Quan Kecheng, Jiang Guimei, Liu Jian, Zhang Zexin, Ren Yijin, Busscher Henk J, van der Mei Henny C, Peterson Brandon W
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P.R. China.
University of Groningen and University Medical Center Groningen, Department of Biomedical Engineering, 9713 AV Groningen, The Netherlands.
Nanoscale. 2021 Mar 4;13(8):4644-4653. doi: 10.1039/d0nr08537e.
Magnetic targeting of antimicrobial-loaded magnetic nanoparticles to micrometer-sized infectious biofilms is challenging. Bacterial biofilms possess water channels that facilitate transport of nutrient and metabolic waste products, but are insufficient to allow deep penetration of antimicrobials and bacterial killing. Artificial channel digging in infectious biofilms involves magnetically propelling nanoparticles through a biofilm to dig additional channels to enhance antimicrobial penetration. This does not require precise targeting. However, it is not known whether interaction of magnetic nanoparticles with biofilm components impacts the efficacy of antibiotics after artificial channel digging. Here, we functionalized magnetic-iron-oxide-nanoparticles (MIONPs) with polydopamine (PDA) to modify their interaction with staphylococcal pathogens and extracellular-polymeric-substances (EPS) and relate the interaction with in vitro biofilm eradication by gentamicin after magnetic channel digging. PDA-modified MIONPs had less negative zeta potentials than unmodified MIONPs due to the presence of amino groups and accordingly more interaction with negatively charged staphylococcal cell surfaces than unmodified MIONPs. Neither unmodified nor PDA-modified MIONPs interacted with EPS. Concurrently, use of non-interacting unmodified MIONPs for artificial channel digging in in vitro grown staphylococcal biofilms enhanced the efficacy of gentamicin more than the use of interacting, PDA-modified MIONPs. In vivo experiments in mice using a sub-cutaneous infection model confirmed that non-interacting, unmodified MIONPs enhanced eradication by gentamicin of Staphylococcus aureus Xen36 biofilms about 10 fold. Combined with the high biocompatibility of magnetic nanoparticles, these results form an important step in understanding the mechanism of artificial channel digging in infectious biofilms for enhancing antibiotic efficacy in hard-to-treat infectious biofilms in patients.
将负载抗菌剂的磁性纳米颗粒以磁靶向方式作用于微米级感染性生物膜具有挑战性。细菌生物膜具有水通道，有助于营养物质和代谢废物的运输，但不足以使抗菌剂深入渗透并杀死细菌。在感染性生物膜中人工挖掘通道涉及通过生物膜磁性推动纳米颗粒以挖掘额外的通道，以增强抗菌剂的渗透。这并不需要精确靶向。然而，尚不清楚磁性纳米颗粒与生物膜成分的相互作用在人工挖掘通道后是否会影响抗生素的疗效。在这里，我们用聚多巴胺（PDA）对磁性氧化铁纳米颗粒（MIONPs）进行功能化，以改变它们与葡萄球菌病原体和细胞外聚合物物质（EPS）的相互作用，并将这种相互作用与磁通道挖掘后庆大霉素对体外生物膜的根除作用相关联。由于氨基的存在，PDA修饰的MIONPs的zeta负电位比未修饰的MIONPs低，因此与带负电荷的葡萄球菌细胞表面的相互作用比未修饰的MIONPs更多。未修饰的和PDA修饰的MIONPs均不与EPS相互作用。同时，在体外培养的葡萄球菌生物膜中使用不相互作用的未修饰MIONPs进行人工通道挖掘比使用相互作用的PDA修饰的MIONPs更能增强庆大霉素的疗效。使用皮下感染模型在小鼠体内进行的实验证实，不相互作用的未修饰MIONPs可使庆大霉素对金黄色葡萄球菌Xen36生物膜的根除作用增强约10倍。结合磁性纳米颗粒的高生物相容性，这些结果是理解感染性生物膜中人工通道挖掘机制以提高患者难治性感染性生物膜中抗生素疗效的重要一步。
