in vitro- and in vivo Evaluation of Methotrexate-Loaded Hydrogel Nanoparticles Intended to Treat Primary CNS Lymphoma via Intranasal Administration

Abstract

Purpose: Although it passes through blood-brain barrier (BBB) very poorly, methotrexate (MTX) is an important therapeutic in the treatment of many central nervous system malignancies. Accordingly, intranasal (IN) administration accompanied with a muco-adhesive chitosan-based nanoformulation is expected to overcome this problem. Methods: Nanogel containing MTX was prepared through an ionic gelation method and then characterized in terms of particle size, morphology, zeta potential, drug loading and drug release behavior. The drug release results were fitted on eight mathematical models to choose the model best describing the phenomenon. Then the nano-formulation and free drug solution in deionized water as control were administered in the nasal cavity for rats and after 15, 30, 60 and 240 minutes their brain and plasma were analyzed for MTX quantity. Results: The nano-formulation demonstrated an average particle size near 100 nm with a zeta potential of 18.65±1.77 mv. Loading efficiency and loading capacity were calculated to be 65.46±7.66 and 3.02±0.34 respectively. The Weibull model was found to be best describing the release phenomenon as a combination of swelling and Fickian diffusion. Moreover in in vivo studies, drug targeting efficiency and direct transport percentage for nanogel (test) and free drug solution (control) were 424.88% and 76.46% and 34842.15% and 99.71% respectively.  Conclusion: According to in vivo studies, nanogel produced significantly higher concentration of MTX in the brain but not in the plasma when compared to the free drug solution. Besides, in comparison to intravenous administration of the same nanogel it was indicated that intranasal administration significantly increases the brain concentration of MTX.