Controlled antibiotic delivery vehicle for treatment of aggressiveperiodontitis

用于治疗侵袭性牙周炎的受控抗生素递送载体

• 批准号: 10662640
• 负责人: Angela C. Brown
• 金额: $ 21.64万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662640
• 关键词: Actinobacillus actinomycetemcomitans; Adolescent; Adsorption; Affect; Affinity; Antibiotic Resistance; Antibiotics; Automobile Driving; Bacteria; Binding; Cell Survival; Cell membrane; Cells; Cholesterol; Clinical; Clinical Treatment; Coculture Techniques; Development; Disease; Disease Progression; Encapsulated; Engineering; Equus caballus; Future; Goals; Gram-Negative Bacteria; Immune; Infection; Left; Lipids; Liposomes; Mediating; Membrane; Membrane Lipids; Mission; Modality; Modeling; National Institute of Dental and Craniofacial Research; Oral health; Outcome; Pathogenesis; Pathogenicity; Patients; Periodontal Infection; Periodontitis; Phase; Plasma Cells; Porifera; Proteins; Recommendation; Research; Role; System; Testing; Therapeutic; Toxin; Virulence Factors; Work; adolescent patient; adverse drug reaction; biophysical analysis; common treatment; delivery vehicle; host colonization; improved; innovation; leukotoxin; liposomal delivery; nanomolar; novel; novel therapeutics; phase change; scaling and root planing; therapeutic target; treatment strategy

PROJECT SUMMARY/ABSTRACT Aggressive forms of periodontitis associated with Aggregatibacter actinomycetemcomitans (Aa) are often difficult to treat with traditional means (scaling and root planing, in combination with systemic antibiotics). During infection, Aa produces a leukotoxin (LtxA) that kills host immune cells, thus reducing the host’s ability to clear the infection. Although an association between LtxA expression levels and pathogenicity of Aa has been well documented, particularly in adolescent patients, and the mechanisms by which LtxA kills host cells have been well studied, few new treatment options have been developed in recent years. We propose that LtxA represents an ideal therapeutic target that could be exploited to develop next generation therapeutics for Aa infections in juveniles. The long-term goal of the PI is to develop LtxA-focused therapeutics for the treatment of Aa. The overall objective of this project is to construct a liposome-based, LtxA-responsive antibiotic delivery vehicle to treat Aa infections. The general hypothesis is that LtxA will enable antibiotic release only in the presence of pathogenic (LtxA- expressing) strains of Aa. The general hypothesis will be tested via the following specific aims: (1) Optimize liposome composition to promote LtxA adsorption and LtxA-mediated disruption and (2) Determine the therapeutic liposome concentrations necessary to enhance host cell survival. In Aim 1, we will optimize the composition of the liposome to enhance LtxA-mediated antibiotic release and LtxA adsorption. In Aim 2, we will test the effect of the liposomes on host cell survival in a co-culture model of infection. At the successful completion of the proposed research, the expected outcome is a novel therapeutic option to treat Aa infections in adolescents. The innovation of the proposed work lies in its use of LtxA as a therapeutic target, as well as the development of a controlled antibiotic delivery vehicle for the treatment of aggressive periodontitis. These results will provide a strong basis for the future development of LtxA-focused therapeutics, which is expected to have a significant impact on the clinical treatment of Aa-associated infections in juveniles by providing additional, non- surgical options. This research aligns with NIDCR’s mission to improve oral health through its development of a new treatment for periodontal infections.

项目摘要/摘要 与聚集放线菌的牙周炎相关的侵袭性形式通常很难 用传统手段（缩放和根计划，与全身性抗生素结合使用）。 感染，AA产生杀死宿主免疫细胞的白细胞毒素（LTXA），从而降低了宿主清除的能力 感染。尽管LTXA表达水平与AA致病性之间的关联状况很好 有记录，特别是在青春期患者中，LTXA杀死宿主细胞的机制已有 近年来研究良好，很少有新的治疗选择。我们建议LTXA代表 可以探索的理想疗法靶标，以开发针对AA感染的下一代疗法 少年。 PI的长期目标是开发以LTXA为中心的疗法来治疗AA。总体目标 该项目中的一个是构建一种基于脂质体的LTXA响应性抗生素递送工具来治疗AA感染。 一般的假设是，LTXA仅在病原性的情况下才能实现抗生素释放（LTXA- 表达）aa菌株。一般假设将通过以下特定目的进行检验：（1）优化 脂质体组成可促进LTXA吸附和LTXA介导的破坏，（2）确定 增强宿主细胞存活所需的治疗性脂质体浓度。在AIM 1中，我们将优化 脂质体的组成，以增强LTXA介导的抗生素释放和LTXA吸附。在AIM 2中，我们将 测试脂质体对宿主细胞存活的影响，在感染的共培养模型中。在成功 拟议研究的完成，预期的结果是治疗AA感染的新型热选择 在青少年。拟议工作的创新在于使用LTXA作为治疗目标，以及 开发用于治疗侵袭性牙周炎的受控抗生素递送工具。这些结果 将为以LTXA为中心的疗法的未来发展提供强大的基础，预计将有一个 通过提供额外的，非 - 手术选择。这项研究符合NIDCR通过开发口服健康的使命 牙周感染的新治疗方法。