Study On Preparation Of Magnetite Nanosphere And Its Application In Drug Delivery

Superparamagnetic Iron Oxide Nanoparticles(SPION) has attracted increasing attention from researchers all over the world due to its favorable biocompatibility, biodegradability andpotential to be used in targeting therapy under external magnetic field. As one major antitumor therapeutic method of three, chemotherapy is extensively applied in the treatment of all kinds of cancers, such as lung cancer, hepatoma, gastric carcinoma and uterine carcinoma. Most of chemotherapeutic agents are cytotoxic, which show strong cytotoxicity to both tumor and normal cells, often cause severe damage to normal cells and tissues. Therefore, development of antiproliferative tumor cell-specific targeted drug delivery system has been a main approach to deal with systematic toxicity of chemotherapeutic drugs. Superparamagnetic iron oxide nanoparticles commonly used as materials for targeted drug delivery system, of which the EPR effect and superparamagnetism assists the accumulation of superparamagnetic iron oxide nanoparticle in cancer tissues as target site, reduces the systematic toxicity of chemotherapeutic agents as a result.Numerous synthetic methods of SPION have been proposed, including aqueous coprecipitation, microemulsion, hydrothermal/solvothermal synthesis, thermal decomposition, sol-gel, sonochemistry, polyols and electrochemical synthesis. The hotspot of current studies is to find an appropriate way to synthesize superparamagnetic iron oxide nanoparticle owning controlled morphology, smaller particle size, narrow size distribution along with superparamagnetism that can be employed in targeted drug delivery system. Based on the investigation on large amount of literature and pre-experiment, research design has been set as follows: On the basis of former studies reported, we attempt to fabricate citric acid-coated paramagnetic magnetite nanocrystal with controlled morphology, smaller particle size and narrow size distribution and furthermore try to design a targeted drug delivery system consisting Fe3O4 as magnetic core and study the drug loading efficiency and in vitro release of this system. Aqueous coprecipitation, one of the most frequently used methods which has been reported many times has usual problems like large particle size, wide size distribution and great potential to aggregate at room temperature. In order to obtain the ideal nanosized paramagnetic magnetite nanoparticles with controlled morphology, ultrasonics-assisted coprecipitation has been chosen as synthetic route. By adjusting reaction parameters an ideal product has been synthesized. Citric acid was utilized to decorate the surface of magnetite nanoparticles to acquire monodisperse state with fewer aggregations. Besides, it is known to us that several problems exists in magnetic-targeted drug delivery systems, for example, low drug loading efficiency, burst-release phenomena, etc. β-Cyclodextrin, well known as materials commonly applied in inclusion complex production, is a cyclo-oligosaccharide compound consisting of 7 d-glucose molecules joined by 1,4-glycosidic bonds. It has a cavity structure that is able to hold hydrophobic drugs. It is quite suitable for improving the hydrophilicity of hydrophobic therapeutic agents. Moreover, its toxicity is negligible. A few hydrophobic therapeutic agents such as 5-FU, paclitaxel had been manufactured in form of inclusion complex preparation for clinical use. Magnetite@β-cyclodextrin nanospheres have been designed to load model drug doxorubicin aiming for improvement of drug loading amount and suppression of burst-release.The major tasks which have been done are listed as follows:1. Magnetite nanoparticles with average size 80 nm have been fabricated by means of ultrasonics-assisted aqueous coprecipitation. By adjusting different reaction parameters such as concentration and molar ratio of Fe3+/Fe2+, reaction time and aging temperature a series of products has been obtained. The optimal reaction conditions was determined as below: Fe3+/Fe2+ molar ratio 2∶1, reaction duration 15 min, aging duration 30 min, aging temperature 90 ℃.The final product has been proven to be pure magnetite with inverse spinel crystal structure by X-ray powder diffraction(XRD). Fourier-transform infrared spectroscopy(FTIR)indicates citric acid has been successfully joined to the nanoparticles. The monodisperse magnetite nanoparticles have spherical appearance as is shown in high resolution transmission electron microscopy. TG analysis also demonstrated the successful attachment of citric acid to magnetite nanoparticles, in accordance with FTIR. The Fe3O4@CA nanoparticles exhibited paramagnetic behaviour and its saturation magnetization(Ms) was 17.5 emu/g which is shown in M-H curve. It is clear that the prepared magnetite nanoparticles can fulfill the requirements of magnetic targeted drug delivery system.2. β–cyclodextrin has been attached to citric acid-coated superparamagnetic magnetite nanoparticles which had been prepared in previous experiment. The result has been confirmed by both FTIR and TG. Magnetite@β-CD-DOX magnetic targeted drug delivery system has been developed with assistance of molecular cavity provided by β-cyclodextrin. Magnetite@β-CD nanospheres were applied as nanosized drug carrier and doxorubicin as model drug. In vitro release process of this system has been investigated carefully. The UV-Vis absorption-mass concentration regression equation of DOX has been worked out, furthermore the drug loading amount, encapsulation efficiency and characteristics of magnetite@β-CD towards doxorubicin have been studied. The maximum drug loading amount of magnetite@β-cyclodextrin towards doxorubicin can reach 12%, corresponding encapsulation efficiency 30%. Besides, maximum drug loading amount was able to achieve under sonication within 30 min. The formation of inclusion complex between nanocomposites and doxorubicin seems to be strongly accelerated by means of ultrasonic irradiation and the inclusion process has been shortened compared with that without sonication. The low release rate of DOX from magnetite@β-CD-DOX drug delivery system has been observed in phosphate buffered saline(PBS) solution. Moreover the continuous release lasted for 12 hours, which demonstrated characteristics sustained release.