Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin

Abstract

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment.

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“…PI3K/AKT is a vital signalling pathway that promotes cell survival and cellular tolerance against multiple apoptotic insults [30,31]. PI3K/AKT pathway plays an important biological role in cell apoptosis, survival, proliferation, cytoskeleton change and other biological processes [32].…”

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“…Notch mediates the proliferation, self-renewal and differentiation of stem and progenitor cells to generate mature cells in the blood ( 122 ). The activation of Notch signaling is associated with poor prognosis of patients with AML ( 123 ), and targeting Nocth1 has been considered as a novel strategy for AML treatment ( 124 ). AIL has been demonstrated to deactivate the Notch and PI3K/AKT signaling pathways by upregulating miR-449a expression ( 38 ).…”