Preparation And Properties Of Magnetic Targeting Deuto-Microspheres Containing 5-Fluorouracil

5-Fluorouracil (5-Fu) has been widely used as the drug of first choice in cancer chemotherapy for more than 40 years. But its adverse effect would influence patients' prognosis and the qualities of their life severely. Magnetic microparticle of anticancer drugs has been studied as a new targeting drug delivery system (TDDS) recent years. It is proved that this kind of TDDS could help drug avoid the phagocytosis of macrophage and to target at the diseased region producing a marked effect: more effective and less poisonous. According to these characteristics of magnetic microparticle, bovine serum albumin (BSA) and magnetic fluid were chosen as carriers in this study to prepare the albumin magnetic deuto-microspheres containing 5-fluorouracil (5-Fu-AMDM). At the same time, the responsive properties and pharmacodynamics of 5-Fu-AMDM were studied as well for the purpose of obtaining suitable magnetic deuto-microspheres, which were expected to localize in tumors and release the drug intensively to reduce the adverse effect and increase the cure rate.The magnetic deuto-microspheres were prepared by a method of emulsion- ultrasound-heat stabilization technique. Uniform design and single factor design were utilized together to choose the best preparing conditions. Based on totally comparing with all-round indexes including drug loading efficiency, drug trapping efficiency, size and shape of each batch magnetic deuto-microspheres, the optimal preparing conditions were obtained. 250 mg BSA and 100μL magnetic fluid cooperating with 50 mg 5-Fu, and 6 mL emulsifier were needed, and emulsified at a constant stirring rate of 1000 rotation per minute (rpm) for 30 min at ordinary temperature. The emulsion was then homogenized by an ultrasound machine with the power of 150W for 4 min. Later, it must be added with a dropwise of 6mL/min to hot dispersant which temperature should be 145℃. At last, being kept at this condition of solidification exactly for 10 min, with a stirring speed of 2500 rpm, the emulsion became into deuto-microspheres.The Magnetic deuto-microspheres we got were light brown powdery with a smooth and glossy, round appearance; and its texture was puff and soft. The shape, size and distribution were observed by the scanning electron microscope and laser light scattering methods. The mean diameter was (321±23) nm with the range from 100nm to 600nm. High-performance liquid chromatography was used to determine the content of fluorouracil. The linear equation was y=1.0441x-1.5921(r=1.000); and the good linearity was abtained when the concentration was between 2.5μg/mL and 50μg/mL. The mean recovery rate was 100.00%,RSD=0.76%; while the RSD of reproducibility and precision were 0.46%, 0.53% respectively; The RSD of stability was 0.27%. The drug loading and drug trapping efficiency of 5-Fu-AMDM were (9.69±0.19)% and (70.36±0.53)% respectively. The content of Fe3O4 in 5-Fu-AMDM was 20.92μg/mg being tested by atomic absorption spectrographic method. The release test of 5-Fu from AMDM in vitro was carried out using constant temperature vibration dialysis assay. And the drug release profile could be described by Higuchi equation. The targeting property was studied in tumor-bearing mice by magnetic resonance imaging mathod. It was shown that 5-Fu-AMDM could target at the tumor tissue intensively when controlled by partis magnetic field.Base on study in qualities, investigation of stability was carried. Results showed that 5-Fu-AMDM was sensitive to high temperature and humility, and should be kept in low temperature and dry conditions. This test supplied experimental documents for the study on preparation and characteristics in vitro of 5-Fu-AMDM, provided good samples for the research of pharmacokinetics and pharmacodynamics of this preparation.Hairless mice bearing tumor were divided into treatment groups and control group in the study. Within each group of hepatoma, cholangiocarcinoma and pancreatic carcinoma model, treatment was performed with different drug via intravenous injection and magnetic field. Significant inhibition variance of tumor growth was demonstrated for 5-Fu-AMDM with magnetic field and other groups.In a word, the preparing technology of 5-Fu-AMDM was stable. Its characteristics could meet the standard of administration. It was concluded that under the action of magnetic field in vitro and vivo, 5-Fu-AMDM had potential prospects in targeting location at tumors and releasing drug. With its considerable advantages, 5-Fu-AMDM appears suitable for clinical use.