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.

• Authors: Binquan Wu, Amin Li, Yinci Zhang, Xueke Liu, Shuping Zhou, Huaiyong Gan, Shiyu Cai, Yong Liang, Xiaolong Tang
• Journal: Expert opinion on drug delivery (Expert Opin Drug Deliv) Vol. 17 Issue 4 Pg. 573-587 (04 2020) ISSN: 1744-7593 [Electronic] England
• PMID: 32056461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Drug Combinations
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Polyesters
• Quinolines
• Vitamin E
• polycaprolactone
• Sorafenib
• TOR Serine-Threonine Kinases
• tocophersolan
• dactolisib

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Drug Carriers (administration & dosage, pharmacokinetics)
• Drug Combinations
• Female
• Hep G2 Cells
• Humans
• Imidazoles (administration & dosage, pharmacokinetics)
• Liver Neoplasms (drug therapy, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles (administration & dosage)
• Phosphoinositide-3 Kinase Inhibitors (administration & dosage, pharmacokinetics)
• Polyesters (administration & dosage, pharmacokinetics)
• Quinolines (administration & dosage, pharmacokinetics)
• Sorafenib (administration & dosage, pharmacokinetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Vitamin E (administration & dosage, pharmacokinetics)