Targeted lung therapy with rosmarinic acid encapsulated in PLGA microspheres for radiation-induced pulmonary fibrosis

Radiation-induced pulmonary fibrosis (RIPF) is a frequent complication among individuals affected by nuclear accidents and patients undergoing chest radiation therapy for tumors. However, the availability of effective drugs for prevention and treatment of RIPF remains limited. Rosmarinic acid (RA), which displays inhibitory properties against RIPF, suffers from poor targeting in previous drug studies. To overcome this issue and achieve optimal therapeutic effects, continuous administration over several days is usually employed. In this study, we developed PLGA microspheres with an average size of 17 μm and drug loading efficiency of 24.97 % (±0.97 %), loaded with RA (RA/PLGAMS) using the membrane emulsification method. By controlling the size of microspheres in the pulmonary capillaries, we achieved lung targeting of microspheres, and based on the release of drugs as PLGA degrades, the residence time of drugs in the body is prolonged. And it was confirmed by in vivo imaging and SEM imaging that PLGAMS could exist in the lungs for at least 7 days. Our results demonstrated successful targeting of the lungs in a mouse model and sustained release of RA encapsulated in the PLGA microspheres. Notably, under the same administration conditions, the therapeutic efficacy of PLGA-encapsulated RA surpassed that of ordinary RA. We observed decreased expression of inflammatory factors, reduced M2 macrophage polarization, and weakened epithelial mesenchymal transformation following our treatment, which might explain the radiation damage alleviating effect of RA. After treatment, it was shown that the deep inspiratory capacity of the mice improved by 57.8 %, and WB showed a decrease of 52.4 % and 28.3 % in the expression of epithelial mesenchymal transition related proteins (TGF-β1 and α-SMA). In summary, PLGA microspheres offer a promising drug delivery system and treatment strategy for radiation-induced pulmonary fibrosis.