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

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          Abstract

          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 ∼12 μm, 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-β progression, and suppressed ECM component production (collagen I and α-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.

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          Highlights

          • The 12 μm-sized aerosolizable μGel consists of p-LP and n-PN.

          • The μGels evade the phagocytosis by alveolar macrophages.

          • The μGels prevent rapid clearance and systemic circulation through alveoli.

          • The μGels exhibit inhibitory effect on the EMT process of epithelial cells.

          • The μGels show significant anti-fibrotic efficacy in mice with pulmonary fibrosis.

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          Most cited references62

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          The basics of epithelial-mesenchymal transition.

          The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
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            Simple method of estimating severity of pulmonary fibrosis on a numerical scale.

            A continuous numerical scale for determining the degree of fibrosis in lung specimens was devised for correlation with other pulmonary variables such as lung function tests or mineral burden. Grading was scored on a scale from 0 to 8, using the average of microscope field scores. The system allows fibrosis to be measured in small samples of tissue (1 cm) which can provide a detailed description of the changes in a lung, currently not possible with most existing methods.
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              Strategies in the design of nanoparticles for therapeutic applications.

              Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biological barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
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                Author and article information

                Contributors
                Journal
                Bioact Mater
                Bioact Mater
                Bioactive Materials
                KeAi Publishing
                2452-199X
                22 November 2023
                March 2024
                22 November 2023
                : 33
                : 262-278
                Affiliations
                [a ]School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do, 16419, Republic of Korea
                [b ]Department of Precision Medicine, School of Medicine, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
                [c ]School of Advanced Materials Science and Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
                Author notes
                []Corresponding author. ysyoun@ 123456skku.edu
                Article
                S2452-199X(23)00354-7
                10.1016/j.bioactmat.2023.11.005
                10708963
                38076650
                4d5a2197-7e43-4bc8-82bf-1fea9e8fe6e5
                © 2023 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 24 August 2023
                : 30 October 2023
                : 10 November 2023
                Categories
                Article

                aerosolizable microgel,lung retention,extracellular matrix,pro-inflammatory cytokines,idiopathic pulmonary fibrosis

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