UC San Diego

An important area of biomedical nanotechnology is based on the interaction of living systems with inorganic and organic materials at the nanoscale. Silica nanoshells (NS) are attractive biomaterials because of their advantages as readily functionalized transport and imaging devices. Some of the advantages of silica include: the porous structure of amorphous silica allows small molecule storage; the surface can be modified easily with trimethoxysilyl reagents; silica has low biotoxicity and good biocompatibility. In addition, titanium and titanium alloys have a long history in medical applications due to the excellent biocompatibility of its surface oxides, and more recently, titania (TiO2) nanomaterials have gained interest in cancer research due to TiO2 nanoparticles producing photo-induced electrons and holes under ultra- violet (UV) excitation leading to their possible use as photodynamic therapy agents. Consequently, silica and titania nanoshells potentially have multiple biomedical applications such as imaging agents, targeted drug delivery agents, or gene transferring motherships. Simple scalable methods to fabricate uniform luminescent europium -doped, hollow silica or titania NS with 200 nm diameters are reported in this thesis. Fluorophore reporter, Eu3+ ions, were incorporated directly into the NS matrix, leaving the surface free for targeting functionalization, while also leaving the nanoshell interior free for drug or other payload encapsulation. Amino polystyrene beads were used as templates and a 5-10 nm thick silica or titania gel coating was formed by the sol-gel reaction. After removing template by calcination, porous dehydrated silica gel or predominately anatase titania phase nanoshells of uniform size were obtained. The structure of the nanoshells were characterized by transmission electron microscopy measurements and XRD analysis, while particle size and zetapotentials of the particles suspended in aqueous solution were characterized by dynamic light scattering and their emission and excitation spectra were analyzed using a luminescence spectrometer. Furthermore, the surfaces of SiO2 NS were functionalized with folic acid in order to specifically target cancer cells. Folic acid, also known as vitamin B9 or folate, is essential for the synthesis of nucleotide bases and binds with high affinity to folate receptors, which are frequently over- expressed in tumor cells such as certain ovarian and cervical carcinomas, for example. With the use of fluorescent and confocal microscopy, it was found that as the amount of folate on the surface of the NS was increased, a higher amount of NS adhered and endocytosed into HeLa cancer cells, a cervical cancer cell line, when compared to non-targeted NS. In addition, a selectivity experiment demonstrated that folate targeted NS did selectively target the folate receptor rich HeLa cancer cells at a higher rate when they were mixed in with human foreskin fibroblast (HFF-1), a normal cell line. Nanoshell interactions with HeLa cervical cancer cells in vitro were also studied and quantified using a luminescence ratio analysis to assess nanoshells adhesion and cell endocytosis