Abstract
This study aimed to assess the suitability of hyperpolarized 129Xe (HPXe) MRI for noninvasive longitudinal evaluation of pulmonary function in preclinical lung cancer models. A mouse model of lung cancer (LC) was induced in 5 mice by intraperitoneal injection of urethane, while a negative-control (NC) mice (N = 5) was prepared by injection of saline solution. Longitudinal HPXe MRI was performed over a 5-month period to monitor lung ventilation and gas exchange. The treatment efficacy of ethyl pyruvate (EP), an anti-inflammatory drug, to the mouse LC model was monitored using HPXe MRI by commencing administration of EP pre (early-phase) and 1-month post (late-phase) injection of urethane (N = 5 mice for each group). Gas-exchange function in LC mice was significantly reduced at 1-month after urethane injection compared with NC mice administered with saline (P < 0.01). Thereafter, it remained consistently lower than that of the NC group for the full 5-month measurement period. In contrast, the ventilation function of the LC model mice was not significantly different to that of the NC mice. Histological analysis revealed alveolar epithelial hyperplasia in LC mice alveoli at 1 month after urethane injection, and adenoma was confirmed 3 months after the injection. The early- and late-phase EP interventions were found to improve HPXe MRI metrics (reduced at 1 month postinjection of urethane) and significantly inhibit tumor growth. These results suggest that HPXe MRI gas-exchange metrics can be used to quantitatively assess changes in the precancerous lesion microenvironment and to evaluate therapeutic efficacy in cancer. Thus, HPXe MRI can be utilized to noninvasively monitor pulmonary pathology during LC progression and can visualize functional changes during therapy.
Highlights
Lung cancer is the leading cause of cancer mortality worldwide [1]
Previous studies were performed only after solid tumor nodules had fully developed [11,12,13,14,15,16,17,18], with few studies exploring dissolved-phase 129Xe in lung cancer models to date [14, 17]. In light of these previous reports, we attempted to perform an exploratory hyperpolarized 129Xe (HPXe) Magnetic resonance imaging (MRI) study in preclinical lung cancer. at is, in this work, we evaluated changes in pulmonary ventilation and gas exchange function during progression of pathology in a mouse model of lung cancer induced by urethane injection [19] using HPXe MRI
Precancerous lesions classified as alveolar epithelial hyperplasia were observed at 1 month after urethane injection [22]. is was followed by a mixture of alveolar epithelial hyperplasia and atypical adenomatous hyperplasia at 2 months, and adenoma at 3 and 5 months
Summary
In Japan alone, the mortality rate and the number of lung cancer associated deaths reached 59.5% and 74,120, respectively, in 2017, and these numbers are predicted to further increase [2]. There is a lack of effective lung cancer treatments and the development of novel drugs, for example, molecular targets and immune checkpoint inhibitors [3, 4], is of significant interest. Preclinical studies using small animals such as mice and rats are key steps in the assessment of the treatment efficacy of new drugs prior to consideration for clinical trials. Magnetic resonance imaging (MRI) is safe, nonionising and well-suited to repeated, longitudinal measurements and is a powerful tool for treatment response assessment in a preclinical setting.
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