Ferumoxytol is a nanoparticle formulation approved by the U.S. Food and Drug Administration for systemic use to treat iron deficiency. Here, we show that, in addition, ferumoxytol disrupts intractable oral biofilms and prevents tooth decay (dental caries) via intrinsic peroxidase-like activity. Ferumoxytol binds within the biofilm ultrastructure and generates free radicals from hydrogen peroxide (H2O2), causing in situ bacterial death via cell membrane disruption and extracellular polymeric substances matrix degradation. In combination with low concentrations of H2O2, ferumoxytol inhibits biofilm accumulation on natural teeth in a human-derived ex vivo biofilm model, and prevents acid damage of the mineralized tissue. Topical oral treatment with ferumoxytol and H2O2 suppresses the development of dental caries in vivo, preventing the onset of severe tooth decay (cavities) in a rodent model of the disease. Microbiome and histological analyses show no adverse effects on oral microbiota diversity, and gingival and mucosal tissues. Our results reveal a new biomedical application for ferumoxytol as topical treatment of a prevalent and costly biofilm-induced oral disease.

Biofilms are surface-bound, structured microbial communities underpinning persistent bacterial infections. Biofilms often create acidic pH microenvironments, providing opportunities to leverage responsive drug delivery systems to improve antibacterial efficacy. Here, the antibacterial efficacy of novel formulations containing pH-responsive polymer nanoparticle carriers (NPCs) and farnesol, a hydrophobic antibacterial drug, were investigated. Multiple farnesol-loaded NPCs, which varied in overall molecular weight and corona-to-core molecular weight ratios (CCRs), were tested using standard and saturated drug loading conditions. NPCs loaded at saturated conditions exhibited ~300% greater drug loading capacity over standard conditions. Furthermore, saturated loading conditions sustained zero-ordered drug release over 48 hours, which was 3-fold longer than using standard farnesol loading. Anti-biofilm activity of saturated NPC loading was markedly amplified using Streptococcus mutans as a biofilm-forming model organism. Specifically, reductions of ~2–4 log colony forming unit (CFU) were obtained using microplate and saliva-coated hydroxyapatite biofilm assays. Mechanistically, the new formulation reduced total biomass by disrupting insoluble glucan formation and increased NPC-cell membrane localization. Finally, thonzonium bromide, a highly potent, FDA-approved antibacterial drug with similar alkyl chain structure to farnesol, was also loaded into NPCs and used to treat S. mutans biofilms. Similar to farnesol-loaded NPCs, thonzonium bromide-loaded NPCs increased drug loading capacity ≥ 2.5-fold, demonstrated nearly zero-order release kinetics over 96 hours, and reduced biofilm cell viability by ~6 log CFU. This work provides foundational insights that may lead to clinical translation of novel topical biofilm-targeting therapies, such as those for oral diseases.

Clinicians may consider the microsurgery as an effective way of retreatment as well as nonsurgical retreatment depending on the clinical situations.

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