Surface-Modified Micellar Formulations of Curcumin Co-Loaded with Chemotherapeutic Agents for Enhanced Anti-Cancer Effect

Even though there have been significant improvements in the detection and treatment of early stage cancers, the ability to successfully treat advanced forms of the disease remains a challenge due to the acquired resistance to chemotherapy. Numerous studies indicate that the nuclear factor-kappa B (NF-kB)-induced cascade of gene expression as being a key factor in producing such chemo-resistant tumor phenotypes. Here, we investigated the efficacy of curcumin (CUR), a potent NF-kB inhibitor, co-loaded with either paclitaxel (PCL) or doxorubicin (DOX) in mixed micelles, made of PEG-PE and vitamin E, against a range of cancer cell types.;First, the combination with PCL 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 CUR 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.;Second, the therapeutic potential of transferrin (TF)-targeted CUR and PCL mixed micelles was also investigated against SK-OV-3 and SK-OV-3TR cells in vitro and in vivo. This TF-targeted formulation was also tested on NCI-ADR-RES resistant ovarian cancer spheroids. 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 vitro and in the spheroid model as well. 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 the cytotoxic effects by decreasing the IC50 values of the combination treatment in vitro. However, there was no significant difference between non-targeted and TF-targeted formulation in vivo possibly because the spontaneous accumulation at the tumor site was enough to exert the maximum tumor inhibition observed.;Third, the therapeutic efficacy of PEG-PE micelles, co-loaded with CUR and DOX, and targeted with anti-GLUT1 antibody (GLUT1), was evaluated against HCT-116 human colorectal adenocarcinoma and MDA-MB-231 breast cancer cells both in vitro and in vivo. CUR and DOX co-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR+DOX micelles did not exhibit any significant tumor inhibition versus control. However, GLUT1-CUR and GLUT1-CUR+DOX micelles showed a significant tumor inhibition effect with an improvement in survival.;In conclusion, we have found that these combination treatments of CUR with PCL or DOX had a robust tumor killing both in vitro (2D and 3D) and in mouse xenografts. Our data show promising antitumor efficacy and these micelles could have significant clinical advantages for the treatment of sensitive and resistant cancers.