| Cisplatin is a common clinical anticancer drug, alone or with other drugsused in a variety of solid tumors chemotherapy, such as reproductive systemtumors, head and neck tumors, as well as melanomas. Although many newcancer treatments chose cisplatin, it has serious side effects such as bonemarrow suppression, nephrotoxicity, and neurotoxicity, which affect theclinical application to a large extent. Therefore, the significant research ofcisplatin is selecting delivery to tumour cells, reducing toxic effects,improving the therapeutic effect.Magnetic solid lipid nanopargiticles (MSLNs) as a new type of targetingdrug delivery system have very good application in cancer treatment，whichtrap or embed magnetic nanoparticles（MNs） or drug in the lipid core. SLNsloaded with magnetic nanoparticles (MNs) permit the SLNs to get throughsystemic blood circulation orientation to the tumor target by magnetic fieldorientation. Therefore, MSLNs selectively deliver drugs to the tumor cell, as aresult, the toxicity as well as dosage decreased, and reliability, validity andpatient compliance is greatly improved.Objective: Selected cisplatin anticancer drugs as the model, lipid,magnetic particles and cisplatin were assembled using a suitable preparationprocess, which could introduced the magnetic particles into the structure ofSLNs to improve SLNs drug encapsulation efficiency and magnetic targetingproperty. Furthermore, the interaction of lipid with a variety of metal ions andthe pattern of metal ion-assisted cisplatin loading model were investigated,which could provide a new approach to increase the drug encapsulationefficiency of SLNs.Methods:Used ferrihydrite and iron powder as precursor, magnetic monodisperse Fe3O4nanoparticles (NPs) were prepared by a novel solvethermal method atmoderate temperatures in aqueous and organic solvent media. The effectsof temperature and solvent medium on the phase and particle size of Fe3O4NPs were investigated. The products were characterized by X-ray powderdiffraction, infrared spectroscopy, differential scanningcalorimetry-thermogravimetric analysis, transmission electron microscopy,and vibrating sample magnetometry.Used glycerol monostearate (GMS) as lipid matrix, hydrogenatedsoybean lecithin (HSPC) and F-68(poloxamer188) as emulsifier, MSLNswere synthesized by film scattering ultrasonic technique. The optimizedprescription of MSLNs was selected by orthogonal experiment in which theencapsulation efficiency of cisplatin was used as parameter and graphitefurnace atomic absorption spectrophotometry (AAS) was used to determin theconcentration of cisplatin. The effects of two different loading procedures ofMNs on the microstructure and physicochemical properties of cisplatin SLNswere investigated by transmission electron microscopy (TEM), Zetasizer,infrared spectroscopy (IR) and fluorescence spectroscopy. At the same time,the drug release character of MSLNs in vitro was evaluated. Furthermore, themagnetic targeting effect in vivo was investigated by animal experiments.Kunming mice were randomly divided into two groups (group A withoutmagnetic field and group B with magnetic field). The left kidney parts of thegroup B were fixed rubidium iron boron rare earth magnet. The MSLNssuspension was intravenously into the tail vein of the mice, after an hour themice were sacrificed by cervical dislocation and organs of interests such asliver, heart, kidneys, brain were quickly removed. Concentration of cisplatin inserum and various tissues was determined. The cytotoxic activity was assessedby MTT against human cervical carcinoma SiHa cells.SLNs were prepared using four kinds of metal ions(Zn2+, Cu2+, Mn2+,Mg2+) assisted loading procedures, and the interactions between metal ionsand lipoid were analyzed by infrared spectroscopy (IR) and fluorescencespectroscopy. The mechanism of its higher drug encapsulation efficiency was investigated. Furthermore, the drug release character of metal ions-assistedloading SLNs in vitro and the cytotoxic activity by MTT against humancervical carcinoma SiHa cells were evaluated.Results:In the organic medium at120℃, uniform organic-ligand-coatingsuperparamagnetic Fe3O4NPs were produced by a novel solvethermal method;the particle size increased with the temperature, and the mean particle size was8.9nm. In the aqueous medium at180℃, pure phase Fe3O4was obtained. Theformation of Fe3O4NPs in the aqueous and organic solvent medium haddifferent mechanisms. The organic solvent serves as not only a solvent butalso an uniform reductive reagent. Compared with the aqueous solvent, theorganic solvent exhibits important roles in the solvethermal process byincreasing the nucleation numbers per unit area, inducing uniform nucleationand preventing particle aggregation.SLNs were synthesized by film scattering ultrasonic technique; theoptimized prescription of MSLNs selected by orthogonal experimental was:10mg·mL-1of GMS,40mg·mL-1of HSPC,20mg·mL-1of F-68,(GMS+HSPC): Fe3O4=3:1(w/w),1mg·mL-1of cisplatin. The effects of twokinds of different preparation procedures on the micro structure of the MSLNswere investigate. MNs were combined with lipids during film formation inprocedure I, as a result, the MNs distributed in the middle of the lipid layer inSLNs. While in procedure II, MNs were mixed with drugs during hydration oflipid film; as a result, MNs and cisplatin were contained in an interiorcompartment in lipid. The encapsulation efficiency of cisplain and the contentof MNs in procedure I and II SLNs were69.20±1.5%and57.65±3.2%,while, MNs content in procedure I and II SLNs were2.16±0.53and2.00±0.91respectively, which were higher than those of MNs-free SLNs. The releaseprofile of the procedure I SLNs in vitro fitted with a first-order equation, while,MNs-free SLNs and procedure II SLNs accorded with Weibull equation. Cellcytotoxicity of procedure I SLNs obviously exceeded the procedure II SLNs.For group B, which were fixed external magnetic field at the left kidney, the content of cisplatin in the left kidney are significantly higher than that inthe right kidney (P <0.05). On the contrary, the drug content in the twokidneys is not significantly different (P>0.05) for the group A (withoutexternal magnetic field). The results show that MSLNs, as cisplatin carrier,can carry the cisplatin to target area under external magnetic field. In thecytotoxicity assay in vitro, the MSLNs show higher cytotoxic activity than thefree drug. It suggested that introduction of MNs into the SLNs had no effecton the cytotoxic activity and MSLNs markedly improved the cell uptake ratefor cisplatin.The electrostatic interaction between the metal ions and phosphatide acylgroup of HSPC lead to the conformation change of HSPC. With the increaseatomic number and the decrease radius of metal ions, the electrostaticinteraction between metal ions and HSPC strengthened. The encapsulationefficiency of the metal ion-assisted loading SLNs was higher than the metalion-free SLNs, which still maintained good sustained release and cytotoxicity.Conclusion: Monodisperse and superparamagnetism Fe3O4NPs wereprepared by a novel solvethermal method. Used Fe3O4NPs as the magneticmaterials, the MSLNs were prepared by procedure I in which combined withMNs and lipid during film formation. MNs were embedded in a lipid bilayer;the encapsulation efficiency of cisplain and the content of MNs were higherthan those of MNs-free SLNs. Owing to higher encapsulation efficiency,procedure I MSLNs improved cell uptake and enhanced the cytotoxicity invitro. At the same time, procedure I MSLNs had obvious magnetic targeting invivo. The investigations on MSLNs in this paper can provide a certainreference for magnetic targeted drug delivery system. In addition, the researchon the interaction between metal ions and lipid privided a theoretical basis forfurther investigations of metal ion-assisted drug loading SLNs... |
PDF Full Text Request