Preparation, Characterization, and In Vivo Evaluation of an Oral Multiple Nanoemulsive System for Co-Delivery of Pemetrexed and Quercetin

Abstract

Co-administration of conventional and natural chemotherapeutics offers synergistic anticancer efficacy while minimizing adverse effects. In this study, an oral co-delivery system for pemetrexed (PMX) and quercetin (QCN) was designed based on water-in-oil-in-water nanoemulsion (NE), which is highly absorbable because it enhances the intestinal membrane permeability of PMX and aqueous solubility of QCN. To create this system, an ion-pairing complex of PMX with Nα-deoxycholyl-l-lysyl-methylester (DCK) was formed and further incorporated with QCN into the NE, yielding PMX/DCK-QCN-NE. The results revealed synergistic inhibitory effects on human lung carcinoma (A549) cell proliferation and migration after combined treatment with PMX/DCK and QCN. The intestinal membrane permeability and cellular uptake of PMX/DCK and QCN from the NE were significantly improved via facilitated transport of PMX by the interaction of DCK with bile acid transporters, as well as NE formulation-mediated alterations in the membrane structure and fluidity, which resulted in 4.51- and 23.9-fold greater oral bioavailability of PMX and QCN, respectively, than each free drug. Tumor growth in A549 cell-bearing mice was also maximally suppressed by 62.7% after daily oral administration of PMX/DCK-QCN-NE compared with controls. Thus, PMX/DCK-QCN-NE is a promising oral nanocarrier of PMX and QCN for synergistic anticancer efficacy and long-term chemotherapy.

The potential anti-cancer effects of quercetin on blood, prostate and lung cancers: An update

“…In addition, after oral administration of PMX/DCK-QCN-NE in rats, the Cmax and AUC last were increased compared with oral quercetin in 0.3% CMC (22.0-and 23.9-fold, respectively). The anti-cancer effect in A549 cell-bearing mice after once-daily oral administration of PMX/ DCK-QCN-NE showed an inhibition and reduction of tumor growth and tumor mass compared with the oral PMX/DCK-NE and control groups (115). Moreover, cell proliferation of A-549 cells in lung cancer depended on quercetin -mediated gold nanoclusters (Que-GNCs) in a dose-dependent manner and a time-reliant manner from 0-24h.…”

“…In vitro + in vivo Que + PMX A-549 showed concentration-dependent synergistic inhibitory effects on cancer cell proliferation/migration. 20 µg/mL (115) Note: Mesoporous silica nanoparticles (SBA-15); Trichostatin A (TSA); (Polymeric microspheres, PMs), PMs loaded with paclitaxel (PTX); Pemetrexed (PMX).…”

Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review

“…Pangeni et al. ( 2018 ) designed an oral co-administration system of pemetrexed (PMX) and Que based on oil-in-water NM (PMX/N α -deoxycholyl-L-lysyl-methylester (DCK)-Que-NM). PMX/DCK-QCN-NE had good intestinal permeability and increased cell absorption of PMX/DCK and Que.…”

Recent Advances in the Structural Design of Photosensitive Agent Formulations Using “Soft” Colloidal Nanocarriers

“…Instead of simple nanoemulsion, multiple systems can be applied as an effective nanocarriers for the aforementioned active compound. The same group [172] obtained multiple W/O/W emulsion for efficient co-delivery of quercetin and pemetrexed (a chemotherapy drug). The formulation occurred to be promising oral delivery system, as it showed significant rise in bioavailability in comparison to a free flavonoid.…”