| Cancer, especially liver cancer, is one of the major diseases endangering lives, and most of cancer patients have low survival rate after exairesis for delayed diagnosis. For inoperable patients, the first and widespread choice is therapeutic arterial embolization (TAE). Doxorubicin hydrochloride as a broad spectrum antibiotics is commonly used for TAE, but high blood drug level of it in liver after TAE is transient and adverse effect is serious of which limited the clinical application of DOX. Purpose of this paper is to prepare magnetic microspheres loading DOX for TAE with Fe3O4 as the magnetic material and Poly(lactide-co-glycolide)(PLGA) as the main matrix, so that drugs can be enriched in targeted tissue to improve the efficacy and reduce adverse effect. Therefore, we prepared Fe3O4 nanoparticles by co-precipitation and characterized its physical and chemical properties, prepared magnetic microspheres loading DOX for TAE by multiple emulsicification in liquid phase method and to investigate its morphology, particle size, drug loading rate, release, magnetic, embolic effect in vivo and other properties preliminary.Part one: Preparation of magnetic Fe3O4 nanoparticals. In this part, Fe3O4 magnetic nanoparticles were prepared using chemical precipitation method with polyethylene glycol (PEG) -6000 as dispersing agent, ferric chloride and ferrous chloride as the reaction agent, characterized its physical and chemical properties such as morphology, size distribution, magnetic properties, dispersion properties using transmission electron microscopy (TEM), laser scattering particle size analyzer, vibrating sample magnetometer (VSM), fourier transform infrared spectroscopy. So, Fe3O4 magnetic nanoparticle was prepared with spherical or spherical appearance, an average diameter of 10±6nm, a saturation magnetization of 76.22 emu/g; and magnetic nanoparticles surface was coated with PEG to improve its in aqueous dispersion media and could be used as magnetic drug targeting of magnetic materials.Part tow: Preparation and investigation on PLGA magnetic microspheres loaded doxorubicine for embolization. This part, Ultra-violet spectroscopy method(UV) was established to detect drug loading rate, magnetic microspheres loading DOX for TAE were prepared by multiple emulsicification methods with PLGA as the main matrix. The optimum technology were determined by single factor and orthogonal design: mass ratio of Doxorubicin hydrochloride and PLGA mass ratio is 1:25, mass ratio of magnetic nanoparticles and PLGA is 1:200, volume ratio of the internal water phase and oil phase is 1:20 , PLGA concentration is 200mg/ml, ultrasonic power is 400W. The microspheres were prepared under optimized technology with 1.35% drug loading rate, average diameter 117±50μm and a certain magnetic response.Part three: Drug release and stability of PLGA magnetic microspheres loaded doxorubicine for embolization in vitro. High performance liquid chromatography (HPLC) was established and constant temperature oscillation dialysis method was applied to investigate drug releasing behavior in vitro. PLGA magnetic microspheres loaded doxorubicine can release slowly, cumulative release percentage was over 95% after 20d without burst effect, drug release pattern consistent with Higuchi equation. Stability of microspheres was investigated by accelerated testing at temperature (40±2)℃and relative humidity (75±5)% for 6 months, and microspheres have good stability.Part four: Investigation on the embolic effect of PLGA magnetic microspheres loaded Doxorubicin hydrochloride in vivo. Rabbit liver area was fixed magnetic field and rabbit hepatic artery was injected microspheres by arterial embolization (TAE). 30min after injection, digital subtraction angiography (DSA) films were taken, and 14d after injection, animals were killed to observe damage to the liver and embolic effects of microsphere. Experimental results show that the microspheres can play embolic effect in the hepatic artery good. |
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