title: Daunorubicin-Loaded DNA Origami Nanostructures Circumvent Drug-Resistance Mechanisms in a Leukemia Model.
abstract: Many cancers show primary or acquired drug resistance due to the overexpression of efflux pumps. A novel mechanism to circumvent this is to integrate drugs, such as anthracycline antibiotics, with nanoparticle delivery vehicles that can bypass intrinsic tumor drug-resistance mechanisms. DNA nanoparticles serve as an efficient binding platform for intercalating drugs (e.g., anthracyclines doxorubicin and daunorubicin, which are widely used to treat acute leukemias) and enable precise structure design and chemical modifications, for example, for incorporating targeting capabilities. Here, DNA nanostructures are utilized to circumvent daunorubicin drug resistance at clinically relevant doses in a leukemia cell line model. The fabrication of a rod-like DNA origami drug carrier is reported that can be controllably loaded with daunorubicin. It is further directly verified that nanostructure-mediated daunorubicin delivery leads to increased drug entry and retention in cells relative to free daunorubicin at equal concentrations, which yields significantly enhanced drug efficacy. Our results indicate that DNA origami nanostructures can circumvent efflux-pump-mediated drug resistance in leukemia cells at clinically relevant drug concentrations and provide a robust DNA nanostructure design that could be implemented in a wide range of cellular applications due to its remarkably fast self-assembly (≈5 min) and excellent stability in cell culture conditions.
authors.affiliation: Department of Mechanical and Aerospace Engineering, College of Engineering, The Ohio State University, Columbus, OH, 43210, USA.|Department of Chemical and Biomolecular Engineering, College of Engineering, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Halley
authors.affiliation: Department of Mechanical and Aerospace Engineering, College of Engineering, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lucas
authors.affiliation: Biomedical Sciences Graduate Program, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: McWilliams
authors.affiliation: Biophysics Graduate Program, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Webber
authors.affiliation: Department of Mechanical and Aerospace Engineering, College of Engineering, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Randy A
authors.initials: RA
authors.lastname: Patton
authors.affiliation: Biophysics Graduate Program, Department of Physics, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Comert
authors.initials: C
authors.lastname: Kural
authors.affiliation: Department of Internal Medicine, College of Medicine, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.affiliation: Department of Internal Medicine, College of Medicine, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Mechanical and Aerospace Engineering, College of Engineering, Biophysics Graduate Program, The Ohio State University, Columbus, OH, 43210, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Castro
mesh_terms: D000818:Animals; D018736:DNA Adducts / Q000737:chemistry* / Q000494:pharmacology* / Q000648:ultrastructure; D003630:Daunorubicin / Q000737:chemistry* / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D018922:HL-60 Cells; D006736:Horses; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry; D007938:Leukemia / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D009690:Nucleic Acid Conformation
chemical_list: D018736:DNA Adducts; D007364:Intercalating Agents; C020270:daunorubicin-DNA; D004317:Doxorubicin; D003630:Daunorubicin
keywords: DNA nanotechnology; DNA origami; drug delivery; drug resistance; leukemia