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. 2017 Apr 3:12:2621-2634.
doi: 10.2147/IJN.S128921. eCollection 2017.

Delivery of curcumin by directed self-assembled micelles enhances therapeutic treatment of non-small-cell lung cancer

Wen-Ting Zhu  1   2 , Sheng-Yao Liu  3 , Lei Wu  1   2 , Hua-Li Xu  4 , Jun Wang  1   2 , Guo-Xin Ni  3   5 , Qing-Bing Zeng  1   2
Affiliations

Delivery of curcumin by directed self-assembled micelles enhances therapeutic treatment of non-small-cell lung cancer

Wen-Ting Zhu et al. Int J Nanomedicine. .

Erratum in

Abstract

Background: It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future.

Materials and methods: In this study, CUR-loaded methoxy polyethylene glycol-polylactide (CUR/mPEG-PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently.

Results: The average size of CUR/mPEG-PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067-0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG-PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG-PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG-PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG-PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax.

Conclusion: The mPEG-PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG-PLA micelles have promising clinical potential in treating NSCLC.

Keywords: A549 cells; HUVECs; angiogenesis; curcumin; mPEG–PLA; polymeric micelles.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Preparation and characterization of CUR micelles. Notes: (A) Preparation scheme of CUR micelles. (B) Particle size distribution of CUR micelles. (C) TEM image of CUR micelles. (D) In vitro drug release profiles of free CUR and CUR micelles in PBS (pH 7.4). CUR micelles, CUR/mPEG–PLA micelles. Abbreviations: CUR, curcumin; mPEG–PLA, methoxy polyethylene glycol–polylactide; PBS, phosphate-buffered saline; TEM, transmission electron microscope.
Figure 2
Figure 2
Confirmation of the absence of CUR crystals in the CUR/mPEG–PLA micelles. Notes: (A) XRD analysis of CUR, physical mixture of CUR and mPEG–PLA, blank mPEG–PLA micelles and CUR/mPEG–PLA micelles. (B) DSC analysis of CUR, blank mPEG–PLA micelles and CUR/mPEG–PLA micelles. Abbreviations: CUR, curcumin; DSC, differential scanning calorimetry; mPEG–PLA, methoxy polyethylene glycol–polylactide; XRD, X-ray diffraction.
Figure 3
Figure 3
Cytotoxicity studies and cellular uptake assay of CUR micelles. Notes: (A) Cytotoxicity studies of A549 cells treated with free CUR and CUR micelles. (B) Fluorescent images of A549 cells treated with free CUR and CUR micelles under a confocal microscope at the indicated time intervals. Nuclei were stained blue with Hoechst 33258, and cellular distribution of CUR is shown as green fluorescence in the cytosol. (Magnifcation 400×) (C) CUR fluorescence means accumulation in A549 cells. (D) FCM histogram for free CUR and CUR micelles at 20 μg/mL on A549 cells for 1 hour. (E) FCM histogram for free CUR and CUR micelles at 20 μg/mL on A549 cells for 4 hours. CUR micelles, CUR/mPEG–PLA micelles. Abbreviations: CUR, curcumin; FCM, flow cytometry; mPEG–PLA, methoxy polyethylene glycol–polylactide; h, hour.
Figure 4
Figure 4
CUR micelles induce cell cycle arrest in A549 cells. Notes: (A) Cell cycle distribution of A549 cells treated with free CUR and CUR micelles. (B) Clonogenic survival assay of A549 cells treated with free CUR or CUR micelles. (C) The histograms exhibit percent of cells in different phages of cell cycle. (D) Analysis of colonies per dish, represented as a percent of control. Blank micelles, blank mPEG–PLA micelles; CUR micelles, CUR/mPEG–PLA micelles. Abbreviations: CUR, curcumin; mPEG–PLA, methoxy polyethylene glycol–polylactide.
Figure 5
Figure 5
CUR micelles induced A549 cells apoptosis and caspase 3 activation. Notes: (A) The apoptosis incidence of A549 cells was evaluated by FCM; cells were treated with blank micelles, free CUR and CUR micelles, respectively. (B) Statistical analysis of apoptotic rate was calculated via the percentage of apoptotic cells. (C) Western blotting for the expression of proteins related to apoptosis Bax and Bcl-2, GAPDH acted as a loading control. (D) Changes of Caspase 3 activity. Blank micelles, blank mPEG–PLA micelles; CUR micelles, CUR/mPEG–PLA micelles. Abbreviations: CUR, curcumin; FCM, flow cytometry; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; mPEG–PLA, methoxy polyethylene glycol–polylactide.
Figure 6
Figure 6
CUR micelles inhibited the migration and invasion of A549 cells in vitro. Notes: (A and C) CUR micelles inhibited A549 cell migration in wound-healing assay. (B and D) CUR micelles inhibited A549 cell invasion in transwell assay. Images in (A and B) were taken by microscope under ×100 magnification. (E) The VEGF, MMP-2 and MMP-9 were analyzed by Western blotting assay, with GAPDH acted as loading controls. Blank micelles, blank mPEG–PLA micelles; CUR micelles, CUR/mPEG–PLA micelles. Abbreviations: CUR, curcumin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MMP, matrix metalloproteinase; mPEG–PLA, methoxy polyethylene glycol–polylactide; VEGF, vascular endothelial growth factor.
Figure 7
Figure 7
CUR micelles induced cytotoxicity and inhibited tube formation, migration and invasion of HUVECs in vitro. Notes: (A and E) CUR micelles inhibited tube formation of HUVECs. (B and F) CUR micelles inhibited HUVECs migration in wound-healing assay. (C and G) CUR micelles inhibited HUVECs invasion in transwell assay. Images in (A–C) were taken by microscope under ×100 magnification. (D) CUR micelles enhanced the cytotoxicity of CUR of HUVECs. Blank micelles, blank mPEG–PLA micelles; CUR micelles, CUR/mPEG–PLA micelles. Abbreviations: CUR, curcumin; HUVECs, human umbilical vein endothelial cells; mPEG–PLA, methoxy polyethylene glycol–polylactide.
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