Nanomicelles loaded with doxorubicin and curcumin for alleviating multidrug resistance in lung cancer

Abstract

Purpose

A new type of polymeric micelle (PM) was assembled using a polyethylene glycol (PEG)-linked (PEGylated) amphiphilic copolymer and d-tocopheryl PEG₁₀₀₀ succinate (TPGS₁₀₀₀). The micelles were used to deliver doxorubicin (DOX) and curcumin (CUR) for alleviating multidrug resistance (MDR) in lung cancer cells while enhancing the therapeutic efficacy of DOX.

Methods

Micelles loaded with DOX and CUR were assembled using a film-forming technique. Micelles were used to treat A549/Adr cells to find out whether micelles had the ability to reverse the MDR of A549/Adr cells. Some investigations were conducted using tumor-bearing mice to assess whether these micelles had enhanced antitumor efficacy as compared to DOX alone or the combination of DOX and CUR.

Results

Some micelles (DOX + CUR)–PMs had a small average size of about 17 nm and showed definite ability to deliver both DOX and CUR into DOX-resistant A549/Adr cells. The PMs had high cytotoxicity toward A549/Adr cells when the applied equivalent DOX dose was 1 µg/mL or higher. The cellular uptake of (DOX + CUR)–PMs into A549/Adr cells was found to be associated with an energy-dependent, caveolae-mediated, and clathrin-independent mechanism. (DOX + CUR)–PMs helped to prolong the circulation of DOX or CUR as compared to the individual administration of DOX or CUR, and they exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects of DOX.

Conclusion

TPGS₁₀₀₀ and CUR could synergistically reverse DOX-resistance of A549/Adr cells. In vivo examinations confirmed that the micelles had the capability to increase the plasma concentration of DOX or CUR, as well as to prolong their respective blood circulation. These micelles were able to significantly inhibit tumor growth in Lewis lung carcinoma tumor-bearing mice while reducing the side effects of DOX. The micelles showed potential in the treatment of lung cancer.

Keywords:

• synergistic effect
• drug-resistance
• doxorubicin
• curcumin
• polymeric micelles

Acknowledgments

This work was supported by the Wu Jieping Medical Foundation of China (grant number 320675013228), the Research Foundation of Hubei University of Science and Technology (grant number BK1432), and the National Natural Science Foundation of China (grant number 81371705).

Disclosure

The authors report no conflicts of interest in this work.