The Role of Self-Nanoemulsifying Drug Delivery Systems of CDODA-Me in Sensitizing Erlotinib-Resistant Non–Small Cell Lung Cancer

Abstract

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 μΜ), 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 μg/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.