Nanoparticle facilitated inhalational delivery of erythropoietin receptor cDNA protects against hyperoxic lung injury

• Published in: Nanomedicine 2016-04, Vol.12 (3), p.811-821
• Main Authors: Ravikumar, Priya, PhD, Menon, Jyothi U., PhD, Punnakitikashem, Primana, MSc, Gyawali, Dipendra, MSc, Togao, Osamu, MD, PhD, Takahashi, Masaya, PhD, Zhang, Jianning, MD, Ye, Jianfeng, MD, Moe, Orson W., MD, Nguyen, Kytai T., PhD, Hsia, Connie C.W., MD
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Aerosol nebulization; Animals; Cell Line; Cytoprotection; DNA, Complementary - administration & dosage; DNA, Complementary - genetics; DNA, Complementary - therapeutic use; Gene therapy; Gene Transfer Techniques; Humans; Hyperoxia; Hyperoxia - genetics; Hyperoxia - pathology; Hyperoxia - therapy; Internal Medicine; Lactic Acid - chemistry; Lung - metabolism; Lung - pathology; Lung Injury - genetics; Lung Injury - pathology; Lung Injury - therapy; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Oxidative stress damage; Poly-lactic-co-glycolic acid nanoparticles; Polyglycolic Acid - chemistry; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin - genetics; Up-Regulation
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2015.10.004

Abstract Our goals were to develop and establish nanoparticle (NP)-facilitated inhalational gene delivery, and to validate its biomedical application by testing the hypothesis that targeted upregulation of pulmonary erythropoietin receptor (EpoR) expression protects against lung injury. Poly-lactic-co-glycolic acid (PLGA) NPs encapsulating various tracers were characterized and nebulizated into rat lungs. Widespread NP uptake and distribution within alveolar cells were visualized by magnetic resonance imaging, and fluorescent and electron microscopy. Inhalation of nebulized NPs bearing EpoR cDNA upregulated pulmonary EpoR expression and downstream signal transduction (ERK1/2 and STAT5 phosphorylation) in rats for up to 21 days, and attenuated hyperoxia-induced damage in lung tissue based on apoptosis, oxidative damage of DNA, protein and lipid, tissue edema, and alveolar morphology compared to vector-treated control animals. These results establish the feasibility and therapeutic efficacy of NP-facilitated cDNA delivery to the lung, and demonstrate that targeted pulmonary EpoR upregulation mitigates acute oxidative lung damage.