title: Methotrexate-loaded chitosan nanogels as 'Trojan Horses' for drug delivery to brain: preparation and in vitro/in vivo characterization.
abstract: 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.
authors.affiliation: Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Azadi
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Hamidi
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Rouini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D048271:Chitosan / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004355:Drug Stability; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D010316:Particle Size; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D048271:Chitosan; D008727:Methotrexate
keywords: Blood–brain barrier; Brain drug delivery; Methotrexate; Nanogel; Release kinetic; Surface modification