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.
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