title: Passive targeting of phosphatiosomes increases rolipram delivery to the lungs for treatment of acute lung injury: An animal study.
abstract: A novel nanovesicle carrier, phosphatiosomes, was developed to enhance the targeting efficiency of phosphodiesterase 4 (PDE4) inhibitor to the lungs for treating acute lung injury (ALI) by intravenous administration. Phosphatiosomes were the basis of a niosomal system containing phosphatidylcholine (PC) and distearoylphosphatidylethanolamine polyethylene glycol (DSPE-PEG). Rolipram was used as the model drug loaded in the phosphatiosomes. Bioimaging, biodistribution, activated neutrophil inhibition, and ALI treatment were performed to evaluate the feasibility of phosphatiosomes as the lung-targeting carriers. An encapsulation percentage of >90% was achieved for rolipram-loaded nanovesicles. The vesicle size and zeta potential of the phosphatiosomes were 154 nm and -34 mV, respectively. Real-time imaging in rats showed a delayed and lower uptake of phosphatiosomes by the liver and spleen. Ex vivo bioimaging demonstrated a high accumulation of phosphatiosomes in the lungs. In vivo biodistribution exhibited increased lung accumulation and reduced brain penetration of rolipram in phosphatiosomes relative to the control solution. Phosphatiosomes improved the lungs/brain ratio of the drug by more than 7-fold. Interaction with pulmonary lipoprotein surfactants and the subsequent aggregation may be the mechanisms for facilitating lung targeting by phosphatiosomes. Rolipram could continue to inhibit active neutrophils after inclusion in the nanovesicles by suppressing O2(-) generation and elevating cAMP. Phosphatiosomes significantly alleviated ALI in mice as revealed by examining their pulmonary appearance, edema, myeloperoxidase (MPO) activity, and histopathology. This study highlights the potential of nanovesicles to deliver the drug for targeting the lungs and attenuating nervous system side effects.
authors.affiliation: Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Lang
authors.initials: CL
authors.lastname: Fang
authors.affiliation: School of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan; Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Wen
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Aljuffali
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA.
authors.forename: Calvin T
authors.initials: CT
authors.lastname: Sung
authors.affiliation: Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan. Electronic address: fajy@mail.cgu.edu.tw.
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Fang
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D010713:Phosphatidylcholines / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D004337:Drug Carriers; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D058988:Phosphodiesterase 4 Inhibitors; C038089:1,2-distearoylphosphatidylethanolamine; D011092:Polyethylene Glycols; D020889:Rolipram
keywords: Acute lung injury; Lung; Niosomes; Phosphatiosomes; Rolipram