Engineered Nanoparticles as Potential Therapeutics for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a malignancy associated with poor prognosis. Particularly, older patients suffer greatly from the standard chemotherapy and have a 5-year survival of only 4%. Hence, new therapeutic agents with higher specificity and lower general cytotoxicity are urgently required. We have discovered that positively charged amino-functionalized polystyrene nanoparticles (NP-PS ) induce accumulation of acidic vesicular organelles with elevated pH and impaired processing of procathepsin B leading to mTOR inhibition, activation of autophagy, and induction of caspase-dependent apoptosis in leukemia cells, but not in normal human macrophages. The antileukemic effect of NP-PS was also preserved in vivo, where NP-PS inhibited proliferation and induced apoptosis in leukemia xenografts grown on chick chorioallantoic membranes. Similar to polystyrene particles, amino-functionalized gold nanoparticles (NP-Au ) exhibited selective cytotoxicity towards AML cell lines as well as primary patient-derived AML cells. Thus, NP-Au particles induced cell death in primary human leukemia cells and reduced their colony-forming potential, whereas normal hematopoietic cells remained unaffected by the treatment with NP-Au . NP-Au targeted specifically the oxidative mitochondrial respiration, which is, different to normal hematopoietic cells, the main source of energy production in AML blasts and leukemic stem cells. Different to NP-Au , conventional chemotherapeutics such ascytarabine act in a cell cycle-dependent manner and target only on proliferating AML blasts but not on quiescent leukemic stem cells. In agreement with the in vitro data, NP-Au exhibited antileukemic efficacy against primary human AML xenografted into mice applied either as monotherapy or as a cytarabine combination regimen in the absence of detectable adverse events. Thus, this engineered nanomaterial that targets particularly resistant quiescent leukemic stem cells holds great promise as a novel nanotherapeutic for the treatment of acute myeloid leukemia independent of its cytogenetic profile.