Beijing Advanced Innovation Centre for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, PR China.
Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, PR China.
Nanoscale. 2022 Oct 27;14(41):15291-15304. doi: 10.1039/d2nr02026b.
The epidemic of multidrug-resistant Gram-negative bacteria is an ever-growing global concern. Polymyxin B (PMB), a kind of "old fashioned" antibiotic, has been revived in clinical practice and mainly used as last-line antibiotics for otherwise untreatable serious infections because the incidence of the resistance to PMB is currently relatively low in comparison with other antibiotics owing to the unique bactericidal mechanism of PMB. However, serious adverse side effects, including nephrotoxicity and neurotoxicity, hamper its clinical application. Herein, we describe the development of a nanoparticle that can target sites of inflammation and forcedly release PMB specifically in the area of Gram-negative bacteria. This particle was constructed through the electrostatic self-assembly of hyaluronic acid (HA) and PMB molecules in order to realize the safe and effective treatment of pneumonia. After systemic administration, PMB-HA nanoparticles were found to actively accumulate in the lungs, precisely target the CD44 receptors over-expressed on the membrane of activated endothelial cells in inflammatory sites, and then come into contact with the bacteria resident in the damaged alveolar-capillary membrane. Due to the electrostatic and hydrophobic interactions between PMB and the lipopolysaccharide (LPS) in the outer membranes of bacteria, the PMB molecules in the PMB-HA nanoparticles are expected to escape from the nanoparticles to insert into the bacteria competitive binding with LPS. Through shielding the cationic nature of PMB, PMB-HA nanoparticles also possess outstanding biosafety performance in comparison to free PMB. It is thus believed that this smart delivery system may pave a new way for the resurrection of PMB in the future clinical treatment of bacterial inflammatory diseases.
耐药革兰氏阴性菌的流行是一个日益严重的全球性问题。多粘菌素 B（PMB）是一种“老式”抗生素，由于其杀菌机制独特，与其他抗生素相比，目前对 PMB 的耐药率相对较低，因此在临床实践中重新得到应用，主要作为其他治疗方法无效的严重感染的最后一线抗生素。然而，严重的不良反应，包括肾毒性和神经毒性，阻碍了其临床应用。在此，我们描述了一种纳米颗粒的开发，该纳米颗粒可以靶向炎症部位，并在革兰氏阴性菌区域强制释放 PMB。该颗粒通过透明质酸（HA）和 PMB 分子的静电自组装构建而成，以实现肺炎的安全有效治疗。系统给药后，发现 PMB-HA 纳米颗粒在肺部积极积聚，精确靶向炎症部位激活的内皮细胞膜上过度表达的 CD44 受体，然后与驻留在受损肺泡毛细血管膜中的细菌接触。由于 PMB 与细菌外膜中的脂多糖（LPS）之间的静电和疏水相互作用，PMB-HA 纳米颗粒中的 PMB 分子有望从纳米颗粒中逃脱，插入细菌，与 LPS 竞争结合。通过屏蔽 PMB 的阳离子性质，与游离 PMB 相比，PMB-HA 纳米颗粒还具有出色的生物安全性。因此，人们相信这种智能递药系统可能为未来临床治疗细菌炎症性疾病中 PMB 的复活开辟新途径。
