Block Compolymer-assisted Synthesis And Biomedical Application Of Multifunctional Gold Nanocomposites

With the rapid development in nanotechnology and biotechnology, multifunctional nanocomposites have attracted more and more attention, among which gold-based multifunctional systems have recently been paid special attention owing to their potential biomedical applications in the various fields such as immunoassay, imaging, photothermal therapy, drug delivery, absorption and separation of biomolecules, etc. In this thesis, by choosing thiol functionalized, shell cross-linked, superparamagnetic block copolymer micelles as cores, a kind of multifunctional nanocomposite have been fabricated through the in situ reduction of Au3+and gold seed-mediated growth.(1) A novel Au NPs decorated, dye doped superparamagnetic hybrid composite nanospheres (Fe3O4@dye-hybrid@Au) have been fabricated. To make it, thiol-functionalized, dye doped superparamagnetic Fe3O4-silica composite nanospheres (SH-SSCNs) were used as cores, which were formed through the self-assembly between amphiphilic block copolymers (PS-b-PAA) and hydrophobic Fe3O4nanoparticles in tetrahydrofuran (THF) and then subsequent cross linking using3-mercaptopropyltrimethoxysilane (MPTMS) with dye molecules (Rhodamine B) simultaneously incorporated in the silica cross-linking framework. Then uniform gold nanoparticles were obtained through in situ reduction of Au3+and simultaneously attached onto the outer surface of SH-SSCNs via strong chemical affinity between Au and thiol groups. It was found that this uniform nanocomposite with regular spherical morphology and high saturation magnetization (0.93emu/g) can not only simultaneously enhance the contrast effect for both MR and CT imaging in vitro/vivo, but can also be effectively used as a dual modal cell labeling agent for both dark-field light scattering and fluorescence imaging.(2) By controlling the concentration of residual MPTMS molecules before reduction, the size of the formed gold nanoparticles could be reduced to about2nm. Furthermore, superparamagnetic gold nanostars were synthesized through the seed-mediated growth. The in vitro experiment displayed that the superparamagnetic gold nanostars could kill cancerous cells through the photothermal effect induced by NIR laser irradiation, while neither the gold nanostars themselves nor the laser irradiation can lead to cell death.(3) A simple but efficient route has been developed for constructing superparamagnetic Fe3O4 core/gold shell structured nanocomposite, in which each particle is composed of superparamagnetic Fe3O4nanoparticles as the core, an organic-inorganic hybrid as the mediate layer and an outer gold nanoshell (Fe3O4@hybrid@Au). UV-vis-NIR spectra and TEM characterization of Fe3O4@hybrid@Au at different growth stages further demonstrated the progressive formation of the gold nanoshells. By using a thermal imaging camera and MRI instrument, the laser-induced temperature increase effects and MRI contrast enhancement by the synthesized Fe3O4@hybrid@Au nanocomposite were investigated in vivo. In5min of laser irradiation, the temperature of the tumor region injected with Fe3O4@hybrid@Au nanocomposite increased from approximately35to60℃, and a significant darkening effect with a T2signal intensity drop by38%was observed at the same tumor region in the T2-weighted MR image. Additionally, histological examinations of major organs and hematology analysis revealed that the as-prepared Fe3O4@hybrid@Au product caused no damage to organs and can be safely used in vivo. These results revealed clearly that the as-prepared Fe3O4@hybrid@Au would be a potential theranostic agent for the simultaneous MR imaging and photothermal therapy of cancers. Additionally, this efficient method of grafting gold nanoparticles is very flexible and can be expanded to grafting gold nanoparticles on the surface of other nanocomposites containing surface thiol groups. By using the similar route, we prepared a nanocomposite which composed of a silica core formed from the polycondensation of MPTMS and an outer gold nanoshell (MPS@Au).(4) Uniform superparamagnetic gold nanoshells with tunable sizes (100nm,150nm and200nm) and high dispersivity were fabricated via the gold seed grafting and a subsequent growing process by changing the initial magnetite concentration in oil phase. The effect of core/shell ratio on the optical properties of gold nanoshells was demonstrated. And it was found that the surface plasmon absorption peak exhibited ever more significant red shift with the increase of the core/shell ratio. Furthermore, we investigated the influence of particle dimension on the MR imaging and photothermal therapy efficacy in vitro/in vivo. The in vitro MR tests showed that the relaxivity r2increases with the increase of the gold shell sizes. Meanwhile, the in vivo experiments showed that the superparamagnetic gold nanoshell with the diameter of150nm and core/shell ratio of4displayed the best photothermal therapeutic efficacy and excellent MRI contrast effect. Finally, we administered gold nanoshells into mice via intravenous or intratumoral injections. By comparison, it was proved that much better imaging and therapeutic efficacy could be obtained by using intratumoral injection. Finally, the Fe3O4@hybrid@Au nanocomposites were modified with tumor targeting ligand (RGD) and preliminary in vitro targeting experiment for killing MDA-MB-435cancerous cells was carried out.