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

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• 作者：Priya Ravikumar ; PhD^a ; ^d ; ¹ ; Jyothi U. Menon ; PhD^b ; ¹ ; Primana Punnakitikashem ; MSc^b ; Dipendra Gyawali ; MSc^a ; Osamu Togao ; MD ; PhD^c ; ² ; Masaya Takahashi ; PhD^c ; Jianning Zhang ; MD^a ; Jianfeng Ye ; MD^a ; ^d ; Orson W. Moe ; MD^a ; ^d ; Kytai T. Nguyen ; PhD^b ; ^{Knguyen@uta.edu" class="auth_mail" title="E-mail the corresponding author} ; Connie C.W. Hsia ; MD^a ; ^{Connie.Hsia@utsouthwestern.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Poly-lactic-co-glycolic acid nanoparticles ; Aerosol nebulization ; Oxidative stress damage ; Gene therapy ; Cytoprotection ; Hyperoxia
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：12
• 期：3
• 页码：811-821
• 全文大小：1899 K

文摘

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.

From the Clinical Editor

Acute lung injury often results in significant morbidity and mortality, and current therapeutic modalities have proven to be ineffective. In this article, the authors developed nanocarrier based gene therapy in an attempt to upregulate the expression of pulmonary erythropoietin receptor in an animal model. Inhalation delivery resulted in reduction of lung damage.