PDF(Pubmed)
Abstract：
Although nebulizers have been developed for delivery of small molecules in human patients, no tunable device has been purpose-built for targeted delivery of modern large molecule and temperature-sensitive therapeutics to mice. Mice are used most of all species in biomedical research and have the highest number of induced models for human-relevant diseases and transgene models. Regulatory approval of large molecule therapeutics, including antibody therapies and modified RNA highlight the need for quantifiable dose delivery in mice to model human delivery, proof-of-concept studies, efficacy, and dose-response. To this end, we developed and characterized a tunable nebulization system composed of an ultrasonic transducer equipped with a mesh nebulizer fitted with a silicone restrictor plate modification to control the nebulization rate. We have identified the elements of design that influence the most critical factors to targeted delivery to the deep lungs of BALB/c mice. By comparing an in silico model of the mouse lung with experimental data, we were able to optimize and confirm the targeted delivery of over 99% of the initial volume to the deep portions of the mouse lung. The resulting nebulizer system provides targeted lung delivery efficiency far exceeding conventional nebulizers preventing waste of expensive biologics and large molecules during proof-of-concept and pre-clinical experiments involving mice. (Word Count =207).
摘要：
尽管已经开发出雾化器用于在人类患者中递送小分子，尚未专门制造可调谐设备，用于将现代大分子和温度敏感性治疗剂靶向递送至小鼠。在生物医学研究中，小鼠是所有物种中使用最多的物种，并且具有与人类相关的疾病和转基因模型的诱导模型。大分子疗法的监管批准，包括抗体疗法和修饰的RNA强调了在小鼠中可量化剂量递送以模拟人类递送的需要，概念验证研究，功效,和剂量反应。为此,我们开发了一种可调谐雾化系统，并对其进行了表征，该系统由一个超声换能器组成，该换能器配备了一个网状雾化器，该雾化器装有一个硅胶限流板修改以控制雾化速率。我们已经确定了影响靶向递送至BALB/c小鼠深肺部的最关键因素的设计要素。通过将小鼠肺的计算机模型与实验数据进行比较，我们能够优化并确认将超过99%的初始体积靶向递送至小鼠肺的深部.所得到的雾化器系统提供了远远超过常规雾化器的靶向肺递送效率,从而在涉及小鼠的概念验证和临床前实验期间防止了昂贵的生物制剂和大分子的浪费。（字数=207）。
