Methotrexate-loaded chitosan nanogels as ‘Trojan Horses’ for drug delivery to brain: Preparation and in vitro/in vivo characterization

Methotrexate-loaded hydrogel nanoparticles were prepared and after in vitro characterization, their transport across blood–brain barrier was investigated in vivo in intact animals in this study. The ionic gelation method was used for preparation of drug-loaded nanogels, after optimized by a systematic multi-objective optimization approach. After surface-modification with polysorbate 80, nanoparticles with the final particle size, poly-dispersity index (PDI), loading efficiency (LE) and loading capacity (LC) of 118.54 ± 15.93 nm, 0.35 ± 0.05, 61.82 ± 6.84%, and 53.68 ± 3.09% were obtained, respectively. The in vitro drug release study indicated non-Fickian diffusion kinetic, apparently governed by both diffusion of the drug out of the nanoparticles and swelling/disintegration of the polymeric network as characterized by a Weibull model for both surface-treated and untreated nanogels. After intravenous administration of surface-modified and unmodified nanogels compared to the free drug, all with the same dose of 25 mg/kg, remarkably higher brain concentrations of methotrexate were achieved with the nanogel formulations in comparison to the free drug (in some cases, more than 10-fold); but there were no significant differences between the surface-modified and unmodified nanogels in all the time points tested.