Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

Abstract

Background

The natural compound n-butylidenephthalide (BP) can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo.

Objective

The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery.

Methods

To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC). Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections.

Results

When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition.

Conclusion

LPPC encapsulation technology is able to protect BP’s structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

Keywords:

• n-butylidenephthalide
• lipo-PEG-PEI complex
• glioblastoma multiforme
• antitumor

Acknowledgments

This work was partially supported by UST-UCSD International Center of Excellence in Advanced Bioengineering sponsored by the Ministry of Science and Technology I-RiCE Program under grant number MOST 103-2911-I-009-101. This work was also partially supported by the MOE ATU Program, Taiwan, and grant PU/CSMU-102-2 from the Chung Shan Medical University Foundation, Taiwan. Zeiss LSM 510 META confocal microscopy was performed in the Instrument Center of Chung Shan Medical University, which is supported by the National Science Council, the Ministry of Education, and Chung Shan Medical University.

Disclosure

The authors report no conflicts of interest in this work.