Yu Qilin, Deng Tian, Lin Fang-Chu, Zhang Bing, Zink Jeffrey I
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, People's Republic of China.
Department of Chemistry & Biochemistry, University of California, Los Angeles, California 90095, United States.
ACS Nano. 2020 May 26;14(5):5926-5937. doi: 10.1021/acsnano.0c01336. Epub 2020 Apr 27.
Pathogenic biofilms protected by extracellular polymeric substances frequently compromise the efficiency of antibacterial drugs and severely threaten human health. In this study, we designed a multi-stimuli-responsive magnetic supramolecular nanoplatform to co-deliver large and low molecular weight drugs for synergistic eradication of pathogenic biofilms. This co-delivery platform was composed of mesoporous silica nanoparticles (MSNs) with large pores (MSNLP) capped by β-cyclodextrin (β-CD)-modified polyethylenimine (PEICD) and adamantane (ADA)-decorated MSNs containing a magnetic core (MagNP@MSNA) capped by cucurbit[6]uril (CB[6]). The host MSNs (, MSNLP@PEICD) and the guest MSNs (, MagNP@MSNA-CB[6]) spontaneously form coassemblies (), based on the host-guest interactions between β-CD and ADA. Under the stimulus of pathogen cells together with heating by an alternating magnetic field (AMF), the supramolecular coassemblies released both the large molecular weight antimicrobial peptide melittin (MEL) and the low molecular weight antibiotic ofloxacin (OFL) with high efficiency. As compared to free drugs (MEL and OFL) or unattached MSNs ( or ), the drug-loading coassemblies (-MEL+-OFL) exhibited much higher capacity for biofilm eradication, thoroughly removing biofilm biomass and killing the pathogenic cells, and displaying no obvious toxicity to mammalian cells. This strong antibiofilm capacity was severely decreased when the host and guest components were prevented from coassembling but administered simultaneously, revealing the critical role of the supramolecular assembly in biofilm removal. Moreover, an implantation model showed that the coassemblies eradicated the pathogenic biofilms from the implants, preventing host tissue damage and inflammation. Therefore, the co-delivering and multi-stimuli-responsive nanocarriers could overcome the anti-infection difficulties during treatment of infections because of protective biofilms.
由胞外聚合物保护的致病性生物膜常常会降低抗菌药物的疗效，并严重威胁人类健康。在本研究中，我们设计了一种多刺激响应性磁性超分子纳米平台，用于共同递送大分子和小分子药物，以协同根除致病性生物膜。该共同递送平台由大孔介孔二氧化硅纳米颗粒（MSNLP）组成，其被β-环糊精（β-CD）修饰的聚乙烯亚胺（PEICD）封端，以及含有磁性核心的金刚烷（ADA）修饰的MSN（MagNP@MSNA），其被葫芦[6]脲（CB[6]）封端。主体MSN（MSNLP@PEICD）和客体MSN（MagNP@MSNA-CB[6]）基于β-CD和ADA之间的主客体相互作用自发形成共组装体。在病原体细胞的刺激以及交变磁场（AMF）加热的作用下，超分子共组装体高效释放大分子抗菌肽蜂毒素（MEL）和小分子抗生素氧氟沙星（OFL）。与游离药物（MEL和OFL）或未附着的MSN（或）相比，载药共组装体（-MEL+-OFL）表现出更高的生物膜根除能力，能彻底清除生物膜生物质并杀死致病细胞，且对哺乳动物细胞无明显毒性。当主体和客体成分无法共组装但同时给药时，这种强大的抗生物膜能力会严重下降，这揭示了超分子组装在生物膜清除中的关键作用。此外，植入模型表明共组装体可根除植入物上的致病性生物膜，防止宿主组织损伤和炎症。因此，这种共同递送和多刺激响应性纳米载体可以克服因保护性生物膜导致的感染治疗中的抗感染困难。
