Preparação de biocompósitos magnéticos à base de gelatina para liberação controlada de doxorrubicina

Abstract

Devices for drug controlled release are polymer-based systems which contain a pharmaceutical filler that is released gradually when in contact with physiological medium. This gradual release offers great advantages when compared to the conventional administration method, for example, medicament higher concentration in diseased tissue and fewer adverse effects. When this type of system contains magnetic material, it can be easily directed and, consequently, the time for the device to reach the desired location as well as the path traveled decrease. In order to obtain a magnetically controlled device for the release of doxorubicin (DOX), the preparation and characterization of biocomposites based on gelatin and magnetite were studied. Microspheres were prepared by water-in-oil emulsion and different crosslinking agents with low cytotoxicity (fructose, glucose, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, glutaraldehyde, genipine) were evaluated instead of the conventional crosslinker glutaraldehyde in order to minimize the adverse effects caused by the release of crosslinking molecules after biocomposite degradation in the target cells.. Magnetite obtained with ferrous chloride, ferrous sulfate or in a magnetic fluid, were evaluated in order to maximize the magnetization of the biocomposites. The influence of constant magnetic field, oscillating magnetic field and absence of magnetic field on the release of doxorubicin was also studied. The biocomposites were characterized by the percentage of gelatin dissolved in water (protein determination technique with biuret reagent), scanning electron microscopy, thermogravimetric analyzes, vibrating sample magnetometer and in vitro drug release tests. The design of experiments tool, varying the type of crosslinker (fructose or glucose), the crosslinker concentration, the heating time and the pH of the reaction medium was performed in order to find which parameters influence the degree of cross-linking of the microspheres. The results showed that both fructose and glucose have their crosslinking reaction strongly influenced by the reaction pH and the reaction time. Comparing all of the crosslinkers studied, genipine was found to be the best cross-linking agent for gelatin protein chains, but its high cost (about R$ 880.00 / g of microspheres) made it impossible to process large-scale processes . The use of fructose as a crosslinker led to the production of gelatin microspheres with better physical properties than glutaraldehyde and low cost (about R$ 2.25 / g microspheres) crosslinked. The synthesized biocomposites presented high saturation magnetization and superparamagnetic behavior. In addition, by varying the external magnetic field it was possible to modify the doxorubicin release profile