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)是儿童健康的主要负担。急性OM是儿科最常见的诊断疾病 4疾病和美国儿童抗菌药处方的头号原因。此外，62%的患有OM的儿童 他们的中耳有病毒感染，抗生素对此无效，但仍给他们开了处方。 6针对如此高的发病率和复发率的疾病，广泛使用全身抗生素是 7据信会产生抗生素耐药性。为了避免全身接触抗生素，我们开发了一种技术 8将抗生素直接输送到中耳作为目标。交付系统的一个重要和实用的特点 9是一种水凝胶，在室温下是一种易于涂抹的液体，接触后快速而牢固地凝胶化 10温鼓膜(TM)。凝胶内的化学渗透促进剂可以克服 11阻隔TM，并将抗生素带入中耳。单次使用该水凝胶 12配方为7天的治疗提供了足够的抗生素。 13目前的申请试图完全消除这种流行的儿童疾病中抗生素的使用 14并通过使用一种独立的疗法来减轻OM相关的抗生素耐药性，该疗法既治疗细菌又治疗肺炎 15例病毒感染。 16 K99相的一个关键成分是开发工程纳米颗粒，它催化 17微量环境中的过氧化氢到次卤酸盐。次卤酸盐具有广谱的抗菌活性 18种病毒、细菌和真菌。重要的是，一些OM病原体，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个纳米粒子可以用于治疗OM，只有在OM病原体存在的情况下才能开始治疗，而且它 21在根除感染后停止。因此，单次应用纳米颗粒就可以治疗复发 22OM或预防性应用。 23本应用程序的R00阶段侧重于1)使用 24单独治疗病毒和细菌；2)了解纳米药物对 25病原菌-宿主相互作用、生物膜形成、鼻咽微生物组和听觉生理学；3)新的 26种跨越耳朵内生物障碍的纳米颗粒输送策略。非侵袭性跨鼓室 27纳米颗粒的输送将与小分子的输送有很大的不同，小分子的输送可能需要更大的TM 28渗透率超过我们现有技术所能达到的渗透率。根据我们的发现，发炎的经皮巨噬细胞 29的通透性是健康的10-15倍，我们假设引发炎症可以 30增强纳米颗粒的渗透性。在R00阶段开发的知识和技术将 31提供了对急性和复发性OM的发病机制的洞察，这可以用于指导设计 32新一代耳部疗法。