Biofilm Elimination and Caries Prevention using Multifunctional Nanocatalysts

使用多功能纳米催化剂消除生物膜和预防龋齿

基本信息

批准号：
10389665
负责人：
Hyun Koo
金额：
$ 62.17万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10389665
关键词：
Acids Affect Apatites Area Award Binding Biocompatible Materials Biodistribution Biological Caries prevention Catalysis Chemicals Clinical Clinical Research Clinical Trials Communication Data Dental Enamel Dental caries Development Dextrans Dose Effectiveness Enzymes FDA approved Fluorides Formulation Funding Funding Mechanisms Gingiva Goals Human Hydrogen Peroxide In Situ In Vitro Individual Industry Intellectual Property Iron deficiency anemia Knowledge Laboratories Lead Legal patent Medical Metagenomics Methods Microbial Biofilms Microbiology Microscopy Modality Modeling Mouth Diseases Mucous Membrane NMR Spectroscopy Nature Oral Oral mucous membrane structure Organ Pathologic Performance Peroxidases Physical Chemistry Population Poverty Precision therapeutics Preventive Property Publications Radiolabeled Regimen Rodent Rodent Model Small Business Innovation Research Grant Source Specificity Structure Study models Surface Technology Testing Topical application Toxic effect Treatment Efficacy Treatment Protocols Virulent Work analog anticaries antimicrobial clinical efficacy clinical translation clinically relevant clinically translatable comparative efficacy cost demineralization dental biofilm effective therapy efficacy study ferumoxytol gut microbiome improved in vivo internal control iron deficiency iron oxide nanoparticle metabolomics multiple omics nano nanoparticle new technology novel novel strategies oral microbiome oral tissue polymicrobial biofilm prevent product development response safety and feasibility soft tissue sugar synergism tomography transcriptomics

项目摘要

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.

预防龋齿的当前方式不足，尤其是当生物膜迅速积累时在易感人群的致骨气条件下，需要新的方法。在上一个资金期间，我们研究了氧化铁纳米颗粒（IONP）的催化（过氧化物酶模仿）的潜力过氧化氢的依赖激活作为一种新型抗生素和抗果脂肪的治疗。我们发现IONP 在致癌（酸性和糖）条件下显示选择性双膜的靶向和消除，而也是减少脱位矿化。体内研究表明，IONP对龋齿非常有效发育而不会影响口腔组织和口腔微生物组的多样性，从而确认了治疗精度。我们还发现，FDA批准的IONP制剂Ferumoxytol（Ferionp）显示出相似的酸pH- 活体内活化的抗体膜和抗药机制。寻找提高功效和适用性的方法为了增强当前的方式，我们测试了将费翁普与氟化物结合的可能性。我们出乎意料在Ferionp和氟化物（SNF2）之间发现了一个显着的协同作用，在在严重的啮齿动物龋齿模型中防止龋齿。在此续约中，我们建议进一步开发这种治疗方法方案，然后了解其作用机理以及使用实验室潜在的有害影响，体内和人类原位模型，以促进临床翻译和产品开发。这项工作的意义是开发一种更有效，有针对性的抗体膜和性能预防性易感人群的方法。我们假设Ferionp与SNF2相互作用以调节这两者生物学和物理化学特性通过增加局部抗体膜的作用并保护搪瓷脱矿化，增强抗果疗效，而无需增加剂的浓度。我们将进行剂量反应研究以提高Ferionp/SNF2的功效并评估局部和全身性体内的生物作用（目标1）。我们将评估在低处的增强抗体胶片和龋齿预防性表现对口服微生物组或毒性对口腔粘膜组织和重要器官的毒性无效的剂量。我们将与先前的Ferionp方案（内部对照）进行比较，并目前使用抗菌氟化物（SNF2）。然后，我们将研究Ferionp-SNF2的作用机理和生物分布（AIM2）。我们将生成特定的Ferionp类似物了解生物膜靶向特异性及其与SNF2的综合作用搪瓷结构。我们将执行多词以评估对生物膜组成和功能的影响通过放射性标记的活动以及Ferionp的生物分布。对搪瓷结构的影响将是通过物理化学和光谱方法确定。在AIM 3中，我们将进一步阐明生物活性使用人体内生物膜模型进行临床相关局部处理的改进制剂方案。我们设想了一种可行而新颖的技术，以靶向有毒的生物膜并防止易感性的龋齿在高的致癌条件下的个体将激发产品开发和临床功效研究。