Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo

Abstract

The aim of the present study was to develop a novel dosage form of multivesicular liposomes for oleanolic acid (OA) to overcome its poor solubility, prolong therapeutic drug levels in the blood, and enhance the antitumor effect on hepatocellular carcinoma. OA-encapsulated multivesicular liposomes (OA-MVLs) were prepared by a double-emulsion method, and the formulation was optimized by the central composite design. The morphology, particle size, and drug-loading efficiency of OA-MVLs were investigated. Furthermore, OA-MVLs were also characterized both in vitro and in vivo. The results showed that OA-MVLs were spherical particles with an average particle size of 11.57 μm and an encapsulation efficiency of 82.3%±0.61%. OA-MVLs exhibited a sustained-release pattern in vitro, which was fitted to Ritger–Peppas equation. OA-MVLs inhibited the growth of human HepG2 cells which was confirmed by the MTT assay and fluorescence microscopy detection. The in vivo release of OA from OA-MVLs exhibited a sustained manner, indicating a longer circulation time compared to OA solution. The in vivo toxicity study indicated that medium-dose OA-MVLs exerted no toxic effect on the hosts. Importantly, OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice. In conclusion, the poorly soluble OA could be encapsulated into MVLs to form a novel controlled-release drug delivery system. The present study may hold promise for OA-MVLs as a new dosage form for sustained-release drug delivery in cancer therapy.

Keywords:

• oleanolic acid
• multivesicular liposomes
• murine hepatocellular carcinoma
• controlled release
• cancer therapy

Acknowledgments

The authors are thankful for the financial support of the National Natural Science Foundation of China (81202479), the Collaborative Fund of Sichuan Province Science and Technology Agency, Luzhou Government, Luzhou Medical University (2014JC0126, 2014JC0800), the Collaborative Fund of Luzhou Government and Luzhou Medical University (2013LZLY-J54), and the Major Cultivation Item of Sichuan Province Educational Department (14CZ0018). They also thank Mr Pei Jing and Miss Shuangli Xiao for their helpful work.

Disclosure

The authors report no conflicts of interest in this work.