Subgingival Drug Delivery for Periodontitis Prevention and Treatment

龈下给药预防和治疗牙周炎

• 批准号: 7668756
• 负责人: Martyn Darby
• 金额: $ 29.36万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668756
• 关键词: 20 year old; Affect; Affinity; American; Animal Model; Antibiotic Therapy; Antibiotics; Area; Bacteriophages; Binding; Biocompatible Materials; Biological; Biological Assay; Biopolymers; Blood Vessels; Caring; Cells; Chlorhexidine; Complex; Conflict (Psychology); Coronary Arteriosclerosis; Debridement; Dental caries; Development; Disease; Drug Delivery Systems; Effectiveness; Environment; Exhibits; Fostering; Gingiva; Gingivitis; Glycopeptide Antibiotics; Goals; Growth Factor; Histocompatibility Testing; Hydrogels; Implant; In Vitro; Infection; Investigation; Irrigation; Lasers; Libraries; Link; Malignant Neoplasms; Mechanics; Medical; Metals; Metronidazole; Microbial Biofilms; Microspheres; Minocycline; Myocardial Infarction; National Institute of Dental and Craniofacial Research; Operative Surgical Procedures; Oral; Oral mucous membrane structure; Peptides; Periodontal Diseases; Periodontal Infection; Periodontitis; Phage Display; Pharmaceutical Preparations; Phase; Phase IV Clinical Trials; Plastics; Play; Polymers; Population; Porphyromonas gingivalis; Prevalence; Prevention; Proteins; Randomized; Reporting; Research; Research Contracts; Rest; Risk; Role; Screening procedure; Site; Solutions; Specific qualifier value; Specificity; Stroke; Surface; Symptoms; Synthesis Chemistry; System; Techniques; Technology; Testing; Tetracyclines; Therapeutic; Therapeutic Agents; Tissues; To specify; Tooth Loss; Tooth structure; Ultrasonography; United States National Center for Health Statistics; Use Effectiveness; Vancomycin; Work; antimicrobial; base; biomaterial compatibility; controlled release; cost; design; effective therapy; improved; in vitro testing; in vivo; innovation; interfacial; killings; medical implant; novel; oral infection; product development; programs; protein aminoacid sequence; prototype; public health relevance; research study; scaling and root planing; standard of care

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.

描述（由申请人提供）：除了口腔感染在促进牙齿脱落中的作用外，牙周炎还与增加其他医疗条件的风险有关，如冠状动脉疾病、中风和心肌梗死。大约50%的20岁以上的美国人口在3颗或更多牙齿周围患有牙龈炎，5%患有晚期牙周炎。由于牙周感染的流行，即使牙周炎的风险略有下降，也可能影响数百万美国人发生这些其他疾病。目前牙周炎的护理标准是机械清创（刮治和根面平整）。已经测试了辅助抗生素疗法用于预防随后的细菌感染，效果好坏参半。全身抗生素以及抗生素溶液局部冲洗在延长清创效果方面有一定改善。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策略，用于控制释放和局部保留抗生素到危险的龈下部位。虽然这些方法改善了牙周炎治疗，但没有一种方法试图直接靶向受影响的组织，而是依赖于生物材料或聚合物来调节药物释放和保留。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（IFBM），旨在结合治疗剂和靶底物（医疗植入物或组织）。使用噬菌体展示技术，可以使用随机化噬菌体文库将肽序列靶向材料、分子或组织类型，能够在一个实验中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，能够在植入表面上指导生物活性。在目前的提案中，我们的目标是使用高亲和力肽将抗生素直接靶向牙齿和牙龈，以促进抗生素在牙周感染易感区域的保留和持续释放。我们先前的工作已经鉴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菌药米诺环素来建立这种肽。将这些肽与牙齿和牙龈结合肽连接将产生新的基于肽的抗生素递送分子。 公共卫生关系：口腔感染是美国最常见的感染之一，20岁以上的美国人中有50%患有牙龈炎，5%患有晚期牙周炎。因此，大约有1500万人需要具有成本效益的抗生素输送系统来治疗这种感染。在这里，我们提出了一个高亲和力的肽为基础的平台，提供米诺环素的牙齿和牙龈的发展。Affinergy已经利用噬菌体展示技术为广泛的分子、组织和材料鉴定了数十种靶向特异性肽。产生结合米诺环素、牙齿和牙龈的肽序列将提供合成双功能肽接头的组分肽，以将抗生素连接到这些组织表面。本提案的最终目标是产生一种肽原型，能够长期保留米诺环素的牙齿和牙龈对牙周炎的治疗和预防。