Development of an Intelligent Reactive Oxygen Species-Responsive Dual-Drug Delivery Nanoplatform for Enhanced Precise Therapy of Acute Lung Injury

Abstract

Dunling Xia,1 Zongqing Lu,1 Shuai Li,1 Pu Fang,1 Chun Yang,2 Xiaoyan He,3 Qinghai You,1 Gengyun Sun1 1Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Emergency Intensive Care Unit, the First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3School of Life Sciences, Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Qinghai You; Gengyun Sun, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Sanli’an Street, Shushan District, Hefei, Anhui Province, 230032, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]; [email protected]: Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) are commonly occurring devastating conditions that seriously threaten the respiratory system in critically ill patients. The current treatments improve oxygenation in patients with ALI/ARDS in the short term, but do not relieve the clinical mortality of patients with ARDS.Purpose: To develop the novel drug delivery systems that can enhance the therapeutic efficacy of ALI/ARDS and impede adverse effects of drugs.Methods: Based on the key pathophysiological process of ARDS that is the disruption of the pulmonary endothelial barrier, bilirubin (Br) and atorvastatin (As) were encapsulated into an intelligent reactive oxygen species (ROS)-responsive nanocarrier DSPE-TK-PEG (DPTP) to form nanoparticles (BA@DPTP) in which the thioketal bonds could be triggered by high ROS levels in the ALI tissues.Results: BA@DPTP could accumulate in inflammatory pulmonary sites through passive targeting strategy and intelligently release Br and As only in the inflammatory tissue via ROS-responsive bond, thereby enhancing the drugs effectiveness and markedly reducing side effects. BA@DPTP effectively inhibited NF-κB signaling and NLRP3/caspase-1/GSDMD-dependent pyroptosis in mouse pulmonary microvascular endothelial cells. BA@DPTP not only protected mice with lipopolysaccharide-induced ALI and retained the integrity of the pulmonary structure, but also reduced ALI-related mortality.Conclusion: This study combined existing drugs with nano-targeting strategies to develop a novel drug-targeting platform for the efficient treatment of ALI/ARDS.Keywords: acute lung injury, acute respiratory distress syndrome, reactive oxygen species-responsiveness, nanoparticles, bilirubin, atorvastatin

Keywords

• acute lung injury
• acute respiratory distress syndrome
• reactive oxygen species-responsiveness
• nanoparticles
• bilirubin
• atorvastatin