Vitamin E-rich Nanoemulsion Enhances the Antitumor Efficacy of Low-Dose Paclitaxel by Driving Th1 Immune Response

Abstract

Purpose

To overcome the drawbacks of high dose regimen and improve the outcomes of chemotherapy at a low dose, an immunotherapeutic nanoemulsion based combination of chemotherapeutic agent (paclitaxel) with immunomodulatory agent (vitamin E) was developed and evaluated for their antitumor effect against breast cancer.

Methods

A total of five nanoemulsions loaded with various content of vitamin E were prepared and characterized. The immunoregulatory effects of vitamin E along with the overall antitumor efficacy of vitamin E-rich nanoemulsion with a low dose of paclitaxel were investigated through in vitro and in vivo experiments.

Results

Vitamin E-rich nanoemulsion exhibited relatively narrow size distribution, high entrapment efficiency and controlled in vitro release profile. In RAW264.7 cells, vitamin E-rich nanoemulsion significantly enhanced the secretion of Th1 cytokines and down-regulated the secretion of Th2 cytokine. In a co-culture system, vitamin E-rich nanoemulsion induced a high apoptosis rate in MDA-MB-231 cells as compared with vitamin E-low nanoemulsion. Furthermore, vitamin E-rich nanoemulsion exhibited superior in vivo antitumor efficacy in comparison with Taxol and vitamin E-low nanoemulsion at a paclitaxel dose of 4 mg/kg.

Conclusions

Vitamin E-rich nanoemulsion has great potential for the treatment of breast cancers with a low dose of paclitaxel via driving Th1 immune response.

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Abbreviations

CFDA-SE:

Carboxyfluorescein diacetate succinimidyl ester

EE:

Entrapment efficiency

ELISA:

Enzyme-linked immunosorbent assay

E:T:

Effector cells: target cells

HPLC:

High performance liquid chromatography

IFN-γ:

Interferon γ

IL-10:

Interleukin 10

IL-12:

Interleukin 12

LDLR:

Low-density lipoprotein receptor

MTD:

Maximum tolerated dose

PBS:

Phosphate buffer solution

PDI:

Polydispersity index

PI:

Propidium iodide

PTX:

Paclitaxel

Th1:

T helper 1

Th2:

T helper 2

VE:

Vitamin E

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Acknowledgments and Disclosures

This work was financially supported by the National Natural Science Foundation of China (No. 81402874) and the Beijing Natural Science Foundation of China (No. 7162135). The authors report no conflicts of interest in this work.

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Corresponding author

Correspondence to Yuling Liu.

Additional information

Jun Ye and Wujun Dong contributed equally to this work.

Electronic supplementary material

Figure S1

The stability of nanoemulsions was monitored at 4°C for 9 months. (a) Particle size and polydispersity index (PDI) of nanoemulsions loaded with paclitaxel and variant content of vitamin E (0.01%, 2.4%, 4.8%, 7.2%, and 10%, w/v). (b) Particle size distribution and standard deviation of nanoemulsions determined by the Zeta Potential/Particle Sizer NICOMP 380 ZLS (PSS NICOMP, Santa Barbara, CA, USA). (GIF 37 kb)

High Resolution Image (TIFF 6904 kb)

Figure S2

In vivo tumor growth inhibition (a) and body weight changes (b) of 4T1 tumor-bearing BALB/c nude mice after intravenous treatment of mice with Taxol, 0.01%VE, or 7.2%VE at the dose of 4 mg/kg PTX. (c) Representative images of excised tumors from different groups at the end of the experiment. a, 7.2%VE vs. Control, p < 0.01; b, 7.2%VE vs. Taxol, p < 0.01; c, 0.01%VE vs. Control, p < 0.01; d, 0.01%VE vs. Taxol, p < 0.01; e, 7.2%VE vs. 0.01%VE, p > 0.05. (GIF 91.1 kb)

High Resolution Image (TIFF 8.63 mb)

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Ye, J., Dong, W., Yang, Y. et al. Vitamin E-rich Nanoemulsion Enhances the Antitumor Efficacy of Low-Dose Paclitaxel by Driving Th1 Immune Response. Pharm Res 34, 1244–1254 (2017). https://doi.org/10.1007/s11095-017-2141-3

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KEY WORDS

  • immunochemotherapy
  • low-dose paclitaxel
  • nanoemulsion
  • Th1 immune response
  • vitamin E