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

1项目摘要 2 3中耳炎（OM）是儿童的主要健康负担。急性OM是最常见的儿科诊断 4疾病和抗菌药物处方美国儿童的头号原因。此外，62%的OM儿童 5例中耳病毒感染，抗生素无效，但仍被处方。 广泛使用全身性抗生素来治疗这种高患病率和复发率的疾病， 7被认为会产生抗生素耐药性。为了避免全身性抗生素暴露，我们开发了一种技术， 8将抗生素直接递送到中耳。输送系统的一个重要而实用的特点是 9是水凝胶，其在室温下是易于施用的液体，并且在接触时快速且牢固地胶凝 10例温热鼓膜（TM）。凝胶内的化学渗透促进剂可以克服 11 TM的不可渗透屏障，并将抗生素带入中耳。水凝胶的单次应用 12配方提供足够的抗生素7天的治疗。 目前的申请试图完全消除这种流行的儿童疾病中的抗生素使用 14和减轻OM相关的抗生素耐药性，通过使用一种独立的治疗方法，治疗细菌和 15病毒感染 K99阶段的一个关键组成部分是开发工程纳米颗粒，催化 17微量的过氧化氢对次卤酸盐。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病原体如肺炎链球菌可以产生 19过氧化氢，通过纳米颗粒促进次卤酸盐的产生。因此，我们假设， 纳米颗粒可用于治疗OM，治疗仅在OM病原体存在的情况下开始， 21、消灭感染。因此，单次应用纳米颗粒可以治疗复发性 22 OM或以化学方式施用。 23本申请的R00阶段侧重于1）使用 24病毒和细菌的独立治疗; 2）了解纳米药物对 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种策略将纳米颗粒穿过耳内的生物屏障。非侵入性经鼓膜 纳米颗粒的递送将与小分子的递送显著不同，小分子的递送可能需要更大的TM 28的渗透率比我们现有的技术所能达到的渗透率要高。根据我们的发现， 29具有比健康人大10 - 15倍的渗透性，我们假设诱导炎症可以 30增强纳米颗粒的渗透。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发病机制的深入了解，可用于指导 32下一代治疗耳朵。

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.