Desenvolvimento e estudos biológicos de dispositivos de liberação controlada de antitumorais utilizando polímeros biodegradáveis e materiais magnéticos

Abstract

In this work, magnetic nanosystems of iron oxide cores coated by the PLGA biodegradable polymer containing the antitumor rhodium(II) citrate or daunorubicin hydrochloride obtained was characterized and evaluated in cancer cell lines and/or murine sponge implant model for assessing inflammation and angiogenesis. Magnetic iron oxides can offer particularly features as an alternative to conventional cancer treatment because they are biocompatible materials that can beused as the core of an antitumor device. An external magnetic field can be applied, attracting these particles, and decreasing their circulation in the blood, which favors the accumulation in the tumor site, increasing their efficacy and decreasing the systemic side effects. Examples are nanoparticles (NPs) produced from iron salts (Fe2+ or Fe3+) or salts of these chlorides with other transition metals such as nickeland zinc, called ferrites (FR). These nanoparticles exhibit biocompatibility and can be used in combination with magnetically carrier polymers for biomaterials. Substances having antitumor activity can be used with these ferrites in order to be guided to the site of action via a magnetic field. As examples, it has been rhodium(II) citrate, an inorganic compound obtained of RhCl3, very effective in cancercells, daunorubicin hydrochloride (DNR), member of the group of anthracycline, chemotherapeutic drug widely used for the treatment of tumors, but have cytotoxic effects in normal cells, the short half-life and the non-selectivity for cancer cells. In this study, rhodium(II) citrate nanosystem was synthesized and daunorubicin with ferrites and poly-lactic-co-glycolic acid (PLGA), have been tested in cancer cells and/or in vivo angiogenesis model. These nanosystems were characterized by physicochemical techniques such as absorption spectroscopy in the infrared (FTIR), thermal analysis (TG and DTA),electronic microscopy (EM), saturation magnetization at room temperature (Msat), among others, and the in vitro release kinetics was evaluated. The synthesis of rhodium(II) citrate was efficient according with the literature. The complex synthesized nanosystem was prepared with PLGA and ferrites loaded with rhodium(II) had diameters of about 250.0 to 300.0 nm, surface charge (zeta potential) of -24.7 mV and a paramagnetic behavior. Furthermore, the daunorubicin nanosystem was prepared from the free drug, PLGA and ferrites, and had the samediameters of about 160.0 to 200.0 nm, zeta potential value of -32.4 mV and superparamagnetic behavior. Kinetics profiles plotted using phosphate buffered saline (PBS) as the middle temperature of 37 0C, conditions that mimic the biological fluids. Rhodium(II) citratefrom nanosystem showed a release profile controlled without the presence of burst effect and the release is maintained for about 70 h. The release of daunorubicin from the nanosystem showed a burst effect and acquired a controlled release profile up to 350 h. Both systems were tested with a magnet and visually attracted to the field. The nanosystem containing rhodium(II) citrate exhibited similar toxicity to freerhodium(II) in vitro assays with tumor cell lines and the daunorubicin nanosystem exhibited cytotoxicity in vitro in cancer cells about 50 times greater, when compared to free daunorubicin. In vivo studies of the daunorubicin nanosystem showed that the system had antiangiogenic effect on sponge model, measured by hemoglobin; in addition acute and chronic inflammatory responses based on levels of cytokinessuch as VEGF and TNF- were measured suggesting a nanosystem lower inflammation. From these results, one could concluded that the release systems of daunorubicin and rhodium(II) citrate from the polymer matrix with the magnetic core, were cytotoxic against cancer cells and shown antiangiogenic properties.