Preparation, characterization of paclitaxel-loaded Pluronic P105 polymeric micelles and in vitro reversal of multidrug resistant tumor / 药学学报

Drug delivery system (DDS) is a novel approach to overcome multidrug resistance (MDR) in tumors nowadays. This work was designed to investigate a new micellar delivery system for in vitro reversal of resistant ovarian tumor cells, based on a nonionic triblock copolymer Pluronic P105 and paclitaxel (PTX). The PTX-loaded polymeric micelles (P105/PTX) were prepared by thin film-hydration methods. Based on the results of single factor experiments, the P105/PTX micelle formulation was optimized by employing the central composite design-response surface methodology. The physico-chemical properties of the P105/PTX micelles were characterized, including micelle size, drug loading coefficient, in vitro release behavior, etc. The cytotoxicity of the P105/PTX micelles was assessed against human ovarian tumor cell line, SKOV-3/PTX, by a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. In order to understand the possible mechanism of Pluronic effects in resistant tumor cells, cellular uptake study of micellar PTX or Rhodamine-123 (R-123) was also carried out. The results showed that the micelle size was about 24 nm with drug loading coefficient of 1.1% and PTX concentration of 700 microg x mL(-1). The cumulative release amount of PTX from the P105/PTX micelles was only 45.4% in 6 h (P < 0.05) and 79.6% in 24 h, whereas Taxol injection in 6 h released 95.2% PTX. The IC50 values of the P105/PTX micelles and Taxol injection against SKOV-3/PTX were 1.14 and 5.11 microg x mL(-1), and resistance reversion index (RRI) was 9.65 and 2.15, respectively. The micellar PTX or R-123 exhibited a significant increase in cellular uptake in resistant SKOV-3/PTX cells compared with free PTX or R-123. These results indicated that PTX could effectively be solubilized by Pluronic P105 block copolymers via thin film-hydration process and formulation optimization, producing nano-scale polymeric micelles with sustained release property in vitro. The P105/PTX micelles were effectively able to reverse resistance to PTX in SKOV-3/PTX tumor cells compared with Taxol injection or free PTX solution, and the enhanced cytotoxicity in the resistant SKOV-3/PTX cell was related to the improved cellular uptake of PTX by Pluronic P105 copolymers.

Mechanism of oral absorption of panaxnotoginseng saponins / 药学学报

<p><b>AIM</b>To study the mechanism of absorption after oral administration of panaxnotoginseng saponins (PNS).</p><p><b>METHODS</b>Caco-2 cells and rat models were applied to evaluate the degradation of both ginsenoside Rb1 (Rb1) and ginsenoside Rg1 (Rg1) in PNS in gastrointestinal lumen, and the transport mechanism of PNS across the intestinal mucosa, and the barrier function of stomach, intestine and liver involved in absorption process.</p><p><b>RESULTS</b>Rb1 and Rg1 proved to be readily eliminated in stomach, but stable in relatively neutral circumstance. Both Rb1 and Rg1 in PNS, especially for Rb1, degraded significantly in the contents of large intestine. However, both of them kept mainly intact in the contents of small intestine. Uptake of both Rb1 and Rg1 by Caco-2 cell monolayer was inhibited at low temperature, but not by cyclosporine A, and the change in the apical pH showed no pronounced effect. Uptake and transport were non-saturable and increased linearly with increasing of concentrations of Rb1 and Rg1 over the range of concentration tested, which indicated a passive transport. There was no significant difference of absorption characteristic between monomer (Rb1 and Rg1) and mixture (PNS). Uptake amount of Rg1 [(1.07 +/- 0.16) microg x mg(-1) (protein)] (C0 = 1 mg x mL(-1)) in Caco-2 cells was a little higher than that of Rb1 [(0.77 +/- 0.03) microg x mg(-1) (protein)] (C0 = 1 mg x mL(-1)). Meanwhile, apparent permeability coefficient of (5.9 +/- 1.0) x 10(-8) cm x s(-1) (C0 = 1 mg x mL(-1)) for Rb1 and (2.59 +/- 0.17) x 10(-7) cm x s(-1) (C0 = 1 mg x mL(-1)) for Rg1 from apical compartment to basolateral compartment predicted an incompletely absorption. Transports of both Rb1 and Rg1 were not influenced by cyclosporine A. The investigation on the pharmacokinetic behavior of Rb1 and Rg1 after different routes of administration to rats showed that the absolute bioavailability after peroral (po), intraduodenal (id), and portal venous (pv) administration is 0.71% , 2.75% and 65.77% respectively for Rb1, and 3.29%, 6.60% and 50.56% respectively for Rg1.</p><p><b>CONCLUSION</b>Transport across Caco-2 cell monolayer for PNS (include Rb1 and Rg1) is a simple passive diffusion process. No efflux transporters in Caco-2 cells and other components in PNS showed effects on it. The elimination in stomach, large intestine and liver contributed to the low bioavailability of PNS, but the low membrane permeability might be a more important factor dominating the extent of absorption.</p>