Methotrexate-Loaded Nanomixed Micelles: Formulation, Characterization, Bioavailability, Safety, and In Vitro Anticancer Study

Methotrexate (MTX), a potent anticancer drug, shows low oral bioavailability due to its low aqueous solubility and permeability. Moreover, its multidrug resistance (MDR) in cancer and toxic effects restricts its clinical applications. The aim of the study was to prepare novel MTX-loaded Poloxamer 407 and Gelucire(A (R))44/14 (GL44) mixed micelles (MTX-PGMM) to improve its oral bioavailability and cytotoxicity and to reduce its systemic toxicity. MTX-PGMM was prepared by dialysis method, compared with blank or MTX-free blank mixed micelles (BMM) and aqueous dispersion of MTX (MTX-AD) with respect to morphology, size, zeta potential, entrapment efficiency, in vitro release, and in vitro cytotoxicity, bioavailability, and toxicity study in rats. The developed MTX-PGMM exhibited small particle size, good encapsulation efficiency, and good stability in media simulating the physiological conditions of the gastrointestinal tract. The MTX-PGMM micelles demonstrated sustained release, enhanced (6.5-fold) oral bioavailability, slow plasma elimination, and long circulation of MTX. Biocompatibility was also established as there were no signs of tissue toxicity. Moreover, MTX-PGMM produced higher in vitro cytotoxicity (GI(50) of 1.44 +/- 0.33 mu g/mL) than free MTX (GI(50) 13.71 +/- 0.99 mu g/mL) in human breast cancer MCF-7 cells. Poloxamer 407 and Gelucire(A (R))44/14 (GL44) mixed micelles are promising carriers for oral delivery of MTX and can be utilized for other Biopharmaceutical Classification System class IV anticancer drugs having poor oral bioavailability and multidrug resistance in cancer.