Abstract
In a previous study, we constructed a lung-targeting lipopolyplex containing polyethyleneimine (PEI), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and N-lauroylsarcosine (LS). The lipopolyplex exhibited an extremely high gene expression in the lung after intravenous administration. Here, we optimized the lipopolyplex and used it to deliver a TGF-β1 shRNA to treat refractory pulmonary fibrosis. We constructed several lipopolyplexes with pDNA, various cationic polymers, cationic lipids, and LS to select the most effective formulation. Then, the pDNA encoding shRNA against mouse TGF-β1 was encapsulated in the lipopolyplex and injected into mice with bleomycin-induced pulmonary fibrosis. After optimizing the lipopolyplex, dendrigraft poly-L-lysine (DGL) and DOTMA were selected as the appropriate cationic polymer and lipid, respectively. The lipopolyplex was constructed with a pDNA, DGL, DOTMA, and LS charge ratio of 1:2:2:4 showed the highest gene expression. After intravenous administration of the lipopolyplex, the highest gene expression was observed in the lung. In the in vitro experiment, the lipopolyplex delivered pDNA into the cells via endocytosis. As a result, the lipopolyplex containing pDNA encoding TGF-β1 shRNA significantly decreased hydroxyproline in the pulmonary fibrosis model mice. We have successfully inhibited pulmonary fibrosis using a novel lung-targeting lipopolyplex.
Highlights
Gene therapy to the lungs has been studied in many genetic and refractory lung diseases, such as idiopathic pulmonary fibrosis (IPF) [1], asthma [2], and several types of lung cancer [3,4].IPF is a progressive, fatal lung disease
The pDNA, a cationic polymer, di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and LS were mixed at a charge ratio of 1:2:2:4
The respiratory administration of small interfering RNA (siRNA) and short hairpin RNA (shRNA) is an effective and safe delivery method, it can be physically difficult for patients with decreased lung function [14]
Summary
Gene therapy to the lungs has been studied in many genetic and refractory lung diseases, such as idiopathic pulmonary fibrosis (IPF) [1], asthma [2], and several types of lung cancer [3,4]. IPF is a progressive, fatal lung disease. Nintedanib and pirfenidone, approved by the Food and Drug Administration to treat IPF in 2014 based on a positive phase 3 trial [5], are recommended in the 2015 ATS/ERS/JRS/ALAT clinical practice guidelines. These drugs are used to suppress IPF progression; they are not radical treatments. Gene therapy is increasingly considered as a new treatment; because it works via a different mechanism from that of existing drugs, it can be a radical treatment
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