Subgingival Drug Delivery for Periodontitis Prevention and Treatment

描述（由申请人提供）：除了口腔感染会导致牙齿脱落外，牙周炎还会增加冠状动脉疾病、中风和心肌梗死等其他疾病的风险。在20岁以上的美国人口中，大约有50%的人患有牙龈炎，大约有3颗或更多的牙齿，5%患有晚期牙周炎。由于牙周感染的普遍存在，即使牙周炎风险的轻微降低也会影响数百万美国人其他疾病的发生。目前牙周炎的标准治疗是机械清创（刮除和牙根刨平）。辅助抗生素治疗已被测试用于预防随后的细菌再定殖，效果好坏参半。全身抗生素以及局部抗生素溶液冲洗在延长清创效果方面有一定的改善。然而，生物材料和药物洗脱聚合物的最新进展已经产生了许多控制抗生素释放和局部保留到牙龈下危险部位的策略。虽然这些方法改善了牙周炎的治疗，但没有一种方法试图直接针对受影响的组织，而是依靠生物材料或聚合物来调节药物的释放和保留。Affinergy Inc.正在开发位点特异性靶向肽，我们称之为界面生物材料（IFBMs），旨在结合治疗剂和目标底物（医疗植入物或组织）。利用噬菌体展示技术，可以利用随机噬菌体文库将肽序列定位到一种材料、分子或组织类型上，在一次实验中可以测试数十亿个候选序列。通过将物质结合肽与治疗结合肽配对，我们产生了一种新的双功能肽，能够指导植入表面的生物活性。在目前的建议中，我们的目标是使用高亲和力肽直接靶向抗生素到牙齿和牙龈，促进抗生素在牙周感染易感区域的保留和持续释放。我们之前的工作已经确定了结合糖肽抗生素万古霉素的高亲和力肽，我们希望通过靶向革兰氏阴性杀伤药物米诺环素来建立。将这些肽与牙齿和牙龈结合肽连接起来，将产生一种新的基于肽的抗生素传递分子。

DESCRIPTION (provided by applicant): In addition to the role oral infections play in promoting tooth loss, periodontitis has also been associated with increasing the risk of other medical conditions such as coronary artery disease, stroke and myocardial infarction. Approximately 50% of the US population over 20 years of age has gingivitis around 3 or more teeth, and 5% have advanced periodontitis. Due to the prevalence of periodontal infections, even a marginal decrease in the risk of periodontitis could affect the occurrence of these other conditions for millions of Americans. The current standard of care for periodontitis is mechanical debridement (scaling and root planing). Adjunctive antibiotic therapies have been tested for the prevention of subsequent bacterial recolonization with mixed effectiveness. Systemic antibiotics, as well as local irrigation with antibiotic solutions have demonstrated some improvement in prolonging the effects of debridement. However, recent advances in biomaterials and drug-eluting polymers have given rise to a number of strategies for the controlled release and localized retention of antibiotic to at-risk subgingival sites. While these approaches have improved periodontitis treatment, none have attempted to target the affected tissue directly, instead relying on the biomaterial or polymer to regulate drug release and retention. Affinergy Inc. is developing site-specific targeting peptides, we have termed interfacial biomaterials (IFBMs) designed to bind a therapeutic agent and a target substrate (medical implant or tissue). Using phage display technology, peptide sequences can be targeted to a material, molecule or tissue type using a randomized phage library, capable of testing billions of candidate sequences in one experiment. By pairing a material-binding peptide with a therapeutic-binding peptide, we generate a novel bifunctional peptide, capable of directing biological activity on an implanted surface. In the current proposal, we aim to target antibiotics directly to teeth and gingiva using high-affinity peptides fostering the retention and sustained release of antibiotics in regions susceptible to periodontal infection. Our previous work has identified high-affinity peptides that bind the glycopeptide antibiotic vancomycin, which we hope to build upon by targeting the gram- negative-killing drug minocycline. Linking these peptides, with teeth and gingiva-binding peptides will give rise to a novel peptide-based antibiotic delivery molecule. PUBLIC HEALTH RELEVANCE: Oral infections are one of the most common infections in the US, with 50% of Americans over 20 years of age affected by gingivitis, and 5% with advanced periodontitis. Therefore, approximately 15 million people require a cost-effective antibiotic delivery system to treat this infection. Here we propose the development of a high-affinity peptide-based platform for the delivery of minocycline to teeth and gingiva. Affinergy has identified dozens of target-specific peptides for a wide range of molecules, tissues and materials using phage display technology. Generating peptide sequences which bind minocycline, teeth and gingiva, will provide the component peptides to synthesize a bifunctional peptide linker to attach antibiotics to these tissue surfaces. The final goal of this proposal is to generate a peptide prototype, capable of long-term retention of minocycline to teeth and gums toward the treatment and prevention of periodontitis.