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 as cytarabine 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.
