title: Tissue distribution of methotrexate following administration as a solution and as a magnetic microsphere conjugate in rats bearing brain tumors.
abstract: A novel magnetic microsphere-methotrexate (MM-MTX) drug delivery system was synthesized and evaluated in rats bearing rat glioma-2 (RG-2) tumors. Methotrexate was linked to the surface of the magnetic particle via an aminohexanol linker that would release free drug following hydrolysis. Male Fischer 344 rats bearing RG-2 tumors were administered 3 mg/kg of methotrexate (MTX) either as MM-MTX or as a solution (MTX-S) over 5 min. A 6000 gauss magnetic field was applied for 15 min from the end of MM-MTX administrations. Serial sacrifices were conducted at 15 min, 30 min and 45 min after drug administrations, organs collected, and analyzed for total MTX by a radioassay. At all times, MTX right brain (ipsilateral), brain tumor, and left brain concentrations were approximately 3.5 to 5-fold greater in the MM-MTX group compared to the MTX-S group. MTX concentrations in all other organs were less following administration of MM-MTX than MTX-S except in lung at 30 and 45 min. The targeting efficacy, an index for site-specificity, for both MM-MTX and MTX-S were similar and indicated some enhancement in MTX localization in brain tumor. Confocal and conventional light microscopic analyses demonstrated a diffuse distribution of MM-MTX in tumor consistent with extravascular uptake, whereas a predominant capillary distribution of MM-MTX was observed in normal brain. Following 45 min, the animals treated with MM-MTX died possibly due to redistribution of particles to the lung. This toxicity was dose-dependent. High brain MTX concentrations coupled with extravascular uptake of MM-MTX provide a basis for further investigations with this novel drug delivery system.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: D
authors.initials: D
authors.lastname: Devineni
authors.forename: A
authors.initials: A
authors.lastname: Klein-Szanto
authors.forename: J M
authors.initials: JM
authors.lastname: Gallo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005069:Evaluation Studies as Topic; D005910:Glioma / Q000378:metabolism*; D008280:Magnetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008863:Microspheres; D051381:Rats; D011916:Rats, Inbred F344; D012996:Solutions; D014018:Tissue Distribution
chemical_list: D012996:Solutions; D008727:Methotrexate