Abstract
To ameliorate multidrug resistance (MDR) observed in leukemia cells, nanomicelles modified by transferrin (Tf-M-DOX/PSO), coencapsulating doxorubicin (DOX) and psoralen (PSO), were designed, synthesized and tested in K562 and doxorubicin-resistant K562 (K562/DOX) cells. In vitro drug release kinetics for constructed nanomicelles were measured using high-performance liquid chromatography. Characterization of the produced nanomicelles was completed using transmission electron microscopy and dynamic light scattering. Uptake of the nanomicelles in K562 cells was investigated using both confocal microscopy and flow cytometry. Apoptosis levels as well as the expression of glycoprotein (P-gp) were analyzing by western blotting and flow cytometry. Cellular cytotoxicity resulting from the exposure of nanomicelles was evaluated using MTT assays. The nanomicelles all showed mild release of DOX in PBS solution. In K562/DOX cells, Tf-M-Dox/PSO exhibited higher uptake compared to the other nanomicelles observed. Furthermore, cellular cytotoxicity when exposed to Tf-M-Dox/PSO was 2.8 and 1.6-fold greater than observed in the unmodified DOX and Tf-nanomicelles loaded with DOX alone, respectively. Tf-M-Dox/PSO strongly increased apoptosis of K562/DOX cells. Finally, the reversal of the drug resistance when cells are exposed to Tf-M-DOX/PSO was associated with P-gp expression inhibition. The Tf-M-Dox/PSO nanomicelle showed a reversal of MDR, with enhanced cellular uptake and delivery release.
Highlights
Leukemia is a common malignant hematopoietic stem cell disease classified as the 6th most lethal cancer accounting for 4% of all cancer cases [1]
Most studies agree with the view that multidrug resistance (MDR) correlates with elevated levels of permeability glycoprotein (P-gp), an ATP-dependent efflux pump that efficiently decreases the concentration of administered medication introduced to the cell
The results showed that cells treated with M, transferrin-modified nanomicelles (Tf-M) or DOX showed no differences in cell apoptosis compared with the control group
Summary
Leukemia is a common malignant hematopoietic stem cell disease classified as the 6th most lethal cancer accounting for 4% of all cancer cases [1]. Chemotherapy is the first treatment choice for this disease. Multidrug resistance (MDR) is an obstacle to the satisfactory application of cancer chemotherapy. New approaches to reverse MDR are needed to improve chemotherapy as well as overall cancer treatment [4,5,6]. Several mechanisms that account for MDR have been reported [7,8,9]. Most studies agree with the view that MDR correlates with elevated levels of permeability glycoprotein (P-gp), an ATP-dependent efflux pump that efficiently decreases the concentration of administered medication introduced to the cell. The use of traditional drug delivery is limited in clinical practice due to increased cytotoxicity [10,11,12]
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