Research Of Functional Fe₃O₄@mSiO₂ Core-shell Nanostructures Drug Sustained/Controlled Release System

All kinds of drug carriers, including polymers, liposomes, dendrimers, some inorganic nanoparticles and so forth, have been used in drug delivery and therapy. Among these, mesoporous silica nanoparticles（MSNs） have been considered as the most potential inorganic hosts to store and release drug molecules due to their excellent properties, such as good biocompatibility and biodegradation, high pore volume and surface area, uniform and tunable morphology and pore size, stable skeleton structure and easily modified surface properties. They are caused wide public concern and considered to have potential clinical application as drug carriers.Magnetic Fe₃O₄ nanoparticles with strong magnetic property and low toxicity have been widely used as targeted drug delivery, thermal therapy, cell separation and magnetic resonance imaging agents. However, pure Fe₃O₄ is prone to aggregation due to anisotropic dipolar attraction and rapid biodegradation when they are exposed to biological systems directly, and pure MSNs always face some practical applicability limitations due to the premature or burst drug release within several hours after incubation in vitro. The core-shell structure with Fe₃O₄ nanoparticles as core and mesoporous silica as shell not only can overcome the limitation compare to pure Fe₃O₄ and MSNs nanoparticles, but also can combine the advantages of the two to improve the performance in the field of targeted drug delivery. Also, it can reduce most anti-cancer drugs direct damage or adverse side effects. Fe₃O₄@mSiO₂ was chose for further modification, and a novel nano-controlled release delivery system was obtained.The main contents include the following three aspects:（1） The core-shell Fe₃O₄@mSiO₂（which diameter is about 60 nm） nanomaterials are synthesized as the host, and DOX is utilized as a model anticancer drug. After the drug loading, pH-sensitive β-thiopropionate-poly（ethylene glycol） is employed to graft outside of Fe₃O₄@mSiO₂ as the blocking caps to inhibit premature drug release. Because of the hydrolysis of the ester bond in β-thiopropionate-poly（ethylene glycol） in an acidic environment, DOX-Fe₃O₄@mSiO₂@P2 is expected to block the pore in a neutral or alkaline environment and to open the pore in an acidic environment（pH 5.8）. Moreover, the small particle size modified with the poly（ethylene glycol） fragment coating causes the DOX-Fe₃O₄@mSiO₂@P2 nanovalves to show improved dispersion, stability, biocompatibility. The structure of the system was characterized and the drug release properties were investigated in detail. Cell experiments were used to reveal its cytotoxicity and cellular uptake etc.（2） The core-shell Fe₃O₄@mSiO₂ nanomaterials were prepared as the drug carriers. At the same time, the synthesized bis-（3-carboxy-4-hydroxy phenyl） disulfide was modified with an amino silane coupling agent（3-aminopropyltriethoxysilane）, denoted as（R-S-S-R1）. After the drug（DOX） loading, the enzyme-sensitive R-S-S-R1 was employed to graft outside of the Fe₃O₄@mSiO₂ as the nanoswitch to inhibit premature drug release. Finally, the magnetic induced enzyme response drug release system was synthesized. It is known that the high expression of glutathione reductase（GSH） in tumor tissue promotes the degradation of-S-S-, thereby allowing the release of DOX. The synthesis of drug controlled release system was characterized and the drug release behavior of the system was studied. At the same time, it was investigated of the cells experiment of the controlled drug release system.（3） Fe₃O₄@mSiO₂ nanoparticles were successfully synthesized as a carrier. HA was used to coat around Fe₃O₄@mSi O2 nanoparticles（named as drug-Fe₃O₄@mSiO₂-HA） by a typical photocrosslinking reaction to block the pore and regulate the drug release. The detailed release kinetics were investigated, revealing the sensitive release triggered by hyaluronidase（HAase）, a major enzyme which is rich in the tumor microenvironment, which can degrade the HA shell to induce the enzyme sensitive drug release. Moreover, a series of the cell experiments were carried out to further reveal the fast cell uptake, and enzyme-responsive triggered for targeted drug release system and cytotoxicity. And the HA receptors and overexpressed HAase in many tumor microenvironment induce the specific targeting enrichment and drug release that combines the magnetic target insure their potential application value on tumor therapy.