title: MicroRNA delivery by cationic lipoplexes for lung cancer therapy.
abstract: Lung cancer is the leading cause of cancer deaths in western countries and carries a poor overall five year survival rate. Several studies demonstrate that microRNAs (miRNAs or miRs) are actively involved in tumor development by serving as tumor suppressors, oncogenes or both. In lung cancer, miRNAs may serve as both diagnostic and prognostic biomarkers as well as regulate in vitro and in vivo tumor progression. However, miRNA-based therapy is faced with several challenges including lack of tissue specificity, lack of optimal delivery systems, poor cellular uptake and risk of systemic toxicity. Here, we report a cationic lipid based miRNA delivery system to address some of these challenges. Among many lung cancer related miRNAs, miR-133b, a tumor suppressor, was selected as a therapeutic target because it directly targets the prosurvival gene MCL-1 thus regulating cell survival and sensitivity of lung cancer cells to chemotherapeutic agents. The efficacy of pre-miR-133b containing lipoplexes was evaluated in A549 non-small cell lung cancer (NSCLC) cells. Compared with siPORT NeoFX transfection agent, lipoplexes delivered pre-miR-133b in a more efficient manner with ~2.3-fold increase in mature miR-133b expression and ~1.8-fold difference in MCL-1 protein downregulation in vitro. In the in vivo biodistribution study, lipoplexes achieved ~30% accumulation in lung tissue, which was ~50-fold higher than siPORT NeoFX transfection agent. Mice treated with pre-miR-133b containing lipoplexes had mature miR-133b expression in lung ~52-fold higher than untreated mice. Our results demonstrated that cationic lipoplexes are a promising carrier system for the development of miRNA-based therapeutics in lung cancer treatment.
authors.affiliation: Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, 174 West 18th Avenue, Room 1012, Columbus, Ohio 43210, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Melissa
authors.initials: M
authors.lastname: Crawford
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Mao
authors.forename: Serge P
authors.initials: SP
authors.lastname: Nana-Sinkam
authors.forename: L James
authors.initials: LJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010316:Particle Size; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D008055:Lipids; D035683:MicroRNAs