Tools for Improved Translation of Novel Inhalable Therapeutics

项目概述：随着对肺部疾病发病机制的描述，正在取得重大进展 在药物治疗干预措施的开发方面取得了进展。新的推定药物在不断涌现 然而，它们最初的可获得性往往极其有限，特别是对于以生物为基础的、 大分子制剂(如蛋白质、基因、RNA和抗体)。这些代理商的翻译尤其 如果分娩方式是吸入性的，则具有挑战性。现有的啮齿动物暴露系统不适合这些 化合物，因为通常99%以上的药物会丢失。虽然可以管理一小部分 用气管内针将该药剂溶解到啮齿动物模型中，这需要麻醉并导致 在肺中分布不佳。该项目解决了高效吸入分娩的关键需求--首先 啮齿动物，然后在更大的动物和人类患者中。一种高效的啮齿动物吸入暴露系统是 不仅需要测试推定的治疗方法，而且还需要感染剂、新疫苗和 纳米材料。 我们建议的方法是非侵入性的，不需要麻醉，因此是无创伤的， 每日服药。气雾剂将由少量液体(例如10微升)产生，基本上没有 被困在设备中的液体。此外，微粒将在靠近动物鼻孔的地方产生，这将 最大限度地减少死气量，从而减少代理商的损失。逃逸肺沉积的气雾剂将 静电沉积在配备有实时读数的质量微天平上。好处包括：(1) 将实时监测气雾剂暴露，以便立即调整剂量，以及(2) 微量天平上的质量沉积将揭示动物的呼吸频率和潮气量。 拟议的设备预计将具有约60%的吸入效率。 我们建议使用“机械啮齿动物”来构建一个原型曝光系统，该系统旨在模拟 啮齿动物呼吸系统的解剖学/生理学研究 适用于小鼠或大鼠的呼吸频率。机械啮齿动物会吸入的气雾剂 被收集在过滤器上以评估沉积情况。此外，我们将在体内用小鼠验证暴露系统 肺总沉降量及吸入气雾剂在肺树中的分布 包裹在配位体外壳中的大分子药物的纳米胶囊，使其能够定向输送到固体中 肿瘤细胞和炎性成纤维细胞。 这项工作的成功完成将确立拟议的高度暴露制度的可行性。 有效的吸入暴露。在第二阶段，该装置将被开发为多动物暴露系统 并用于纳米胶囊治疗肺癌和慢性阻塞性肺疾病的安全性和有效性研究 肺部疾病。

Project Summary: With delineation of the pathogenesis of lung diseases, significant advances are being achieved in the pharmaceutical development of therapeutic interventions. New putative drugs are continually being identified; however, their initial availability is often extremely limited, particularly for biologically-based, macromolecule agents (e.g. proteins, genes, RNA, and antibodies). Translation of these agents is particularly challenging if the delivery mode is inhalation. Existing rodent exposure systems are unsuitable for these compounds, as typically more than 99% of the drug is lost. While it is possible to administer a small volume of solution of the agent to rodent models with an endotracheal needle, this requires anesthesia and results in poor distribution in the lung. This project addresses the critical need of efficient inhalation delivery--first in rodents and then in larger animals and human patients. An efficient rodent inhalation exposure system is needed not only for testing putative therapies but also infectious agents, new vaccines and engineered nanomaterials. Our proposed approach is non-invasive and will not require anesthesia and thus is amenable for trauma-free, daily dosing. Aerosols will be generated with a small volume of liquid (e.g. 10 micro-liters) with essentially no liquid trapped in the device. Further, the particles will be produced close to the nares of the animal, which will minimize the dead volume and thereby the loss of the agent. Aerosols escaping lung deposition will be electrostatically deposited on a mass microbalance equipped for real-time readout. The benefits include: (1) aerosol exposure will be monitored in real time allowing immediate dosing adjustments, and (2) fluctuations in the mass deposition on the microbalance would reveal the breathing frequency and tidal volume of the animal. The proposed device is expected to have an inhalation efficiency of about 60%. We propose to construct a prototype exposure system utilizing “mechanical rodents” designed to simulate the anatomy/physiology of a rodent’s respiratory system with adjustable respiratory minute volume as well as breathing frequency for application to either a mouse or a rat. Aerosols inhaled by the mechanical rodent will be collected on a filter to assess deposition. Further, we will validate the exposure system in-vivo with mice for the total pulmonary deposition as well as distribution of inhaled aerosol in the pulmonary tree using ‘nanocapsules’ of macromolecular drugs encapsulated in a ligand shell enabling targeted delivery to solid tumor cells and inflamed fibroblastic cells. Successful completion of this work would establish the feasibility of the proposed exposure system for highly efficient inhalation exposure. In Phase II, this device will be developed into a multiple animal exposure system and used for safety and efficacy studies of nanocapsules in treating lung cancer and chronic obstructive pulmonary disease.