Engineered pH-Responsive Nanoparticle Drug Delivery to Inhibit Oral Biofilm Formation

工程化 pH 响应纳米颗粒药物递送以抑制口腔生物膜形成

基本信息

批准号：
9326511
负责人：
Kenneth R Sims
金额：
$ 4.48万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326511
关键词：
Acids Adult Adverse effects Affect Anti-Bacterial Agents Antibiotics Apigenin Bacteria Binding Biological Assay Calculi Characteristics Child Chlorhexidine Clinical Crosslinker Dental Calculus Dental Enamel Dental Plaque Dental caries Development Disease Drug Carriers Drug Delivery Systems Effectiveness Engineering Exhibits Farnesol Fluorides Goals Health Care Costs In Vitro Influentials Kinetics Lead Microbial Biofilms Modeling Mouth Diseases Oral Outcome Pathogenicity Pharmaceutical Preparations Polymers Prevention Research Research Training Salivary Staining method Stains Streptococcus mutans Surface Testing Therapeutic Time Tooth structure Topical application United States Virulent Work clinically relevant cost course load design improved in vivo in vivo Model killings microbial monomer myricetin nanoparticle oral biofilm pathogen premature prevent tooth surface

项目摘要

ABSTRACT: Over two-thirds of children and nearly all adults worldwide are affected by oral biofilm diseases, such as dental caries (i.e. tooth decay), resulting in billions of dollars of healthcare costs annually. The main microbial pathogen associated with this disease, Streptococcus mutans (S. mutans), forms biofilms (i.e. dental plaque) containing an exopolysaccharide (EPS) matrix and acidic microenvironments capable of dissolving enamel at the tooth surface. Current treatments exhibit a technological gap because they are poorly retained within EPS due to salivary clearance. To overcome this gap, the long-term goal of this research is to develop anti-biofilm drug delivery approaches. Specifically, these approaches will be capable of enhanced drug retention within oral biofilms and pH-responsive drug release within acidic microenvironments where enamel dissolution and cavity development occur. Prior collaborative work between the Sponsor’s and Co-sponsor’s labs has created polymer nanoparticle carriers (NPCs) that enhance the anti-biofilm effects of farnesol in vitro and in vivo. However, the current approach has limitations: 1) the pKa value of the existing NPC (≥ 6) is poorly aligned with biofilm pH values (≤ 5.5), so drug release begins at pH ~6, which may lead to premature release due to common oral pH variability; 2) the NPC exhibits modest control over pH-responsive drug release kinetics in pathogenic, acidic microenvironments (pH ≤ 5.5) versus normal oral pH (~7.2); and 3) NPC anti-biofilm efficacy has only been shown using farnesol although multiple drugs, including myricetin and apigenin, synergistically disrupt biofilms when combined with farnesol. The central hypothesis of this proposal is that modifying the NPC polymer composition and establishing the NPC capability to simultaneously load multiple synergistic drugs will improve anti-biofilm effectiveness in vitro and in vivo. Two aims will be developed. Aim 1 is to modify NPC polymer composition to control the pH at which drug release occurs to improve biofilm disruption in vitro and in vivo. For Aim 1, we will modify the NPC polymer composition using different monomers with pKa values more closely aligned with oral biofilm pH values (pH ≤5.5) and incorporate an acid-degradable crosslinker to create a physical barrier for drug release at neutral pH. Anti-biofilm effectiveness of NPCs with the greatest pH-responsive characteristics will be tested using established in vitro and in vivo oral biofilm models. Aim 2 is to establish NPC capability to load and release multiple synergistic anti-biofilm drugs and that co-loading NPCs improves biofilm disruption in vitro and in vivo. For Aim 2, we will investigate molecular interactions indicative of loading and release between known anti- biofilm drugs (e.g. myricetin, apigenin, and farnesol) and the existing NPC to characterize which drug classes load and release successfully. The anti-biofilm efficacy of successfully co-loaded drugs will be investigated using in vitro and in vivo models. This work is significant because it will move this approach closer to a promising, clinically relevant therapeutic platform to prevent dental caries and other oral diseases.

摘要：全世界超过三分之二的儿童和几乎所有成年人都受到口腔生物膜疾病的影响，例如龋齿（即蛀牙），每年造成数十亿美元的医疗费用。与这种疾病相关的微生物病原体，变形链球菌（S. mutans），形成生物膜（即牙科斑块）含有胞外多糖（EPS）基质和能够溶解的酸性微环境目前的治疗方法在牙齿表面的牙釉质方面存在技术差距，因为它们的保留效果很差。为了克服这一差距，本研究的长期目标是开发具体来说，这些方法将能够增强药物递送能力。口腔生物膜内的滞留和牙釉质酸性微环境中的 pH 响应性药物释放申办者和共同申办者之前进行过合作工作。实验室已经创建了聚合物纳米颗粒载体（NPC），可以增强法呢醇的抗生物膜作用然而，目前的方法有局限性：1）现有NPC（≥6）的pKa值是与生物膜 pH 值（≤ 5.5）的一致性较差，因此药物释放在 pH ~6 时开始，这可能会导致过早释放由于常见的口腔 pH 变化而释放；2) NPC 对 pH 响应药物表现出适度的控制致病性酸性微环境 (pH ≤ 5.5) 与正常口腔 pH (~7.2) 中的释放动力学；以及 3) NPC 尽管有多种药物，包括杨梅素和芹菜素与金合欢醇结合时可协同破坏生物膜。建议修改 NPC 聚合物成分并建立 NPC 能力同时负载多种协同药物将提高体外和体内的抗生物膜有效性开发的两个目标是修改 NPC 聚合物成分以控制药物的 pH 值。释放发生以改善体外和体内生物膜破坏对于目标 1，我们将修改 NPC 聚合物。使用不同单体的组合物，其 pKa 值与口腔生物膜 pH 值更接近（pH ≤5.5）并加入可酸降解的交联剂，为中性 pH 下的药物释放形成物理屏障。具有最大 pH 响应特性的 NPC 的抗生物膜有效性将使用建立体外和体内口腔生物膜模型，目标2是建立NPC的加载和释放能力。多种协同抗生物膜药物和共同负载 NPC 可改善体外和体内生物膜破坏。对于目标 2，我们将研究已知抗-药物之间的装载和释放的分子相互作用指标生物膜药物（例如杨梅素、芹菜素和金合欢醇）和现有 NPC 来表征药物类别成功负载和释放的药物的抗生物膜功效将被研究。使用体外和体内模型这项工作意义重大，因为它将使这种方法更接近于真实的方法。有前景的临床相关治疗平台，可预防龋齿和其他口腔疾病。