Study On The Performance And Mechanism Of New Nano - Materials As Anticancer Drugs

Nano medicine is emerging as a new field of interdisciplinary research, including nano technology and pharmaceutical technology. Nano medicine, based on nano materials, has been used in diagnosis and targeted therapy effectively. The functionalized nanoparticles can be developed into ideal transmembrane carriers of probes, drugs and DNAs, thus help to reduce the toxicity of anti-cancer drugs to normal tissues. For the transmembrane carrier, one of the most important challenges is to reduce the side effects as well as transport enough drugs to the targeted area.Encouraged by the meaningful applications of nano medicines, my thesis is mainly foucesd on the research and development of mesoporous silica nano materials and mesoporous carbon nano particles as the carriers of anti-cancer drugs. The thesis includes the design and synthesis of novel mesoporous materials, the development of drug carriers for controlled or targeted release, and the endocytosis mechanisms of nano particles.In the first chapter, we first briefly introduced cancer nanotechnology, different targeted pathways of nanoparticles, then we reviewed the recent reports on several novel nano carriers, such as mesoporous silica nanoparticles, carbon nanotubes, and magnetic nanoparticles.In the second chapter, we synthesized the ultrasmall, well-dispersed hollow silica nanospheres (HSSs) on the understanding of the hard-sphere packing mechanism for mesoporous materials. After removing the surfactant core of as-synthesized, spherical, silica-coated block-copolymer micelles, HSSs with a uniform particle size of24.7nm, a cavity diameter of11.7nm, and a wall thickness of6.5nm are obtained. It is shown that by surface functionalization with methyl groups during synthesis, HSSs can be further dispersed in solvents such as water or ethanol to form a stable sol. Moreover, the hollow cavities are accessible for further loading of functional components. In addition, it is demonstrated that HSSs possess superior endocytosis properties for HeLa cells compared to those of conventional mesoporous silica nanoparticles. It’s expected that HSSs may find broad applications in bionanotechnology, such as drug carriers, cell imaging, and targeted therapy.In the third chapter, we found that the small mesoporous silica nanoparticles (=37nm in diameter) have a high loading capacity for a hydrophobic photosensitizer, SiPcCl2(82.6%in weight), and excellent endocytosis properties. As a result, the amount of SiPcCl2being delivered to cancer cells is increased by approximately two orders of magnitude compared to pure SiPcCl2at the same dosage, and the photodynamic therapy efficiency is enhanced by over fourfold. Our method can be widely used to increase the dosage of hydrophobic anti-cancer drugs in cancer cells and therefore increase the cytotoxicity of the drugs.In the fourth chapter, we investigated the cellular uptake efficiency, mechanism and cytotoxicity of silica nanoparticles with various sizes. The largest silica nanopartciles (=307.6nm) take an energy dependent uptake pathway (clathrin dependent and caveolin independent) while the process for the medium size silica nanoparticles(≈167.8nm) involves clathrin and caveolin dependent endocytosis. In contrast, the smallest silica nanoparticles (=55.6nm) follow not only energy required clathrin and caveolin dependent endocytosis but also an energy independent pathway to efficiently enter the cells. Moreover, the cellular uptake efficiency of SNPs, which show excellent biocompatibility, is size dependent in the order of55.6nm>167.8nm>307.6nm. The comprehension of the uptake mechanism, efficiency, and cytotoxicity of SNPs is fundamentally important and will facilitate further development of size-defined SNPs as the transporters for different purposes.In the fifth chapter, mesoporous carbon nanospheres with small diameters of≈90nm are developed as an efficient transmembrane delivery vehicle of an anticancer drug, doxorubicin. Mesoporous carbon nanospheres exhibit a high loading capacity toward doxorubicin due to hydrophobic interactions and the supramolecular π stacking between doxorubicin and the carbonaceous structures, on which the pH-dependent drug release are successfully achieved. Specifically, doxorubicin can be loaded onto mesoporous carbon nanospheres in basic solution and in a physiological pH range, while release occurs in acidic solution in its ionized state. By effective passive and active targeting, mesoporous carbon nanospheres can be readily internalized into HeLa cells, where the carried doxorubicin can be efficiently released in the acidic microenvironment of the tumors for further therapy. This smart pH-dependent drug loading and release property of the system makes it possible to reduce the cytotoxicity to normal tissues during circulation in the body since the normal physiological pH is≈7.4.In the sixth chapter, we introduced folic acid to the surface of mesoporous carbon nanospheres, and the results from confocal laser scanning microscope and flow cytometry demonstrated that the cellular uptake efficiency of mesoporous carbon nanospheres toward HeLa cells was increased through the functionalization with folic acid, and the folate modified mesoporous carbon nanospheres show much higher endocytosis properties toward HeLa cells (folate receptor positive) than toward MCF-7cells (folate receptor negative). The cytotoxicities toward HeLa cells were studied by MTT method, which indicated that the cytotoxicities of doxorubicin loaded mesoporous carbon nanoparticles was also enhanced due to the introduction of folic acid and targeted delivery, while the mesoporous carbon nanospheres show very good biocompatibility toward both HeLa and KB cells.