A mechanistic investigation on methotrexate-loaded chitosan-based hydrogel nanoparticles intended for CNS drug delivery: Trojan horse effect or not?

Abstract

Chitosan-based hydrogel nanoparticles provide a higher brain concentration of methotrexate (MTX) following IV administration in comparison with the drug's simple solution. The present study investigates the mechanism of this phenomenon, focusing on the possible role of P-gp. A previously developed MTX containing chitosan nanogel was fabricated and characterised. Then 48 rats were divided into four groups: two receiving nanogels and two receiving solution of MTX, while 1 of each two had received a verapamil dose 30 min before MTX. Then, rats were sacrificed in four time points in triplicate, and MTX concentration in their plasma and brains were quantified and were compared statistically. Following IV injection, spherical nanogels with a mean diameter of <200 nm, zeta potential of 22.8 ± 6.55 mv, Loading efficiency of 72.03 ± 0.85, and loading capacity of 1.41 ± 0.02 produce a significantly higher brain concentration compared with the simple solution. Furthermore, those receiving verapamil presented a higher brain concentration. It seems that in the short term after drug administration (<1 h) nanogels facilitate MTX passage by providing a higher concentration of drug in contact with BBB, but in a more extended period nanogels pass the BBB and release their content beyond that.

Keywords: Blood-brain barrier; Chitosan; Hydrogel; Methotrexate; P-glycoprotein.