In-biofilm generation of nitric oxide using a magnetically-targetable cascade-reaction container for eradication of infectious biofilms.

Abstract

Cascade-reaction chemistry can generate reactive-oxygen-species that can be used for the eradication of infectious biofilms. However, suitable and sufficient oxygen sources are not always available near an infection site, while the reactive-oxygen-species generated are short-lived. Therefore, we developed a magnetic cascade-reaction container composed of mesoporous Fe₃O₄@SiO₂ nanoparticles containing glucose-oxidase and l-arginine for generation of reactive-oxygen-species. Glucose-oxidase was conjugated with APTES facilitating coupling to Fe₃O₄@SiO₂ nanoparticles and generation of H₂O₂ from glucose. l-arginine was loaded into the nanoparticles to generate NO from the H₂O₂ generated. Using an externally-applied magnetic field, cascade-reaction containers could be homogeneously distributed across the depth of an infectious biofilm. Cascade-reaction containers with coupled glucose-oxidase were effective in killing planktonic, Gram-positive and Gram-negative bacteria. Additional efficacy of the l-arginine based second cascade-reaction was only observed when H₂O₂ as well as NO were generated in-biofilm. <i>In vivo</i> accumulation of cascade-reaction containers inside abdominal <i>Staphylococcus aureus</i> biofilms upon magnetic targeting was observed real-time in living mice through an implanted, intra-vital window. Moreover, vancomycin-resistant, abdominal <i>S. aureus</i> biofilms could be eradicated consuming solely endogenous glucose, without any glucose addition. Herewith, a new, non-antibiotic-based infection-control strategy has been provided, constituting a welcome addendum to the shrinking clinical armamentarium to control antibiotic-resistant bacterial infections.