Targeted combinatiorial therapy for treatment of periodontal disease

描述（由申请人提供）：一个新兴的概念是，复杂的微生物群落组成牙周联盟包括有益和致病的物种。这意味着牙周病可以通过选择性地消除假定的病原体来治疗，同时最大限度地减少对社区共生成员的破坏。我们建议设计一个纳米平台家族，将光敏剂（PS）和PS/药物或抗菌肽对靶向牙周病原体。我们将验证这一假设，即适当的PS/药物或PS/抗菌肽组合可以显著增强靶向PS的选择性杀伤。我们将设计被称为蛋白质笼的纳米平台来实施我们的设计策略。在初步研究中，我们已经开发出了用光敏剂（PS）功能化的蛋白质笼来靶向和杀死形成生物膜的病原体的方法。与此同时，我们开发了一种与蛋白质笼偶联的药物触发释放方法。我们将建立在这方面的专业知识制造多功能纳米平台靶向组合治疗。我们的工程纳米平台选择性杀死牙周病原体的能力将在浮游生物和体外生物膜系统中进行表征。我们将确定PS和增强剂的哪种组合在保持选择性的同时最有效地产生添加剂或协同杀死病原体。具体目标（SA）根据三种治疗方式组合进行组织：SA1)靶向PS与非靶向广谱抗菌药物联合；SA2)靶向PS联合两种广谱抗菌药物的靶向触发释放和SA3)靶向PS联合抗菌肽。我们的研究团队的实力在于两个中心的专业知识的结合：生物启发纳米材料中心和生物膜工程中心。我们特别设计了实验，以便最有希望的系统可以在牙周病的动物模型中进行测试。

DESCRIPTION (provided by applicant): An emerging concept is that the complex microbial communities that comprise periodontal consortia consist of both beneficial and pathogenic species. The implication is that periodontal disease can be treated by selectively eliminating putative pathogens, while minimizing the destruction of the commensal members of the community. We propose to engineer a family of nanoplatforms to target photosensitizers (PS) and PS/drug or antimicrobial peptide pairs to periodontal pathogens. We will test the hypothesis that the selective killing of targeted PS can be significantly enhanced by appropriate PS/drug or PS/antimicrobial peptide combinations. We will engineer nanoplatforms known as protein cages to implement our design strategy. In preliminary studies we have developed methods to target and kill biofilm-forming pathogens with protein cages functionalized with a photosensitizer (PS). In parallel, we developed a method for triggered release of a drug coupled to a protein cage. We will build upon this expertise to fabricate multifunctional nanoplatforms for targeted combinatorial therapy. The ability of our engineered nanoplatforms to selectively kill periodontal pathogens will be characterized in planktonic and established biofilm in vitro systems. We will determine which combinations of PS and enhancer are most effective in producing additive or synergistic killing of pathogens while maintaining selectivity. The specific aims (SA) are organized in terms of three combinations of treatment modalities: SA1) Targeted PS combined with non-targeted broad spectrum antimicrobials; SA2) Targeted PS combined with targeted triggered release of two types of broad spectrum antimicrobials and SA3) Targeted PS combined with an antimicrobial peptide. The strength of our research team lies in the combined expertise of two centers: the Center for BioInspired Nanomaterials and the Center for Biofilm Engineering. We have specifically designed the experiments so that the most promising systems can be tested in an animal model of periodontal disease. PUBLIC HEALTH RELEVANCE: The bone loss and tissue destruction that accompany periodontal disease are caused by the response of the immune system to bacteria. However, we know that the immune system can live in harmony with many types of bacteria. Our research will provide a tool to selectively eliminate bacteria suspected of causing immune malfunction while sparing bacteria thought to be beneficial.