title: Neuropharmacokinetic evaluation of methotrexate-loaded chitosan nanogels.
abstract: Delivery of the hydrophilic drugs to the brain is still a great challenge for the treatment of many CNS-related diseases. Nanogels loaded by methotrexate (MTX) were prepared using the ionic gelation method. After intravenous administration of surface-modified (SMNs) and unmodified nanogels (UMNs) compared to the free drug, the neuropharmacokinetic evaluations were applied mainly by tissue drug uptake and graphic estimation of the uptake clearance methods. In optimized condition, the particle sizes of UMNs and SMNs were 118.54±15.93 nm and 106.68±7.23 nm, respectively. Drug entrapment efficiency and drug loading capacity were 61.82±6.84%, and 53.68±3.09%, respectively. The brain concentrations of MTX were shown to be higher in the case of both types of the nanogels. There were no significant differences between SMNs and UMNs in terms of the brain concentrations and AUCs of brain concentration-time profiles. Meanwhile, the brain uptake clearance of the drug loaded in SMNs were significantly higher than UMN ones (i.e. about 3- and 1.6-times for the high and low MTX doses, respectively). It can be concluded that, while the drug loading in both forms of nanogels have a significant increasing effect on the brain penetration of MTX, surface treatment of nanogels exerts an additional effect on the plasma volume cleared from MTX via brain tissue in time unit.
authors.affiliation: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Biopharmaceutics and Pharmacokinetics Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Azadi
authors.affiliation: Biopharmaceutics and Pharmacokinetics Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Rouini
authors.affiliation: Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, Zanjan, Iran; Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran. Electronic address: hamidim@zums.ac.ir.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Hamidi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002199:Capillary Permeability; D048271:Chitosan / Q000737:chemistry*; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods; D065546:Drug Liberation; D005782:Gels; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics*; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties
chemical_list: D000964:Antimetabolites, Antineoplastic; D005782:Gels; D048271:Chitosan; D008727:Methotrexate
keywords: Blood–brain barrier; Hydrogel nanoparticles; Methotrexate; Surface modification; Uptake clearance