Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative–lipid complex

Abstract

In this study, a system for oral delivery of etoposide (ETP) was designed to avoid the problems associated with low and variable bioavailability of a commercially available ETP emulsion comprised of polyethylene glycol, glycerol, and citric acid anhydrous. ETP was complexed with low-molecular-weight methylcellulose (ETP/LMC) and loaded into a water-in-oil-in-water multiple nanoemulsion to formulate an ETP/LMC-nanoemulsion (ELNE). To further enhance the oral bioavailability, an ionic complex formed by anionic lipid 1,2-didecanoyl-sn-glycero-3-phosphate (sodium salt) and cationic N α -deoxycholyl- l -lysyl-methylester was incorporated into ELNE, yielding ELNE#7. As expected, ELNE#7 showed 4.07- and 2.25-fold increases in artificial membrane and Caco-2/HT29-MTX-E12 permeability ( P app ), respectively, resulting in 224% greater oral bioavailability compared with the commercially available ETP emulsion. In contrast, inhibition of clathrin- and caveola-mediated endocytosis, macropinocytosis, and bile acid transporters by chlorpromazine, genistein, amiloride, and actinomycin D in Caco-2/HT-29-MTX-E12 monolayers reduced the P app by 45.0%, 20.5%, 28.8%, and 31.1%, respectively. These findings suggest that these routes play important roles in enhancing the oral absorption of ELNE#7. In addition, our mechanistic study suggested that P-glycoprotein did not have an inhibitory effect on the permeation of ELNE#7. Notably, ELNE#7 showed significantly enhanced toxicity in LLC and A549 cells compared with ETP-E. These observations support the improved oral absorption of ETP in ELNE#7, suggesting that it is a better alternative than ETP emulsion.

Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity

“…PMX) through the cell membrane by ASBT (Pangeni et al., 2019 ; Deng & Bae, 2020 ). In addition, DL, as well as Kolliphor P188 and Labrasol, can increase membrane flexibility to increase drug partitioning across the membrane (Gupta et al., 2013 ; DiMarco et al., 2017 ; Pavlović et al., 2018 ; Jha et al., 2020 ) DA in DL, as well as surfactants in CD, can reversibly open the tight junctions by autophosphorylation of epidermal growth factor receptor (EGFR) or dephosphorylation and rearrangement of zonula occludens-1 (ZO-1), which may facilitate the permeation of PMX or PMX/DL released from PMX/DL-CD through the cell membrane via the paracellular pathway (Raimondi et al., 2008 ; Stojančević et al., 2013 ; Zhou et al., 2013 ; Pavlović et al., 2018 ). Moreover, PMX/DL-CD is known to be transported by caveola/lipid raft-mediated endocytosis and micropinocytosis (Kou et al., 2018 ; Pavlović et al., 2018 ; Pangeni et al., 2019 ).…”

Transporter-Mediated Drug Delivery

“…This formulation showed improved cellular permeability in Caco-2/HT29-MTX-E12 cells and also higher oral bioavailability in in vivo studies in rats [43]. Inhibition of ASBT with actinomycin D and the heteromeric organic solute transporter OST α/SLC51A and OST β/SLC51B with clofazimine reduced permeability, indicating the involvement of bile acid transporters in this process [43].…”

“…A variety of chemical substances have been used as nanocarriers and substrates for further chemical modification to fine-tune pharmacokinetic properties. Among them, liposomes or liposome-based formulations such as functionalized liposomes [8,10,26,29,30], solid lipid nanoparticles/nanostructured lipid carriers [31], various polymer-based nanomicelles/nanoparticles [8,30,[32][33][34][35][36][37][38][39], carbon dots [40], mesoporous silica nanoparticles [41,42] or nanoemulsions [43] have been used for functionalization and transporter-targeted drug delivery.…”

“…Cellular uptake of such nanoparticles usually occurs through binding the target transporter/receptor on the cell surface, followed by endocytosis via caveolin-dependent, clathrin-dependent or clathrin/caveolin-independent pathways such as micropinocytosis [8,10,26,29,[43][44][45], rather than uptake by the transporter itself (Figure 1). Endocytosed particles can be trapped in lysosomes, which can lead to their degradation and prevent their transcytosis, thus reducing their efficiency [46,47].…”

“…To avoid problems with bioavailability of the chemotherapeutic agent etoposide, a topoisomerase II inhibitor, the medication was embedded in a nanoemulsion based on low molecular weight methylcellulose, which also contains the ion pair of the anionic 1,2didecanoyl-sn-glycero-3-phosphate, a lipid, and the cationic N α -deoxycholyl-L-lysylmethylester, a derivative of deoxycholic acid [43]. This formulation showed improved cellular permeability in Caco-2/HT29-MTX-E12 cells and also higher oral bioavailability in in vivo studies in rats [43]. Inhibition of ASBT with actinomycin D and the heteromeric organic solute transporter OST α/SLC51A and OST β/SLC51B with clofazimine reduced permeability, indicating the involvement of bile acid transporters in this process [43].…”