A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis, characterization, cytotoxicity, and pharmacokinetic evaluation

Abstract

In the current study, retinoic acid (RA) was conjugated to Pluronic F127 (PF127) through an esterification process. Mixed micelles were formed with tocopheryl polyethylene glycol 1000 (TPGS) for co-delivery of paclitaxel (PTX) and RA to the cancer cells. Mixed micelles of RA-PF127 and TPGS in different weight ratios (10:0, 7:3, 5:5, 3:7, 0:10 w/w) were prepared and physicochemical properties including, particle size, zeta potential, critical micelle concentration (CMC), drug loading content, entrapment efficiency, drug release, cellular uptake and in vitro cytotoxicity, were investigated in details. Furthermore, the pharmacokinetics of PTX-loaded optimized mixed micelles were evaluated in Sprague-Dawley rats and compared with Stragen((R)) (PTX in Cremophor EL((R))). Particle sizes and zeta potentials of the drug-loaded micelles were in the range of 102.6-223.5 nm and -5.3 to -9.6 mV, respectively. The 7:3 and 5:5 micellar combinations had lower CMC values (0.034-0.042 mg/mL) than 0:10 (0.124 mg/mL). The entrapment efficiencies of 10:0, 7:3, and 5:5 were 53.4 +/- 9.3, 61.3 +/- 0.5, and 78.7 +/- 1.66, respectively. The release rates of PTX from 7:3 and 5:5 mixed micelles were significantly slower than other formulations. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to free PTX. The Vd and t1/2ss of PTX-loaded RA-PF127/TPGS (7:3) were increased by 2.61- and 1.27-fold, respectively, while the plasma area under the curve (AUC) of the micelles was 2.03-fold lower than those of Stragen((R)). Therefore, these novel mixed micelles could be effectively used for delivery of PTX and RA to the cancer cells. Moreover, TPGS as part of micelle composition could enhance the therapeutic effect of PTX and reduce side effects.