Resistance of hepatocellular carcinoma to sorafenib can be overcome with co-delivery of PI3K/mTOR inhibitor BEZ235 and sorafenib in nanoparticles

ABSTRACT

Background: The combination of BEZ235 with sorafenib (SFB) enhances anti-hepatocellular carcinoma (HCC) efficacy of the two agents. However, pharmacokinetic profiles in vivo and different endocytosis abilities of these two drugs hinder their therapeutic application.

Research design and methods: In this work, we developed d-α-tocopheryl polyethylene glycol 1000 succinate - polycaprolactone polymer nanoparticles (NPs) for co-delivery of SFB and BEZ235 (SFB/BEZ235-NPs). Explored the anti-proliferative and pro-apoptotic effects of SFB/BEZ235-NPs through in vitro and in vivo experiments.

Results: Stabilized SFB/BEZ235-NPs were prepared with optimized drug ratio, yielding high encapsulation efficiency, low polydispersity, and enhanced cellular internalization in HepG2 cells. Synergistic cytotoxicity and pro-apoptotic ability were documented. In vivo pharmacokinetic results revealed extended circulation and bioavailability of SFB/BEZ235-NPs compared with those of free drugs. SFB/BEZ235-NPs enhanced antitumor effectiveness in SFB-resistant HCC xenograft mouse models.

Conclusion: Taken together, the results of this study describe a promising strategy using SFB and BEZ235 in a nanoparticle formulation for treatment of SFB-resistant HCC.

KEYWORDS:

• Hepatocellular carcinoma
• BEZ235
• sorafenib
• PI3K/mTOR
• nanoparticles
• polycaprolactone
• apoptosis

Acknowledgments

Thanks to Professor Dong Ma (Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Department of Biomedical Engineering, Jinan University, Guangzhou) for his support in the preparation of nanomedicine.

Author contributions

Conception and design: Xiaolong Tang; Development of methodology: Xiaolong Tang, Binquan Wu, Amin Li, Yinci Zhang, XueKe Liu; Acquisition of data: XueKe Liu, Shuping Zhou, Huaiyong Gan, Shiyu Cai, Yong Liang; Analysis and interpretation of data: Xiaolong Tang, Binquan Wu, Amin Li, Yinci Zhang; Writing and/or revision of the manuscript: Binquan Wu, Amin Li, Yinci Zhang.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by The National Natural Science Fundation of China [81872017, 81572431, 81773281], University Natural Science Research Project of Anhui Province [KJ2018ZD011, KJ2019A0305, KJ2019A0093].