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. 2014 Apr 10;464(1-2):178-84.
doi: 10.1016/j.ijpharm.2014.01.009. Epub 2014 Jan 17.

Polyethylene glycol-phosphatidylethanolamine (PEG-PE)/vitamin E micelles for co-delivery of paclitaxel and curcumin to overcome multi-drug resistance in ovarian cancer

Abraham H Abouzeid  1 , Niravkumar R Patel  1 , Vladimir P Torchilin  2
Affiliations

Polyethylene glycol-phosphatidylethanolamine (PEG-PE)/vitamin E micelles for co-delivery of paclitaxel and curcumin to overcome multi-drug resistance in ovarian cancer

Abraham H Abouzeid et al. Int J Pharm. .

Abstract

The therapeutic potential of mixed micelles, made of PEG-PE and vitamin E co-loaded with curcumin and paclitaxel, was investigated against SK-OV-3 human ovarian adenocarcinoma along with its multi-drug resistant version SK-OV-3-paclitaxel-resistant (TR) cells in vitro and in vivo. The addition of curcumin at various concentrations did not significantly enhance the cytotoxicity of paclitaxel against SK-OV-3 in vitro. However, a clear synergistic effect was observed with the combination treatment against SK-OV-3TR in vitro. In vivo, this combination treatment produced a three-fold tumor inhibition with each of these cell lines. Our results indicate that such co-loaded mixed micelles could have significant clinical advantages for the treatment of resistant ovarian cancer.

Keywords: Combination therapy; Curcumin; Mixed micelles; Multi-drug resistance; Nuclear factor-kappa B (NF-κB); Ovarian cancer.

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Conflict of interest statement

No conflict of interest is declared.

Figures

Figure 1
Figure 1
Release profiles of the drug-loaded micelles. Drug-loaded micelles (1 ml) placed in 1 L of PBS pH 7.4 supplied with 0.2% tween-80 to maintain sink conditions at 37°C using a 3500 Da MWCO membrane.
Figure 2
Figure 2
Cell viability of SK-OV-3 (panel A) and SK-OV-3TR (panel B) cells after 48 hrs of continuous incubation with free PCL/CUR or micellar PCL/CUR at various concentrations. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments performed in triplicate.
Figure 3
Figure 3
Cell viability of SK-OV-3 and SK-OV-3TR after 48 hrs of continuous incubation with micellar CUR at various concentrations. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments performed in triplicate.
Figure 4
Figure 4
Cell viability of SK-OV-3 (A) and SK-OV-3TR (B) cells after 48 hrs of continuous incubation with combination micelles at various concentrations of PCL and CUR. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments performed in triplicate.
Figure 5
Figure 5
Comparison of cell death of SK-OV-3TR cells after the treatment with various concentrations of PCL, 10 µM CUR, or combination treatment. MDR reversal capability of CUR was best demonstrated at a concentration of 10 µM. Cell viability was determined using CellTiter Blue cell viability assay. Data shown are representative of 3 independent experiments and each performed in triplicate.
Figure 6
Figure 6
Tumor inhibition studies with various micellar formulations. Nude mice bearing ~200 mm3 SK-OV-3 (A) and SK-OV-3TR (B) tumors were treated every 3 days at a dose of 25 mg/kg CUR and 10 mg/kg PCL IP starting at day zero. Empty micelle dose was equivalent to the amount of micelle-forming material from the drug-loaded micelle groups. (One way ANOVA was performed from day 45–75 on A and from day 30–60 on B, * p<0.05 with n ≥5 /group and all values are expressed as mean ± SEM. SK-OV-3 (C) and SK-OV-3TR (D) tumors were harvested when the average tumor volume in the control group reached 1000 mm3. (Student’s two tailed unpaired T-test, * p<0.05) n ≥5/group ± SEM.
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