Abstract
Excessive architectural re-modeling of tissues in pulmonary fibrosis due to proliferation of myofibroblasts and deposition of extracellular matrix adversely affects the elasticity of the alveoli and lung function. Progressively destructive chronic inflammatory disease, therefore, necessitates safe and effective non-invasive airway delivery that can reach deep alveoli, restore the surfactant function and reduce oxidative stress. We designed an endogenous surfactant-based liposomal delivery system of naringin to be delivered as an aerosol that supports pulmonary mechanics for the management of pulmonary fibrosis. Phosphatidylcholine-based liposomes showed 91.5 ± 2.4% encapsulation of naringin, with a mean size of 171.4 ± 5.8 nm and zeta potential of −15.5 ± 1.3 mV. Liposomes with the unilamellar structure were found to be spherical and homogeneous in shape using electron microscope imaging. The formulation showed surface tension of 32.6 ± 0.96 mN/m and was able to maintain airway patency of 97 ± 2.5% for a 120 s test period ensuring the effective opening of lung capillaries and deep lung delivery. In vitro lung deposition utilizing Twin Stage Impinger showed 79 ± 1.5% deposition in lower airways, and Anderson Cascade Impactor deposition revealed a mass median aerodynamic diameter of 2.35 ± 1.02 μm for the aerosolized formulation. In vivo efficacy of the developed formulation was analyzed in bleomycin-induced lung fibrosis model in rats after administration by the inhalation route. Lactate dehydrogenase activity, total protein content, and inflammatory cell infiltration in broncho-alveolar lavage fluid were substantially reduced by liposomal naringin. Oxidative stress was minimized as observed from levels of antioxidant enzymes. Masson’s Trichrome staining of lung tissue revealed significant amelioration of histological changes and lesser deposition of collagen. Overall results indicated the therapeutic potential of the developed non-invasive aerosol formulation for the effective management of pulmonary fibrosis.
Highlights
Airway delivery of therapeutics as nano-formulation has been demonstrated to be a viable approach for site-specific of medicines for treating chronic, progressive, and fatal lung diseases like fibrosis [1]
Nintedanib and pirfenidone changed the treatment paradigm in pulmonary fibrosis and increased our understanding of mechanisms of disease progression, several challenges and unmet needs still need to be managed to improve the quality of life of patients
To date, there is no report on the development of a product that could act in a multifactorial way for the management of pulmonary fibrosis
Summary
Airway delivery of therapeutics as nano-formulation has been demonstrated to be a viable approach for site-specific of medicines for treating chronic, progressive, and fatal lung diseases like fibrosis [1]. Pulmonary fibrosis needs long-term treatment and rationalizes the quest for the local delivery of novel and safe antiinflammatory and anti-fibrotic medications. The focus of the research has always been the use of nano-carriers for aerosol delivery that will eventually lead to the improved therapeutic efficacy of the drug [4]. Being a treatment of vital organs, the material-borne toxicity of such carriers should not be overlooked [5]. This concern becomes more important as many nanoparticulate systems have shown pulmonary toxicity after inhalation. Effective clinical translation of therapeutically effective aerosol drug delivery would need a biocompatible and safe nano-carrier
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