Abstract
For the past 50 years, the route of inhalation has been utilized to administer therapies to treat a variety of respiratory and pulmonary diseases. When compared with other drug administration routes, inhalation offers a targeted, non-invasive approach to deliver rapid onset of drug action to the lung, minimizing systemic drug exposure and subsequent side effects. However, despite advances in inhaled therapies, there is still a need to improve the preclinical screening and the efficacy of inhaled therapeutics. Innovative in vitro models of respiratory physiology to determine therapeutic efficacy of inhaled compounds have included the use of organoids, micro-engineered lung-on-chip systems and sophisticated bench-top platforms to enable a better understanding of pulmonary mechanisms at the molecular level, rapidly progressing inhaled therapeutic candidates to the clinic. Furthermore, the integration of complementary ex vivo models, such as precision-cut lung slices (PCLS) and isolated perfused lung platforms have further advanced preclinical drug screening approaches by providing in vivo relevance. In this review, we address the challenges and advances of in vitro models and discuss the implementation of ex vivo inhaled drug screening models. Specifically, we address the importance of understanding human in vivo pulmonary mechanisms in assessing strategies of the preclinical screening of drug efficacy, toxicity and delivery of inhaled therapeutics.
Highlights
Respiratory diseases are among the leading causes of mortality worldwide, with chronic obstructive pulmonary disease (COPD), lung infections, lung cancer and tuberculosis all listed in the top 10 causes of death (World Health Organisation [WHO], 2019a,b)
Conventional in vitro impactor studies have utilized air-liquid interface (ALI) culture models to measure the permeability of a drug solution once pipetted onto the cell layer but overlook the important physiochemical characteristics of aerosolized particles that affect in vivo drug deposition, therapeutic efficacy and clinical relevance
Similar to the mNGI and modified ACI (mACI), a modified version of the twin stage impinger (TSI) has integrated an ALI cell culture model at the base of stage 2 (Figure 5) enabling aerosolized drugs to be deposited directly at the respiratory epithelia to better mimic in vivo biopharmaceutical processes (Figure 5; Grainger et al, 2012; Haghi et al, 2012; Ong et al, 2014)
Summary
Respiratory diseases are among the leading causes of mortality worldwide, with chronic obstructive pulmonary disease (COPD), lung infections (viral and bacterial), lung cancer and tuberculosis all listed in the top 10 causes of death (World Health Organisation [WHO], 2019a,b). ALI culture models provide a unique in vitro platform to mimic drug deposition onto the respiratory epithelial surface allowing downstream drug transport, efficacy and cytotoxicity studies to be performed (Grainger et al, 2006; Ong et al, 2011; Salomon et al, 2014).
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