Trans-Tympanic Drug Delivery for Treatment and Prophylaxis of Otitis Media

经鼓室给药治疗和预防中耳炎

• 批准号: 9928149
• 负责人: Rong Yang
• 金额: $ 24.9万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9928149
• 关键词: Acute; Adverse effects; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antiviral Agents; Artificial nanoparticles; Audiology; Auditory Physiology; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Biological; Biology; Biometry; Breeding; Cell Membrane Permeability; Cells; Charge; Chemicals; Child; Child Health; Childhood; Chinchilla (genus); Ciprofloxacin; Clinical; Communicable Diseases; Development; Diagnosis; Disease; Drug Delivery Systems; Drug resistance; Ear; Effectiveness; Encapsulated; Enhancers; Evaluation; Formulation; Functional disorder; Gel; Health; High Prevalence; Human; Hydrogels; Hydrogen Peroxide; Hydrophobicity; In Vitro; Infection; Infection prevention; Inflammation; Inflammatory Response; Investigation; Knowledge; Labyrinth; Liquid substance; Local Anti-Infective Agents; Measures; Mentors; Microbial Biofilms; Modeling; Monitor; Morphology; Nanotechnology; Nontypable Haemophilus influenza; Otitis Media; Pathogenesis; Pediatrics; Permeability; Pharmaceutical Preparations; Phase; Production; Property; Prophylactic treatment; Recurrence; Research; Research Personnel; Resistance; Streptococcus pneumoniae; Structure; Surface; System; Techniques; Technology; Temperature; Testing; Therapeutic; Therapeutic Uses; Thick; Time; Toxic effect; Treatment outcome; Tympanic membrane; Viral; Virus; Virus Diseases; Work; antimicrobial; base; biomaterial compatibility; cytotoxicity; design; fungus; in vivo; insight; knowledge base; microbiome; middle ear; nanomedicine; nanoparticle; nanoparticle delivery; novel therapeutics; pathogen; pathogenic bacteria; prophylactic; small molecule; synergism; systemic toxicity; targeted delivery; treatment duration; vanadium pentoxide

1 Project Summary Abstract 2 3 Otitis media (OM) is a major child health burden. Acute OM is the most commonly diagnosed pediatric 4 disease and the #1 reason for antimicrobial prescription to US children. Moreover, 62% of children with OM 5 demonstrate viral infections in their middle ear, to which antibiotics are ineffective but prescribed nonetheless. 6 The wide spread use of systemic antibiotics against a disease of such high prevalence and recurrence is 7 believed to breed antibiotic resistance. To avoid systemic antibiotic exposure, we developed a technology to 8 target the delivery of antibiotics directly to the middle ear. A crucial and practical feature of the delivery system 9 is a hydrogel, which is an easy-to-apply liquid at room temperature and gels quickly and firmly upon contacting 10 warm tympanic membrane (TM). Chemical permeation enhancers inside the gel can overcome the 11 impermeable barrier of the TM and bring antibiotics into the middle ear. A single application of the hydrogel 12 formulation provides enough antibiotics for a 7-day treatment. 13 The current application attempts to completely eliminate antibiotic usage in this prevalent childhood disease 14 and to mitigate OM-related antibiotic resistance by using a stand-alone therapy that treats both bacterial and 15 viral infections. 16 A key component of the K99 phase is to develop engineered nanoparticles that catalyze the conversion of 17 trace amount of ambient hydrogen peroxide to hypohalites. Hypohalites have broad-spectrum activity against 18 viruses, bacteria, and fungi. Importantly, some OM pathogens such as Streptococcus pneumoniae can produce 19 hydrogen peroxide, fueling the production of hypohalites by the nanoparticles. We thus hypothesized that the 20 nanoparticles can be used to treat OM, the treatment only commences in the presence of OM pathogens, and it 21 stops upon eradication of the infection. Therefore, a single application of the nanoparticles could treat recurrent 22 OM or be applied prophylactically. 23 The R00 phase of this application focuses on 1) demonstration of cure and prophylaxis of OM using a 24 stand-alone treatment for both viruses and bacteria; 2) understanding the effects of the nanomedicines on 25 pathogen-host interactions, biofilm formation, nasopharyngeal microbiome, and auditory physiology; 3) new 26 strategies to deliver nanoparticles across biological barriers in the ear. The non-invasively trans-tympanic 27 delivery of the nanoparticles will differ considerably from that of small molecules, which may require greater TM 28 permeability than can be achieved with our established technology. Based on our finding that inflamed TMs 29 have 10-15 times greater permeability than healthy ones, we hypothesized that inducing inflammation can 30 enhance permeation of nanoparticles. The knowledge and techniques developed during the R00 phase will 31 provide insight into the pathogenesis of acute and recurrent OM, which could be applied to direct the design of 32 next-generation therapeutics for the ear.

1 项目概要 摘要 2 3 中耳炎 (OM) 是儿童健康的主要负担。急性 OM 是最常见的儿科诊断 4 种疾病以及美国儿童使用抗菌药物的第一大原因。此外，62% 患有 OM 的儿童 5 名患者的中耳出现病毒感染，抗生素对此无效，但仍开了处方。 6 针对如此高患病率和复发率的疾病，广泛使用全身抗生素是 7 据信会滋生抗生素耐药性。为了避免全身性抗生素暴露，我们开发了一项技术 8 将抗生素直接输送至中耳。输送系统的一个重要且实用的特征 9是水凝胶，在室温下是一种易于涂抹的液体，接触后会快速牢固地凝胶化 10 温暖鼓膜（TM）。凝胶内的化学渗透增强剂可以克服 11 不可渗透的 TM 屏障并将抗生素带入中耳。水凝胶的单次应用 12 配方提供足够 7 天治疗所需的抗生素。 13 当前的应用试图完全消除这种流行的儿童疾病中抗生素的使用 14 并通过使用同时治疗细菌和细菌的独立疗法来减轻与 OM 相关的抗生素耐药性 15 病毒感染。 16 K99 相的一个关键组成部分是开发工程纳米粒子，以催化转化 17 环境中微量的过氧化氢为次卤酸盐。次卤酸盐具有广谱活性 18 种病毒、细菌和真菌。重要的是，一些 OM 病原体，例如肺炎链球菌，可以产生 19 过氧化氢，促进纳米颗粒产生次卤酸盐。因此我们假设 20纳米粒子可用于治疗OM，治疗仅在OM病原体存在的情况下开始，并且它 21 号在消灭感染后停止。因此，纳米粒子的单次应用可以治疗复发性 22 OM 或预防性应用。 23 该应用的 R00 阶段重点关注 1) 使用 24 种针对病毒和细菌的独立治疗方法； 2）了解纳米药物对人体的影响 25 病原体-宿主相互作用、生物膜形成、鼻咽微生物组和听觉生理学； 3）新 跨越耳内生物屏障递送纳米颗粒的 26 种策略。非侵入性经鼓室 27 纳米颗粒的递送将与小分子的递送有很大不同，这可能需要更大的 TM 比我们现有技术所能达到的渗透率高 28。根据我们的发现，TM 发炎 29 的渗透性比健康的高 10-15 倍，我们假设诱发炎症可以 30 增强纳米粒子的渗透。 R00阶段开发的知识和技术将 31 深入了解急性和复发性 OM 的发病机制，可用于指导设计 32 种下一代耳部疗法。