Interaction of Silica Nanoparticles with Human Cells and Their Biomedical Applications.

摘要

With recent development of nanotechnology, various nanoparticulate systems have been proposed to serve as functional units for biomedical applications in many innovative ways. Among various possible choices, silica nanoparticles (NPs) enjoys easily modifiable surface chemical characteristics and excellent stability in physiological environment. Therefore, it is considered as one of the most promising carrier candidate for therapeutic and diagnostic applications.;A systematic study on the interaction between silica nanoparticles and human cells is first carried out in the present thesis work. Endocytosis and exocytosis are identified as major pathways for NPs entering, and exiting the cells, respectively. Most of the NPs are found to be enclosed in membrane bounded organelles, which are fairly stable (against rupture) as very few NPs are released into the cytoplasma. The nanoparticle-cell interaction is a dynamic process, and the amount of NPs inside the cells is affected by both the amount and morphology (degree of aggregation) of NPs in the medium. These interaction characteristics determine the low cytotoxicity of SiO2 NPs at low feeding concentration.;Experiments were then designed to compare the biological consequence of two most common form of SiO2 nanoparticles, i.e., crystalline and amorphous NPs, when they were introduced to human cells. Although the apparent cytotoxicity of both types of NPs seems to be low, more detailed characterizations disclose the profound difference induced by the crystalline and amorphous ones, resulting in significantly different cell evolution pathways. Crystalline NPs but not amorphous ones are found to drastically increase the recative oxygen species (ROS) level in the cells, which can cause mitochondria dysfunction (being expressed as mitochondria proliferation), and eventually direct the cell into apoptosis. Nonetheless, only p53 deficient cells are subjective to such ROS induced cell damage, while p53 proficient cells can accommodate the stimulation from crystalline SiO2 NPs. The amorphous SiO2 NPs are found to be benign in the biological systems, and have great potential to be developed as nanomedicine.;Base on the understanding obtained from the toxicology study of the SiO 2 NPs, we have designed a special nanocarrier system for drug delivery. We have combined advantages of both SiO2 and Au NPs by constructing Au-core/SiO2-shell (Au@SiO2) nanocarriers with the photosensitizer (PS) drug embedded in the SiO2 shell layer. Compared with free PS, PS loading in the Au@SiO2 NPs shows an enhanced drug efficacy. In particular, the cells treated with the NP drug take necrosis as a major death path instead of apoptosis, which is a much less effective route. The Au plasmonic effect is found to promote the photo-response of the PS drug under light irradiation, contributing to the largely decreased cell viability. Nevertheless, one shall note that spatial confinement of the drug moledules to the close proximity of the Au core and an energy match between the drug absorption and the Au surface plasmon resonance are critical in manifesting the plasmonic effect. At the same time, embedding the drug in the SiO 2 matrix leads to favorable change in the photochemical process. The combined effects brought by the Au@ SiO2 NP carrier is responsible for the high drug efficacy. These mechanisms can be generally valid in engineering drug molecule incorporation into NP carriers and also give guidance for the optimum design of the NP drug carrier.