Inhaled Lipid Nanoparticles Alleviate Established Pulmonary Fibrosis

Pulmonary fibrosis,a lung disease with a high incidence and fatality rate,poses a great threat to people’s physical and mental health.It is characterized by loss of lung function,excessive deposition of extracellular matrix and breathing difficulties.Although clinically used drugs have played a certain effect on delaying the development of pulmonary fibrosis,their therapeutic effects need to be improved and the toxic side effects are relatively large.How to improve the therapeutic effect of small molecule drugs,improve the local concentration of drugs in the focal site and reduce their toxic and side effects are still difficult problems to be solved in the field of pulmonary fibrosis.In this dissertation,a series of liposomes containing anti-fibrosis drugs metformin and nintedanib were synthesized by chemical self-assembly strategy,and the best liposome was obtained through optimization,which could effectively reduce bleomycin-induced pulmonary fibrosis and promote lung repair.The following is the specific research content:1.Study on the preparation and characterization of liposomes and its inhibition of pulmonary fibrosis at the cellular level.Three kinds of liposomes with different surface potentials were synthesized by thin film hydration method,and amphiphilic linear polymer phospholipid-polyethylene glycol 5000(DSPE-PEG5K),which can be crosscoated on the surface of liposomes to form steric hindrance layer was added.The composition of neutral,cationic,or anionic and DSPE-PEG5K in liposomes was optimized by evaluating the retention of inhaled liposomes in the lungs.It was found that the neutral liposomes containing PEG had the longest retention time in the lungs of mice,so it could be used as an ideal carrier for pulmonary drug delivery.On this basis,metformin,a firstline anti-diabetic drug that has been reported to treat pulmonary fibrosis by regulating various metabolic pathways,and nintedanib,a clinical anti-fibrosis drug,were respectively encapsulated in liposomes.Their inhibitory effect on pulmonary fibrosis at the cellular level was also studied.It was found that the prepared metformin/nintedanib liposomes had good safety on murine lung epithelial cells and could significantly reduce pulmonary fibrosis at the cellular level.2.Study on the inhibition of bleomycin-induced pulmonary fibrosis by inhalable liposomes.A mouse model of pulmonary fibrosis using bleomycin was constructed,and the metformin/nintedanib liposomes were delivered to the lung lesion by inhalation delivery to achieve the treatment of pulmonary fibrosis.It was found that inhaled delivery of metformin/nintedanib liposomes can promote the inactivation and apoptosis of myofibroblasts,inhibit transforming growth factor β1(TGF-β1)and the formation of collagen,and reduce the cytokine storms caused by pulmonary fibrosis,thus effectively reducing the development of bleomycin-induced pulmonary fibrosis and improving lung function.In general,this work successfully prepared three kinds of liposomes with different surface potentials,and obtained the ideal drug carrier suitable for lung delivery.On this basis,the non-invasive delivery system of inhalable liposomes was developed,which showed good therapeutic effect in inhibiting pulmonary fibrosis at the cellular level and bleomycin induced pulmonary fibrosis in mice.Thus,it presents a versatile platform with promising clinical translation potential for the noninvasive inhalation delivery of drugs for respiratory disease treatment.