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项目摘要摘要 2 3中耳炎（OM）是主要儿童健康负担。急性OM是最常见的小儿 4疾病和对我们儿童抗菌处方的＃1原因。此外，有62％的OM儿童 5在其中耳中证明了病毒感染，抗生素无效，但仍处方。 6针对这种高流行和复发疾病的全身性抗生素的广泛使用是 7被认为会繁殖抗生素耐药性。为了避免系统性抗生素暴露，我们开发了一项技术 8将抗生素直接递送到中耳中。交付系统的关键和实用特征 9是水凝胶，在室温下是一种易于涂抹的液体，接触时会迅速而牢固地凝胶 10温暖的鼓膜膜（TM）。凝胶内的化学渗透增强剂可以克服 11 TM的不可渗透障碍，并将抗生素带入中耳。水凝胶的单一应用 12配方为7天治疗提供了足够的抗生素。 13当前的申请试图完全消除这种普遍的儿童疾病中的抗生素使用率 14并通过使用独立治疗细菌和 15种病毒感染。 16 K99阶段的关键组成部分是开发工程的纳米颗粒，以催化催化的转化 17痕量的环境氢过氧化盐至低人气。低人气具有广泛的活性 18个病毒，细菌和真菌。重要的是，某些OM病原体（例如肺炎链球菌）可以产生 19过氧化氢，加剧了纳米颗粒的低人气产生。因此，我们假设 20个纳米颗粒可用于治疗OM，该治疗仅在OM病原体的存在下开始，并且 消除感染后21停止。因此，纳米颗粒的单个应用可以治疗复发 22 OM或预防性应用。 23本应用的R00阶段的重点是1）使用A的治疗和预防的证明 24病毒和细菌的独立治疗； 2）了解纳米医学对 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 26在耳朵中的生物屏障中运送纳米颗粒的策略。非侵入性的反式薄膜 27纳米颗粒的递送将与小分子的分子有很大差异，这可能需要更大的TM 28渗透性比我们既定的技术实现的渗透性。根据我们的发现，即发炎的TMS 29的渗透性比健康的渗透性高10-15倍，我们假设诱发炎症可以 30增强纳米颗粒的渗透。在R00阶段发展的知识和技术将 31提供有关急性和经常性OM发病机理的见解，可以应用于指导设计 32耳朵的下一代疗法。