Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 109, Issue 6, Pages 1867-1882Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2020.01.010
Keywords
non-small cell lung cancer; drug resistance; erlotinib; epidermal growth factor receptor; self nano-emulsifying drug delivery system; combination therapy
Funding
- Research Center in Minority Institute (RCMI) [2454MD007582-34A1 U54]
- FAMU CREST Center for Complex Designs [1735968]
Ask authors/readers for more resources
We have investigated the effects of combination treatment involving ERL (erlotinib) with a glycyrrhetinic acid analog, CDODA-Me in overcoming ERL resistance, providing efforts to improve the oral bioavailability of this treatment using self-nanoemulsifying drug delivery systems (SNEDDS). A Qbd (quality-by-design) approach was used to prepare CDMS (CDODA-SNEDDS, 2 mu M), which was characterized using surface response methodology to optimize drug content, particle size, and drug release. CDMS/ERL combinations showed synergism in wild-type and resistant H1975 and HCC827 cell lines with combination index values less than 1. Increased apoptosis, mitochondrial membrane potential depletion, and enhanced intracellular ROS levels were also observed in combination therapy. Western blot analysis showed that combination therapy inhibited phosphorylation of epidermal growth factor receptor (EGFR) (p < 0.01 in all cell lines) and Met receptor tyrosine kinase (MET) (p < 0.01 in all cell lines). In vivo, the relative bioavailability of CDMS increased significantly from 22.13 to 151.76 mu g/mL compared to the dosing of oral suspension (dose equivalent). Our results demonstrate that combination therapy involving ERL and CDODA-Me overcomes resistance through dual inhibition of p-EGFR and p-MET leading to the induction of apoptosis, intracellular ROS accumulation, and decreased mitochondrial potential. Furthermore, CDMS improved the oral bioavailability of CDODA-Me. (C) 2020 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available