Transferrin-targeted polymeric micelles co-loaded with curcumin and paclitaxel: efficient killing of paclitaxel-resistant cancer cells

Abstract

Purpose: The ability to successfully treat advanced forms of cancer remains a challenge due to chemotherapy resistance. Numerous studies indicate that NF-κB, a protein complex that controls the expression of numerous genes, as being a key factor in producing chemo-resistant tumors. In this study, the therapeutic potential of transferrin (TF)-targeted mixed micelles, made of PEG-PE and vitamin E co-loaded with curcumin (CUR), a potent NF-κB inhibitor, and paclitaxel (PCL), was examined.

Methods: The cytotoxicity of non-targeted and TF-targeted CUR and PCL micelles as a single agent or in combination was investigated against SK-OV-3 human ovarian adenocarcinoma along with its multi-drug resistant (MDR) version SK-OV-3-PCL-resistant (SK-OV-3TR) cells in vitro.

Results: Our results indicated that the TF-targeted combination micelles were able to improve the net cytotoxic effect of CUR and PCL to clear synergistic one against the SK-OV-3 cells. In addition, even though the non-targeted combination treatment demonstrated a synergistic effect against the SK-OV-3TR cells, the addition of the TF-targeting moiety significantly increased this cytotoxic effect. While keeping CUR constant at 5 and 10 μM and varying the PCL concentration, the PCL IC50 decreased from ~1.78 to 0.68 μM for the non-targeted formulations to ~0.74 and 0.1 μM for the TF-targeted ones, respectively.

Conclusion: Our results indicate that such co-loaded targeted mixed micelles could have significant clinical advantages for the treatment of resistant ovarian cancer and provide a clear rational for further in vivo investigation.

Figure 1

Cell association of the various TF-targeted micelles by flow cytometry to determine optimal ligand density. A- SK-OV-3, B- SK-OV-3TR. Different concentrations of TF-PEG₃₄₀₀-PE (0.5–5 mol %) of TF-targeted Rh-labeled micelles were incubated with the cells for 1 hour at a lipid concentration of 0.3 mg/mL and then analyzed. Values represent % increase in cellular association versus control (empty micelle treated) cells. N=9 + SD, p < 0.05.

Figure 2

Cell viability of SK-OV-3 (A) and SK-OV-3TR (B) cells after 48hrs of continuous incubation with PCL or TF-PCL micelles at various concentrations. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments performed in triplicate, mean + SD * P < 0.05.

Figure 3

Cell viability of SK-OV-3 (A) and SK-OV-3TR (B) cells after 48hrs of continuous incubation with CUR or TF-CUR micelles at various concentrations. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments performed in triplicate, mean + SD * P < 0.05.

Figure 4

Cell viability of SK-OV-3 cells after 48hrs of continuous incubation with non-targeted and TF-targeted combination treatment of 5 or 10 μM of CUR and various concentrations of PCL. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments performed in triplicate, mean + SD * P < 0.05.

Figure 5

Cell viability of SK-OV-3TR cells after 48hrs of continuous incubation with the non-targeted and TF-targeted combination treatment of 5 or 10 μM of CUR and various concentrations of PCL. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments performed in triplicate, mean + SD * P < 0.05.