Amphiphilic Copolymeric Micelles for Doxorubicin and Curcumin Co-Delivery to Reverse Multidrug Resistance in Breast Cancer

Abstract

Development of multidrug resistance against chemotherapeutic drugs is one of the major obstacles to successful cancer therapy in the clinic. Thus far, amphiphilic polymeric micelles and chemosensitizers have been used to overcome multidrug resistance in cancer. The goals of this study were to prepare poly(ethylene glycol)-bock-poly(lactide) (PEG(2k)-PLA(5k)) micelles for co-delivery of the chemotherapeutic drug doxorubicin (DOX) with a chemosensitizer curcumin (CUR), investigate the potential of the dual drug-loaded micelles ((DOX+CUR)-Micelles) to reverse multidrug resistance, and explore the underlying mechanisms. (DOX + CUR)-Micelles were prepared using an emulsion solvent evaporation method. The cellular uptake, drug efflux, down-regulation of P-glycoprotein expression and inhibition of ATP activity of (DOX+ CUR)-Micelles were studied in drug-resistant MCF-7/ADR cells. In vitro analyses demonstrated that (DOX + CUR)-Micelles were superior to free DOX, free drug combination (DOX + CUR), and DOX-loaded micelles in inhibiting proliferation of MCF-7/ADR cells. This effect of (DOX + CUR)-Micelles was partially attributable to their highest cellular uptake, lowest efflux rate of DOX, and strongest effects on down-regulation of P-glycoprotein and inhibition of ATP activity. Additionally, (DOX+CUR)-Micelles showed increased tumor accumulation and strong inhibitory effect on tumor growth in the xenograft model of drug-resistant MCF-7/ADR cells compared to that of other drug formulations. These results indicate that (DOX + CUR)-Micelles display potential for application in the therapy of drug-resistant breast carcinoma.

Nanomedicine-Mediated Combination Drug Therapy in Tumor

“…Cisplatin and paclitaxel PEG-PGlu90-PPhe25 hybrid micelles Ovarian cancer [56] Linear-dendritic telodendrimer micelles Ovarian cancer [57] Doxorubicin and disulfiram Polymeric micelles Breast cancer [58] Doxorubicin and curcumin Polymeric micelles Breast cancer [59] Doxorubicin and paclitaxel Pluronic mixed micelles Breast cancer [60] Docetaxel and chloroquine PEO-PPO-PCL/TPGS micelles Breast cancer [61] Paclitaxel and curcumin PEG-PE and vitamin E micelles Ovarian cancer [62] In order to eradicate ovarian cancer, Desale et al [56] synthesized biodegradable triblock copolymers containing ethylene glycol, glutamic acid, and phenylalanine (PEG-PGlu-PPhe). These copolymers self-assembled to form micelles for the co-delivery of CDDP and PTX, and the resulting nanomedicine mounted strong tumor suppression effects both in vitro and in vivo.…”

Curcumin as a Modulator of P-Glycoprotein in Cancer: Challenges and Perspectives

“…The encapsulation of curcumin (alone or in combination with another drug) within micelles has also been described [52,53,54,55]. The improved effects of this type of formulation could be attributed to the solubilization of the hydrophobic curcumin in the micelle core, together with the P-gp inhibitory effect of curcumin.…”

“…The co-delivered micelles exhibited excellent cytotoxicity, reverted the MDR phenotype, and promoted an increase in the cellular uptake of doxorubicin, which induced apoptosis in MCF7/Adr MDR cells [54]. Finally, in another work, amphiphilic polymeric micelles were prepared, also in order to encapsulate doxorubicin and curcumin [55]. MCF7/Adr MDR cells were treated with those micelles, and the cellular uptake of doxorubicin, the cellular drug efflux rate, the downregulation of P-gp expression, and the inhibition of ATP activity were assessed.…”

“…Results showed a higher cellular uptake and lower efflux rate of doxorubicin, and a stronger effect on the downregulation of P-gp and inhibition of ATP activity in cells treated with the co-encapsulated micelles, when compared to control treatments (curcumin and/or doxorubicin alone). Additionally, those micelles presented increased tumor accumulation and stronger inhibitory effect on tumor growth in a xenograft model of the same MDR cells, when compared to other drug formulations [55]. …”

Amphiphilicity Regulation of AgI Nanoclusters: Self‐Assembly and Its Application as a Luminescent Probe

“…Amphiphilic molecules are molecules with both hydrophilic groups and hydrophobic groups. One prominent feature of amphiphilic molecules is that they can self‐assembly into ordered aggregates (micelles, vesicles, nanosheets, and so on) spontaneously . Thus, it can be speculated that introducing amphiphilicity into metal NCs is perhaps one of methods to enhance the luminescence of NCs.…”