| In this research, a new type of drug-loaded magnetic microspheres, which was named adriamycin-loaded ion-exchange magnetic microspheres, was developed by the two pharmaceutical technologies of preparing the regular magnetic microspheres and ion-exchange resin. The new magnetic microspheres (ADR-CMC-Mag-MS) were prepared with the anti-cancer drug adriamycin hydrochloride (ADR) as the model drug, with carboxymethylated chitosan (CMC) as the solid support and Fe3O4 ultrafine particles as the magnetic material. One of the aims of investigating the ADR-CMC-Mag-MS was to minimize the burst effect, which was one of the biggest problems observed in most microspheres. Meanwhile, by the magnetic force of the external magnetic field the ADR-CMC-Mag-MS intended to delivery the anti-cancer drug specifically to the targeting area, leading to a maximum of drug therapeutic effects and a minimum of side effects.Blank CMC magnetic microspheres (CMC-Mag-MS) were prepared by emulsion cross-linking techniques. Single factor influence selection was studied emphatically and the optimal formulation was decided based on an orthogonal design. It showed that the CMC-Mag-MS of the optimal formulation were of a fine particle size distribution. The Fe3O4 was of 10.04%weight of the microspheres. The saturation magnetization of the Fe3O4 ultrafine particles was 169.95emu·g-1, and 9.15 emu·g-1 of the magnetic microspheres. Both of the CMC-Mag-MS and Fe3O4 ultrafine particles had the characteristic of superparamagnetism.ADR-CMC-Mag-MS was made by the technique of preparing ion-exchange resin. The optimal formulation was chosen by means of single factor influence selection. The drug loading and embedding ratio of ADR-CMC-Mag-MS were 107.6μg·mg-1 and 90.6%, which were with a mean diameter of 3.853±1.484μm. The Fe3O4 was of 8.96%weight of the microspheres. The results of DSC and FTIR indicated that ADR was well loaded in the microspheres and ion-exchange happened between ADR and CMC-Mag-MS. Results of the drug release behavior fitted by kinetic models showed that it fitted First-order model, which indicated the burst effect of the ADR-CMC-Mag-MS was significantly reduced.The pharmacokinetics studies were carried out of four different ADR preparations/administrating methods. The results showed that it fitted two-compartment model. Compared with the other three ADR praparations/methods, Cmax of the ADR-CMC-Mag-MS+magnetic field was much lower, as well as the other drug concentrations in plasma at the time spots.The targeting efficiency of ADR-CMC-Mag-MS was systematically learned both in vitro and in vivo. A model of simulating in-vitro human blood microcirculation was established. Biodistribution studies on rats displayed the fine targeting efficiency of the ADR-CMC-Mag-MS, compared with other preparations. The ADR concentration in the targeting area was much higher, at the same time the drug concentration in heart was much lower. Histological study on liver (as the targeting area) proved that this prepared ADR-CMC-Mag-MS could delivery the anti-cancer drug specifically to the targeting area.Anti-proliferation effects on Hep3B human hepatic tumor cells were investigated. The IC50 values of crude drug, ADR non-magnetic microspheres and ADR-CMC-Mag-MS on Hep3B for 72h by MTT assay was 0.100μg·mL-1, 0.086μg·mL-1 and 0.052μg·mL-1 respectively.From the results above, it was clearly seen that in this research ADR-CMC-Mag-MS has been successfully prepared and it could well reach the signed goals of this research by low burst effects and fine targeting efficiency in external magnetic field. |
PDF Full Text Request