的弥散与分布，从而为实现抗生素的高效抗感染提供一种新的思路。