Development and Characterization of FLT3-Specific Curcumin-Loaded Polymeric Micelles as a Drug Delivery System for Treating FLT3-Overexpressing Leukemic Cells

Abstract

This study aimed to develop a curcumin (CM) nanoparticle targeted to Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3) protein on the surface of leukemic cells and to evaluate their properties, specificity, cytotoxicity, and inhibitory effect on FLT3 protein level in FLT3 overexpressing leukemic cells, EoL-1 and MV-4-11 cells. FLT3-specific peptides were conjugated onto modified poloxamer 407 (P407) using the copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC). The thin film hydration method was performed for FLT3-specific CM-loaded polymeric micelles (FLT3-CM-micelles) preparation. Flow cytometry and fluorescence microscopy were used to determine rate of cellular uptake. 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to test the cytotoxicity of the micelles on leukemic cells. FLT3-CM-micelles demonstrated a mean particle size less than 50 nm, high entrapment efficiency, and high rate of CM uptake by leukemic cells. The intracellular CM fluorescence is related to FLT3 protein levels on the leukemic cell surfaces. Moreover, FLT3-CM-micelles demonstrated an excellent cytotoxic effect and decreased FLT3 protein expression in the leukemic cells. The FLT3-CM-micelles could enhance both solubility and cytotoxicity of CM on FLT3 overexpressing leukemic cells. These promising nanoparticles may be used for enhancing anti-leukemic activity of CM and developed as a targeted drug delivery system in the future.

The effect of co-treatments of chemotherapeutic drugs and curcumin on cytotoxicity and FLT3 protein expression in leukemic stem cells

“…It is mostly found to overexpress on the cell surface of AML leukemic stem cells and leukemic cells and plays an important role in cell survival and proliferation of leukemic cell blasts 33 . Cur has previously been shown to have an inhibitory effect on FLT3 protein expression in many types of FLT-3 expressing leukemic cell lines, such as EoL-1 and MV4-11 27 . Thus, it was selected as a target protein for Dox-Cur treatment.…”

“…FLT3 is a key driver of AML, and its mutations are associated with the development of high risk of relapse in patients. Previous studies demonstrated that Cur has an inhibitory effect on FLT3 protein expression in leukemic cells 27 . Thus, the combination of Dox and Cur for AML treatment may lead to FLT3 protein expression reduction, which is involved in the proliferation process of leukemic cells.…”

“…It exhibits a wide range of pharmacological activities, such as antioxidant, anti-cancer, anti-in ammatory, and antimicrobial effects [22][23][24] . Previous studies reported that Cur exhibited an excellent cytotoxic effect; induced cell death in several types of leukemic cell lines 25,26 ; and showed inhibitory effects on WT1 and FLT3 protein expression, which are associated with cell proliferation 26,27 . Moreover, it inhibited the activity of Pglycoprotein (MDR1) 28 and exhibited cancer chemopreventive properties, especially in myocardial protection 29 by inhibiting ROS generation 30 .…”

Augmentation of therapeutic potential of curcumin using nanotechnology: current perspectives

“…FLT3 specific peptide with poloxamer formed micelle containing curcumin. In vitro studies using flow cytometry and fluorescence microscopy showed that FLT3-curcumin killed leukaemic cells by enriched internalization [104]. Further studies in detail about the mechanism can quickly transform curcumin from benchside to bedside and clinical applications since it has an impressive performance against various diseases including cancers.…”

Molecular Targets of Curcumin and Future Therapeutic Role in Leukemia

“…Curcumin have inhibiting effects on it, FLT3 interruption, and development of cell cycle (Figure 5).Curcumin loaded miceSlle formation has been used to inhibit formation cancerous cells[57]. Many FLT3 inhibitors such as PKC412, AC220, CEP-701, and AR200 have been used to overcome the levels of phosphorylated FLT3 protein.Significant decline was detected in cellular level of FLT3 protein after curcuminoid treatment as it arrested the activity of cell cycle at the G0/G1 phase and decreased the FLT3 and STAT protein levels[65]. Effects of curcumin on different S.Rafiq et al…”