(44e) Enhanced Therapeutic Index in Acute Myeloid Leukemia Models By Gold Nanoparticles Directly Passivated With Chemotherapeutics

An enduring, fundamental issue in cancer medicine is that of poor therapeutic index. Treatments typically destroy normal as well as cancer cells, causing toxicity that limits the safety and efficacy. Enabling cancer-selective drug delivery would substantially address this problem, by identifying and exploiting the difference between normal and cancer cells. In this study, we utilize the higher redox stress of cancer cells, and consequently the higher glutathione (an endogenous anti-oxidant) expression, as the key to realize selective delivery. We have developed Au nanoparticles directly passivated with amine-containing drug molecules as drug vehicles, where drug release would be triggered by glutathione via ligand exchange. Au nanoparticles are commonly passivated by thiol-containing molecules via strong thiol-Au bond. Our amine drug-passivated Au nanoparticles relies on amine-Au interaction that is of lower affinity than thiol-Au interaction, and hence drug delivery mediated by in situ ligand exchange with bioavailable thiols e.g. glutathione could be facilitated compared to the conventional thiol-pasivated Au nanoparticles. Using Au nanoparticles directly passivated with methotrexate (Au:MTX), the mechanism of drug delivery is elucidated in vitro and in vivo. Enhanced therapeutic index of Au:MTX is demonstrated using a murine xenotransplant model of primary human acute myeloid leukemia (AML), a cancer which is disseminated without large tumor masses: therefore the improved efficacy suggests a mechanism involving cancer-selective drug delivery at the cellular level, as opposed to e.g. the enhanced permeability and retention (EPR) effect via leaky neovasculature in solid tumor models. The structural simplicity of the amine drug-Au nanoparticles moreover allows for facile functionalizations and scale-up, and could positively impact a breadth of therapeutics.