Biofilm Elimination and Caries Prevention using Multifunctional Nanocatalysts

点击翻译按钮获取中文摘要

Current modalities for preventing dental caries are insufficient, particularly when biofilms rapidly accumulate under cariogenic conditions in susceptible individuals, requiring new approaches. In the previous funding period, we studied the potential of catalytic (peroxidase mimics) iron oxide nanoparticles (IONP) for controlled, pH- dependent activation of hydrogen peroxide as a novel antibiofilm and anticaries treatment. We found that IONP displays selective-biofilm targeting and elimination under cariogenic (acidic and sugar-rich) conditions, while also reducing apatitic demineralization. In vivo studies revealed that IONP are highly effective against caries development without affecting oral tissues and the oral microbiome diversity, confirming therapeutic precision. We also discovered that an FDA-approved IONP formulation, ferumoxytol (FerIONP), displays similar acid pH- activated antibiofilm and anticaries mechanisms in vivo. In search for ways to improve efficacy and applicability to enhance current modalities, we tested the possibility of combining FerIONP with fluoride. We unexpectedly found a remarkable synergy between FerIONP and stannous fluoride (SnF2) that was exceptionally effective in preventing caries in a severe rodent caries model. In this renewal, we propose to further develop this treatment regimen, and then understand its mechanisms of action as well as potential deleterious effects using laboratory, in vivo and human in situ models to facilitate clinical translation and product development. The significance of this work is to develop a more effective and targeted antibiofilm and caries preventive approach for susceptible populations. We hypothesize that FerIONP interacts with SnF2 to modulate both biological and physicochemical properties by increasing localized antibiofilm action and protection against enamel demineralization, potentiating anticaries efficacy without increasing the concentration of agents. We will perform dose-response studies to improve the efficacy of FerIONP/SnF2 and assess local and systemic biological actions in vivo (Aim 1). We will assess enhanced antibiofilm and caries preventive performance at low doses without deleterious effects on oral-gut microbiome or toxicity on oral mucosal tissues and vital organs. We will compare with previous FerIONP regimen (internal control) and currently used antimicrobial fluoride (SnF2). Then, we will investigate the mechanisms of action and biodistribution of FerIONP-SnF2 (Aim2). We will generate specific FerIONP analogues to understand biofilm targeting specificity and their combined effects with SnF2 on enamel structure. We will perform multi-omics to assess the influence on biofilm composition and functional activities as well as biodistribution of FerIONP via radiolabeling. The impact on enamel structure will be determined via physical-chemistry and spectroscopic methods. In Aim 3, we will further elucidate the bioactivity of the improved formulations using the human intra-oral biofilm model with a clinically relevant topical treatment regimen. We envision a viable and novel technology to target virulent biofilms and prevent caries in susceptible individuals under high cariogenic conditions that will motivate product development and clinical efficacy studies.