Fluorescent Pirfenidone-Cerium(III) nanocomplexes protect against radiation-induced pulmonary fibrosis and inhibit tumor cell growth

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a common adverse effect of thoracic radiation therapy. Although pirfenidone is approved for treating pulmonary fibrosis, its utility is limited by its short half-life and ability to scavenge reactive oxygen species (ROS). Thus, a nanoscale complexes of cerium(III), 10-carboxyl-pirfenidone, and 1,10-phenanthroline (NPs Ce(phen)Pirf3) was developed to prevent RIPF in a mouse model. NPs Ce(phen)Pirf3 was successfully prepared using a simple moderate solvothermal method and characterized using FTIR, electrospray ionization MS, 1H nuclear magnetic NMR, and transmission electron microscopy. The cerium(III) nanocomplexes exhibited a near-spherical shape and dissolved in water with a diameter of ∼125.2 nm, as characterized by dynamic light scattering. Compared with pirfenidone, NPs Ce(phen)Pirf3 with blue fluorescence exhibited prolonged retention times with thoracic-specific accumulation in vivo. Mice received 15 Gy gamma-ray treatment on the thorax with or without NPs Ce(phen)Pirf3 or pirfenidone administration. NPs Ce(phen)Pirf3 improved lung function, alleviated radiation-induced pathological changes in the lung tissues, and reduced collagen deposition 16 weeks after radiation. Our results from in vivo and in vitro experiments demonstrated that NPs Ce(phen)Pirf3 increased the ROS-scavenging ability. Additionally, NPs Ce(phen)Pirf3 regulated epithelial-mesenchymal transition (EMT)-related proteins, including up-regulate E-cadherin and down-regulate N-cadherin, α-SMA, and TGF-β1 in RLE-6TN cells, which suggested NPs Ce(phen)Pirf3 may alleviate RIPF by inhibiting EMT. Finally, NPs Ce(phen)Pirf3 also inhibited the growth of thoracic tumor cells in mice. NPs Ce(phen)Pirf3 had a protective role against RIPF and antitumor effects, suggesting that they are a promising therapy for thoracic radiation-induced RIPF.