| Controlled drug delivery system (CDDS) can realize targeted delivery of the anti-cancer drug to the lesion locations, which in turn improves the therapeutic effect and decreases the toxic side effects. Therefore, CDDS has great potential application in biomedical and other related fields. Ideal CDDS should have no "Zero premature release" before it gets to the targeted area, while release as much drug as possible after getting there in a controllable way. Recently, lots of CDDSs have been developed, such as pH sensitive, thermo sensitive and oxidation-reduction responsive drug carriers. However, these CDDSs always have some disadvantages, for example, some cannot avoid leaking of drugs before getting to the targeted area while others have very low drug release ratio. For reasons above, study about CDDSs still has high significance.Ordered mesoporous materials have been used as drug carries because of its well-defined channels, tunable pore size and huge surface area which can be modified easily. Disulfide bond can keep very stable in the blood circulation for long time, while break when it enters into the cancer cells. Herein, we rationally combined mesoporous silica material with disulfide bond and design three novel kinds of drug delivery systems with different mechanism for loading drug. The main works were summarized as follows:1. Mercapto-propyl functionalized mesoporous silica nanospheres (MSN) were synthesized by one-step method. According to TGA and element analysis, the content of thiols on the surface of the MSN is2.5×10-3mol/g. Then, cysteamine is grafted onto the surface of the MSN in methanol through the reaction between thiols. Solid content and mole ratio of the raw material are studied so as to find out the best reaction condition. Following, fluorescein isothicyanate (FITC) is grafted to the surface by the reaction between isothiocyanate and-NH2on the surface of the mircorspheres. In theory, FITC will be released from the system if the disulfide bond breaks. Therefore, the cleavage behavior of the disulfide bond is studied in the PB buffer by detecting the UV and fluorescence absorption of the FITC in the environment. The experiment result shows that, in PB buffer with pH=7.4, the disulfide bond would be cleaved in the solution with glutathione at concentration of2mM, while it will keep stable if no glutathione is added.2. Composite microsphere with MSN as core and polyacrylic acid (PAA) as shell is synthesized. The weight content of the PAA shell is35.6%using TGA as the analysis method. According to BET result, compared to the surface area of MSN (1034cm2/g), the composite microsphere with PAA shell is much smaller (225.1cm2/g). Hence, most of the pores on the surface are blocked by the polymer chains. In the next step, anti-cancer drug DOX is loaded into the pores and shells of the drug carriers through hydrogen bond and electrostatic interaction. At the main time, the polymer chains are cross-linked by cystamine (a cross-linker with disulfide bond). Theoretically, the drugs will be sealed in the pores of the microspheres due to the highly cross-linked polymer shells and the drug loading efficiency can reach as high as40.2%. The drug release experiments show that DOX will rarely be released in the PB buffer (pH=7.4) while49.42%of the drug will be released if glutathione at the concentration of2mM existed in the environment. While in pH=5.0PB buffer,53.1%of the drug will be released even without glutathione because the solubility of DOX increase dramatically in this condition and the polymer shell can hardly prevent DOX from diffusing into the buffer. However, with the help of glutathione, the release ratio could be further improved, which definitely indicate that this system owns great pH and oxidation-reduction responsiveness.3. Magnetic Composite microspheres with magnetic sensitive and oxidation-reduction responsive characters are synthesized. Firstly, Fe3O4@SiO2composite nanoparticles are prepared with stober method using citric acid stabilized magnetic nanoparticles as seed. Secondly, the surface of the composite microspheres was further modified with different polymers to get Fe3O4@SiO2@PAA and Fe3O4@SiO2@PHEMA nanospheres. Thirdly, anti-cancer drug DOX is loaded into the drug carrier through hydrogen bond and electrostatic interaction while the polymer chains are cross-linked by cross-linker with disulfide bond in the mean time. As a result, the drugs are trapped in the polymer shell. The drug loading efficiency of Fe3O4@SiO2@PAA and Fe3O4@SiO2@PHEMA is24.9%,15.5%respectively. According to the drug release experiment, these two kinds of drug delivery system whose drugs are trapped in the polymer shell all exhibited oxidation-reduction responsiveness. |
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