Tools for Improved Translation of Novel Inhalable Therapeutics

改进新型吸入疗法转化的工具

• 批准号: 10088009
• 负责人: AMIR A NAQWI
• 金额: $ 5.5万
• 依托单位: ABBE VISION, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088009
• 关键词: Address; Aerosols; Air Movements; Anatomy; Anesthesia procedures; Animals; Antibodies; Biological; Breathing; Canis familiaris; Cells; Charge; Chronic Obstructive Airway Disease; Cone; Deposition; Development; Devices; Dimensions; Dose; Electrostatics; Encapsulated; Engineering; Equipment; Family suidae; Felis catus; Ferrets; Film; Formulation; Frequencies; Genes; Human; Immunotherapy; Infectious Agent; Inhalation; Inhalation Exposure; Legal patent; Ligands; Liquid substance; Lung; Lung diseases; Malignant neoplasm of lung; Mechanics; Monitor; Mus; Nebulizer; Needles; Nose; Particle Size; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiology; Plethysmography; Procedures; Proteins; RNA; RNA Interference; Rattus; Respiratory System; Rodent; Rodent Model; Sheep; Solid Neoplasm; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Tidal Volume; Time; Trachea; Translations; Trauma; Trees; Tube; Vaccines; Work; aerosolized; base; design; drug inhalation; efficacy study; endotracheal; improved; improved outcome; in vitro testing; in vivo; in vivo evaluation; macromolecule; nanocapsule; nanomaterials; nanoparticle; neoplastic cell; novel; novel therapeutics; novel vaccines; particle; pediatric patients; preclinical study; prototype; real time monitoring; respiratory; safety study; submicron; targeted delivery; therapeutic development; therapeutic nanoparticles; time use; tool

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.

项目概述：随着肺部疾病发病机制的阐明， 在治疗干预的药物开发中取得的成就。新的假定药物不断 然而，它们的初始可用性往往极其有限，特别是对于基于生物的， 大分子试剂（例如蛋白质、基因、RNA和抗体）。这些代理的翻译特别 如果递送模式是吸入，则具有挑战性。现有的啮齿动物暴露系统不适合这些 药物的损失通常超过99%。虽然可以施用小体积的 将试剂溶液用气管内针注射到啮齿动物模型中，这需要麻醉并导致 肺内分布不佳。该项目解决了有效吸入给药的关键需求-首先在 啮齿类动物，然后是大型动物和人类患者。一种有效的啮齿动物吸入暴露系统， 不仅需要测试假定的疗法，而且还需要感染因子，新疫苗和工程 纳米材料 我们提出的方法是非侵入性的，不需要麻醉，因此适用于无创伤， 每日剂量。气溶胶将用小体积的液体（例如10微升）产生，基本上不产生任何气溶胶。 液体被困在装置中。此外，颗粒将靠近动物的鼻孔产生，这将 最小化死体积，从而最小化药剂的损失。逸出肺部沉积的气溶胶将 静电沉积在配备实时读数的质量微量天平上。好处包括：（1） 将真实的时间监测气雾剂暴露，允许立即调整剂量，和（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。 所提出的装置预期具有约60%的吸入效率。 我们建议利用“机械啮齿动物”来构建一个原型暴露系统， 啮齿动物呼吸系统的解剖学/生理学，每分钟呼吸量可调，以及 呼吸频率以应用于小鼠或大鼠。机械啮齿动物吸入的气溶胶 在过滤器上收集以评估沉积。此外，我们将在小鼠体内验证暴露系统， 总肺沉积以及吸入气溶胶在肺树中的分布， 包封在配体壳中的大分子药物的“纳米胶囊”， 肿瘤细胞和发炎的成纤维细胞。 这项工作的成功完成将确立拟议的暴露系统的可行性， 有效的吸入暴露。在第二阶段，该设备将发展成为一个多动物接触系统 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