Abstract
The targeted nano-encapsulation of anticancer drugs can improve drug delivery and the selective targeting of cancer cells. Nuclear factor kappa B (NF-kB) is a regulator for different biological responses, including cell proliferation and differentiation. In acute myeloid leukemia (AML), constitutive NF-κB has been detected in more than 50% of cases, enabling leukemic cells to resist apoptosis and stimulate uncontrolled proliferation. We evaluated NF-kB expression in bone marrow samples from 103 patients with AML using quantitative real time polymerase chain reaction (RT-PCR) and found that expression was increased in 80.5% (83 out 103) of these patients with AML in comparison to the control group. Furthermore, overexpressed transmembrane glycoprotein (CD44) on leukemic cells in comparison to normal cells is known to play an important role in leukemic cell engraftment and survival. We designed poly lactide co-glycolide (PLGA) nanoparticles conjugated with antiCD44 and encapsulating parthenolide (PTL), a nuclear factor kappa B (NF-kB) inhibitor, in order to improve the selectivity and targeting of leukemic cells and to spare normal cells. In vitro, in leukemic cell lines Kasumi-1, KG-1a, and THP-1, proliferation was decreased by 40% (** p < 0.01) with 5 µM PLGA-antiCD44-PTL nanoparticles in comparison to the same concentration of free PTL (~10%). The higher uptake of the nanoparticles by leukemic cells was confirmed with confocal microscopy. In conclusion, PLGA-antiCD44-PTL nanoparticles improved the bioavailability and selective targeting of leukemic cells, thus holding promise as a drug delivery system to improve the cure rate of AML.
Highlights
Acute myeloid leukemia (AML) is associated with a high relapse rate and poor overall survival, even with up-to-date chemotherapeutic drugs
Various studies have reported clones known as leukemic stem cells (LSCs) as the main cause of relapse and chemotherapeutic resistance [2]
We found that expression of NF-κB was increased in 80.5% of patients with acute myeloid leukemia (AML) (83 out of 103)
Summary
Acute myeloid leukemia (AML) is associated with a high relapse rate and poor overall survival, even with up-to-date chemotherapeutic drugs. The overall leukemia incidence rate increased by almost. 2% per year (2004–2013), driven primarily by AML; AML incidence increased from 3.4 (per 100,000) in 2004 to 5.1 in 2013. In spite of achievements in the survival for patients with AML, especially younger patients, AML long-term survival is still an area of active research. Various studies have reported clones known as leukemic stem cells (LSCs) as the main cause of relapse and chemotherapeutic resistance [2]. LSCs are described as a small chemoresistant clones that have endless self-renewal and produces blast cells in huge numbers [3]. As a step forward to improving the long-term survival for patients with
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