Design and evaluation of magnetic chitosan microspheres for targeting the anticancer drug, oxantrazole, to the brain

Treatment of malignant brain tumors by chemotherapy is usually disappointing, due to inadequate delivery of anticancer drugs to the tumor. This project proposed a novel approach for targeting anticancer drugs to the brain via magnetic microspheres. Magnetic microspheres, prepared from cationic polymer, chitosan, were hypothesized to be localized in brain capillaries by an external magnet, and by binding to anionic domains on the cerebral endothelium surface or blood-brain barrier. Plain magnetic chitosan microspheres (MCM) in the submicron size range were formulated by a solvent evaporation technique. Binding displacement and fluorescent polarization techniques showed that chitosan and MCM, due to their cationic nature, bind to the anionic glycosaminoglycan (GAG) model, e.g. heparin, and to cultured brain capillary cells, respectively.; Entrapment of the anticancer drug, oxantrazole (OX), into MCM was achieved by cross-linking with glutaraldehyde. Statistical procedures such as central composite experimental design and stepwise regression analysis were applied to examine effects of formulation factors on microsphere characteristics.; An HPLC assay was developed to quantitate OX in rat blood and tissues. Pharmacokinetic studies of OX in the rat suggested that the rat may be a suitable model for OX's pharmacokinetics in humans.; Intraarterial administration of OX in solution (OX-S) and in MCM resulted in significantly greater OX brain concentrations for the MCM treatment. The MCM treatment resulted in maintaining the targeted OX in the brain even 1.5 h after removal of the magnetic field. Microspheres administration also resulted in OX accumulation in lungs. The microspheres were toxic at no or low magnetic fields while at a magnetic field of 6000 G, MCM were well tolerated. Findings of this project support the hypothesis that OX can be targeted to the brain via MCM. Further studies will help determine the mechanism of the MCM localization in the brain and the OX distribution within the brain.