title: Ligand exchange on gold nanoparticles for drug delivery and enhanced therapeutic index evaluated in acute myeloid leukemia models.
abstract: Cancer chemotherapy is typically toxic. This problem could be addressed by using differences between cancer and normal cells for controlled delivery of drugs to cancer cells. One such difference is the ubiquitously elevated glutathione expression in cancer cells. We report a simple and versatile synthesis of water-soluble gold nanoparticles passivated with amine-containing molecules, which allow for controlled drug release via ligand exchange with bio-available glutathione. Taking methotrexate-passivated gold nanoparticles (Au:MTX) as an example, drug delivery and controlled release via glutathione-mediated ligand exchange was evaluated. Furthermore, the possibility of using Au:MTX to improve therapeutic index in acute myeloid leukemia (AML) models was examined in vitro and in vivo. Au:MTX exhibited cancer selectivity in vitro. Au:MTX had an elevated potency toward an AML cell line THP-1 in a dosage range of 1-5 nM, and therefore an enhanced delivery of drug, whereas normal hematopoietic stem/progenitor cell (HSPC) growth was minimally affected by Au:MTX and MTX treatments within the same range of dosage. In vivo efficacy and safety of Au:MTX was evaluated in a murine xenotransplant model of primary human AML. Au:MTX treatment, compared to control groups including MTX-only and Au nanoparticle-only treatments, produced better leukemia suppression without added toxicity, indicating an enhanced therapeutic index.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Shunji
authors.initials: S
authors.lastname: Egusa
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Quteba
authors.initials: Q
authors.lastname: Ebrahem
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Reda Z
authors.initials: RZ
authors.lastname: Mahfouz
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA saunthy@ccf.org.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
keywords: Nanoparticles; amine; cancer; drug delivery; leukemia; methotrexate