Nanoparticles as potential therapeutics for acute myeloid leukemia

Abstract

Abstract Acute myeloid leukemia (AML) is associated with an unfavourable prognosis. Hence, new therapeutic agents with higher specificity and lower general cytotoxicity are urgently required. We synthesized biocompatible engineered nanoparticles and used various physico-chemical methods for their characterization. Cell viability was assessed by analysis of activities of mitochondrial dehydrogenases and colony-formation assay. Intracellular targets were identified by Western immunoblotting, fluorescent microscopy, flow cytometry, and various functional tests. We have previously shown that amino-functionalized polystyrene nanoparticles (PS-NH2) induce autophagy in leukemia cells and are selectively cytotoxic to leukemia cells compared to human macrophages and PBMC. We created now biocompatible amino-functionalized nanoparticles with an inert metallic gold core, Au-NH2, which were selectively highly cytotoxic towards different AML cell lines and PBMC from acute myeloid leukemia patients, but not to PBMC from healthy donors. We show that in leukemia cells, Au-NH2 treatment induces BID cleavage to tBID, increases mitochondrial superoxide levels, inhibits activity of complexes I, III, IV of the mitochondrial electron transport chain, and induces loss of the mitochondrial membrane potential as well as cytochrome c release from the mitochondrial intermembrane space and caspase 3 activation. Likewise, Au-NH2 treatment induces a rapid decrease in mTOR pathway activity, induces lysosomal rupture in THP-1 and HL-60 leukemia cells but not so in macrophages and PBMC. Thus, this engineered material holds great promise as a novel nanotherapeutic for treatment of acute myeloid leukemia independent of cytogenetic profile.