Alveolar macrophage phagocytosis-evading inhaled microgels incorporating nintedanib-PLGA nanoparticles and pirfenidone-liposomes for improved treatment of pulmonary fibrosis  

作　　者：Woo Tak Lee Hyunjun Lee Juho Kim Yujin Jung Eojin Choi Ji Hoon Jeong Jee-Heon Jeong Jung Heon Lee Yu Seok Youn 

机构地区：[1]School of Pharmacy,Sungkyunkwan University,2066 Seobu-ro,Jangan-gu,Suwon,Gyeonggi-do,16419,Republic of Korea [2]Department of Precision Medicine,School of Medicine,Sungkyunkwan University,2066 Seobu-ro,Jangan-gu,Suwon,16419,Republic of Korea [3]School of Advanced Materials Science and Engineering,Sungkyunkwan University,2066 Seobu-ro,Jangan-gu,Suwon,16419,Republic of Korea

出　　处：《Bioactive Materials》2024年第3期262-278,共17页生物活性材料（英文）

基　　金：supported by a National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT;No.NRF-2019R1A5A2027340);by the Bio&Medical Technology Development Program of the NRF funded by the Korean government(MSIT,No.NRF-2022M3A9G8017220).

摘　　要：Idiopathic pulmonary fibrosis(IPF)is a chronic inflammatory and fibrotic response-driven lung disease that is difficult to cure because it manifests excessive profibrotic cytokines(e.g.,TGF-β),activated myofibroblasts,and accumulated extracellular matrix(ECM).In an attempt to develop an inhalation formulation with enhanced antifibrotic efficacy,we sought to fabricate unique aerosolizable inhaled microgels(μGel)that contain nintedanib-poly(lactic-co-glycolic acid)(PLGA)nanoparticles(NPs;n-PN)and pirfenidone-liposomes(p-LP).The aero-μGel was~12μm,resisted phagocytosis by alveolar macrophages in vitro and in vivo,and protected inner-entrapped n-PN and p-LP.The n-PN/p-LP@aero-μGel caused enhanced/extended antifibrotic efficacy in a bleomycin-induced pulmonary fibrosis mouse presumably due to prolonged lung residence.Consequently,the results obtained by intratracheal aerosol insufflation of our n-PN/p-LP@aero-μGel twice a week were much better than those by as many as seven doses of single or mixed applications of n-PN or p-LP.The antifibrotic/pharmacokinetic results for the n-PN/p-LP@aero-μGel included reduced fibrosis progression,restored lung physiological functions,deactivated myofibroblasts,inhibited TGF-βprogression,and suppressed ECM component production(collagen I andα-SMA)along with prolonged lung retention time.We believe that our n-PN/p-LP@aero-μGel increased the local availability of both nintedanib and pirfenidone due to evasion of alveolar macrophage phagocytosis and prolonged lung retention with reduced systemic distribution.Through this approach,our inhalation formulation subsequently attenuated fibrosis progression and improved lung function.Importantly,these results hold profound implications in the therapeutic potential of our n-PN/p-LP@aero-μGel to serve as a clinically promising platform,providing significant advancements for improved treatment of many respiratory diseases including IFP.

关 键 词：Aerosolizable microgel Lung retention Extracellular matrix Pro-inflammatory cytokines Idiopathic pulmonary fibrosis 

分 类 号：TQ427.2[化学工程]