Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel.

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

The preliminary exploration of Calu-3 cell air-liquid interface culture and exposure research / 中国药理学通报

Aim To explore the air-liquid interface(ALI)culture conditions of Calu-3 cells and their tolerance to exposure to clean air in the exposure system. Methods Calu-3 cells were cultured in three stages:flask expansion,liquid-liquid culture until full Transwell membrane covered,and ALI culture,and the cell barrier status was determined by cell trans-epithelium electrical resistant(TEER)measurement and expression of tight junction protein ZO-1; Calu-3 cells were exposed to clean air using the air-liquid interface exposure system for 1,2,3,4,5,6 hours,and cells cultured in incubators were used as controls to detect changes in Calu-3 cell activity and TEER after exposure,and to determine the single maximum exposure time of Calu-3 cells in the in vitro exposure system based on ALI culture. Results Calu-3 cells were cultured in liquid-liquid culture for 8±1 days to grow full Transwell membranes and barrier formation,and then were transferred to ALI culture. The barrier was intact and in a stable state for 1 to 18 days of ALI culture,and could be used for exposure experiments. The activity of Calu-3 cells decreased significantly after 6 hours of clean air exposure(P<0.01),and TEER decreased significantly after 4,5,and 6 hours of clean air exposure(P<0.05,P<0.01,P<0.01). Conclusions Calu-3 cells cultured for 1 to 18 days in ALI can be used for air-liquid interface exposure experiments; the combined changes in cell activity and TEER suggest that the maximum single exposure time for Calu-3 cells exposed to clean air in the exposure system is 3 hours.