Inhalation of tetrandrine liposomes for the treatment of bleomycin induced idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease of unknown cause, with limited therapeutic options and an urgent need to develop new treatment methods. However, there is still a lack of suitable inhaled drugs for the treatment of IPF due to non-specific side effects, inability to cross the pulmonary barrier, and inadequate management of heterogeneity. In this study, we hypothesized that tetrandrine liposomes (TET-LIPs) delivered by inhalation might have a direct targeting effect on lung tissue, effectively treat IPF and limit its adverse side effects on other organs. Morphology, particle size, zeta potential, and in vitro dissolution studies of the prepared TET-LIPs were performed. Blood aspartate aminotransferase (AST), alanine aminotransferase (ALT), Urea nitrogen (BUN), creatinine (Cr) were measured to determine the liver and renal function. Bleomycin-induced mice model of IPF was used to evaluate the in vivo pharmacodynamics of TET-LIPs. The levels of hydroxyproline, tumor necrosis factor (TNF-α), and transforming growth factor (TGF-β 1 ) were examined by enzyme-linked immunosorbent assay (ELISA). Finally, alveolar lavage fluid lipid profiles were obtained by using ultra-performance liquid chromatography combined with quadrupole-Exactive Orbitrap mass spectrometry (UPLC-Q-Exactive Orbitrap MS). Inhaled TET-LIPs significantly inhibited the progression of bleomycin-induced acute inflammation and pulmonary fibrosis in lung tissue. Furthermore, delivering the drug locally to the lungs showed little accumulation in the liver and kidneys after long-term inhalation and had a favorable safety profile. Interestingly, we observed a relationship between inhaled TET-LIPs and increased levels of triglycerides (TG), fatty acids (FA) while decreased levels of lysophosphatidylcholine (LPC) in BALF. Overall, as TET-LIPs were safe and well-tolerated in the BLM-induced mice model, tetrandrine encapsulation in liposomes could be an effective method for locally delivering to patients with IPF. Simultaneously, our findings revealed that various lipid metabolic disorders were linked to the early inflammatory phase of the fibrosis process, and the regulation of lipid metabolism may be one of the mechanisms to improve pulmonary fibrosis using TET-LIPs.