Citrus pectin-coated inhalable PLGA nanoparticles for treatment of pulmonary fibrosis†

Abstract

Pulmonary fibrosis (PF) is a chronic interstitial disorder of the respiratory system that can be debilitating as it progresses and has experienced a slow rise in incidence in past years. Treatment is complicated by the complex aetiology of the disease and the off-target effects of the two FDA-approved therapeutics available on the market: pirfenidone and nintedanib. In this work, we propose a multipurpose nanoparticle system consisting of poly(lactic-co-glycolic) acid polymer (PLGA) and a coating of citrus pectin (CP) for galectin-3 targeting and anti-fibrotic therapy. Pectin from citrus peels has been observed to have anti-fibrotic activity in a range of fibrotic tissues, causing a decrease in the expression and activity of galectin-3: a key, upregulated marker of fibrosis. We show that the CP-PLGA nanoparticles (NPs) have an average diameter of 340.5 ± 10.6 nm, compatible with inhalation and retention in the deep lung, and that CP constitutes, on average, 40.3% of the final CP-PLGA formulation. The NPs are well-tolerated by MRC-5 lung fibroblasts up to 2 mg mL⁻¹. We demonstrate the NPs’ ability to target transforming growth factor β (TGFβ)-treated fibrotic MRC-5 cells in a specific, dose-dependent manner, saturating at approx. 250 μg mL⁻¹in vitro, and that our NPs have potent anti-fibrotic activity in vivo in particular, reversing bleomycin-induced fibrosis in mouse lungs, accompanied by marked reduction in profibrotic markers including collagen 1, fibronectin, α-smooth muscle actin, β-catenin and galectin-3. In all, we present an inherently therapeutic inhalable nanocarrier for galectin-3 targeting and anti-fibrotic therapy. We envision this carrier to be doubly effective against fibrotic lung tissue when combined with an encapsulated anti-fibrotic drug, improving overall/total therapeutic efficacy and patient compliance via the reduction of off-target effects and additive therapeutic effects.