Bio-Responsive and Immune Protein-Based Therapies for Inhibition of Proteolytic Enzymes in Dental Tissues

用于抑制牙齿组织中蛋白水解酶的基于生物响应和免疫蛋白的疗法

• 批准号: 10555093
• 负责人: Ana Paula Piovezan Fugolin
• 金额: $ 66.13万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-17 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555093
• 关键词: Address; Adhesives; Amino Acid Sequence; Animal Model; Antibodies; Bacteria; Binding; Biochemistry; Biocompatible Materials; Biodegradation; Biology; Biotechnology; Chemicals; Clinical; Collagen; Complex; Dental; Dental Restoration Failure; Dental caries; Dentin; Dentistry; Development; Diffusion; Disease; Drug Delivery Systems; Employment; Encapsulated; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Epigallocatechin Gallate; Extracellular Matrix; Formulation; Gel; Gelatinases; Generations; Goals; Heart Diseases; Human body; Hydrogels; Immune; Immunology; Infiltration; Llama; Maintenance; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Medical; Medicine; Metalloproteases; Micelles; Morphogenesis; Mucous Membrane; National Institute of Dental and Craniofacial Research; Oral health; Organ; Pathogenicity; Pathologic; Pathway interactions; Patient Care; Peptide Hydrolases; Peptides; Periodontal Diseases; Periodontal Pocket; Periodontitis; Pharmaceutical Preparations; Physiological; Play; Polymers; Procedures; Process; Proteins; Public Health; Quercetin; Recurrence; Research; Research Personnel; Role; Rupture; Sepsis; Specificity; System; Techniques; Technology; Therapeutic; Therapeutic Agents; Time; Tissue Engineering; Tissue Preservation; Tissues; Tooth Extraction; Tooth Loss; Tooth structure; Translating; Translations; United States; Vulnerable Populations; Water; alveolar bone; clinical care; collagenase; cytokine; delivery vehicle; dental adhesive; dental structure; design; design verification; efficacy evaluation; experimental study; forging; functional group; immunoregulation; improved; inhibitor; innovation; materials science; metastatic colorectal; microbial; multidisciplinary; nanobodies; nanomicelles; nanomolar; nanoparticle; oral condition; oral tissue; particle; polyphenol; preservation; prevent; repaired; restorative material; screening; skills; stem; tissue regeneration; tool; treatment strategy; tumor

SUMMARY This multidisciplinary proposal translates the efforts of a highly skilled group of researchers forging unprecedented pathways to promote hard and soft dental tissues preservation. Cutting-edge strategies inspired in approaches used in the medical field are employed to inhibit selectively endogenous metalloproteinases responsible for mediating the degradation of the collagen. In Dentistry, the destruction of this essential component of the extracellular matrix is strongly associated with the progression of periodontal disease and the breakdown of the dental substrate/restorative material interface leading to bacteria recolonization and recurrent caries, the primary cause of failure of dental restorations. These pathological conditions together are responsible for almost 80% of the tooth extractions in the United States. In order to address this serious public health issue, two innovative platforms are proposed. The first strategy is based on the encapsulation of two potent MMP inhibitors, the polyphenols quercetin and epigallocatechin gallate, in nano micelles cleavable by MMPs. The shell of the particles is composed of peptides with specific sequences of amino acids recognized and cleaved by the targeted MMPs, leading to rupture of the micelles and the release of the inhibitor molecules. In essence, this system enables the MMP to inhibit itself. The second strategy is an immunomodulatory platform based on the introduction of anti-MMP nanobodies, single domain antibodies derived from llama heavy-chain only antibodies, to inhibit/cease MMP proteolytic activity. As nanoparticles or nanobodies delivery vehicles, a dental primer formulation and a newly-designed multifunctional hydrogel are used for the adhesive interface and periodontal pockets, respectively. To validate the designed platforms, tooth-on-a-chip and animal models are being added in order to fast-track their translation into clinical care. The innovation of this proposal stems from: (1) the employment of a pioneering approach to inactivate MMPs in dental tissues based on enzymatic-responsive nanoparticles to deliver inhibitors, and (2) the introduction of a new paradigm based on the modulation of the MMPs activity by nanobody technology. After completing this project, we will have these two platforms tailored and validated to be delivered in vehicles compatible with the current clinical techniques employed to treat periodontitis and to hybridize the dentin during the restorative procedures, which will allow to bridge the gap between cutting-edge research and improved patient care. In addition, these platforms can be either combined or tailored in more complex and multi-functional entities and programmed to respond to a variety of enzymes and cytokines, which provides new opportunities to develop innovative dental tissue regeneration/preservation therapeutics to minimize tooth loss especially in highly vulnerable population.

概括 这项多学科提案体现了一群高技能研究人员的努力，打造了前所未有的成果 促进硬牙组织和软牙组织保存的途径。受所用方法启发的尖端策略 医学领域用于选择性抑制负责介导的内源性金属蛋白酶 胶原蛋白的降解。在牙科中，细胞外基质的这种重要成分的破坏是强烈的 与牙周病的进展和牙科基质/修复材料的分解有关 界面导致细菌重新定植和复发性龋齿，这是牙齿修复失败的主要原因。这些 在美国，近 80% 的拔牙都是由病理状况造成的。为了 针对这一严重的公共卫生问题，提出了两个创新平台。第一个策略基于 将两种有效的 MMP 抑制剂（多酚槲皮素和表没食子儿茶素没食子酸酯）封装在纳米胶束中 可被 MMP 裂解。颗粒的外壳由具有特定氨基酸序列的肽组成 并被目标 MMP 裂解，导致胶束破裂并释放抑制剂分子。在 本质上，该系统使MMP能够自我抑制。第二种策略是基于免疫调节平台 引入抗 MMP 纳米抗体，即源自美洲驼仅重链抗体的单域抗体， 抑制/停止 MMP 蛋白水解活性。作为纳米颗粒或纳米抗体递送载体、牙科底漆配方和 新设计的多功能水凝胶分别用于粘合界面和牙周袋。到 验证设计的平台，正在添加牙齿芯片和动物模型，以便快速跟踪其翻译 进入临床护理。本方案的创新之处在于：（1）采用了开创性的灭活方法。 牙组织中的 MMP 基于酶响应纳米粒子来传递抑制剂，以及 (2) 引入 基于纳米抗体技术调节 MMP 活性的新范例。完成这个项目后，我们 将对这两个平台进行定制和验证，以便在与当前临床兼容的车辆中交付 用于治疗牙周炎和在修复过程中使牙本质杂交的技术，这将允许 缩小尖端研究和改善患者护理之间的差距。此外，这些平台可以是 组合或定制更复杂和多功能的实体，并编程以响应各种酶 和细胞因子，这为开发创新的牙组织再生/保存提供了新的机会 减少牙齿脱落的治疗方法，特别是对于高度脆弱的人群。