Nanoshell-assisted cancer therapy: Targeted photothermal tumor ablation
Lowery, Amanda Raley
West, Jennifer L.
Doctor of Philosophy thesis
This thesis details the development of a targeted nanoshell therapy for cancer specific photothermal ablation. By attaching targeting antibodies or ligands to the nanoshell surface, these targeted nanoshells preferentially bind to tumor sites. When NIR light is applied over the tumor region containing nanoshells, the nanoshells heat, thus destroying the tumor. The targeted nanoshells therapy is demonstrated here in vitro and in vivo, targeting both the cancer cells and the angiogenic vasculature. In vitro, anti-HER2 antibody was used to bind nanoshells directly to the cancer cells, which express HER2. The cancer vasculature was targeted in vitro and in vivo by vascular endothelial growth factor (VEGF), which binds to the VEGF receptor on endothelial cells. Nanoshells targeted against cancer cells were conjugated with anti-HER2 antibodies to facilitate the binding on nanoshells to SKBR-3 breast cancer cells. Upon NIR excitation, the nanoshell-laden cells were thermally ablated. Both membrane-bound nanoshells and NIR laser irradiation are required simultaneously to destroy the cancer cells. Cells incubated with targeted nanoshells without laser irradiation continued to be viable. When healthy cells and cancerous cells were co-cultured, cancer cells could still be targeted and ablated without damaging the adjacent healthy cells. Similar to anti-HER2 nanoshells binding cancer cells, nanoshells conjugated with the soluble VEGF bound vascular endothelial growth factor receptors on endothelial cells. Selectively killing endothelial cells removes the blood supply sustaining the tumor and demonstrates the feasibility of targeted nanoshells as an anti-angiogenic strategy. VEGF nanoshells incubated with endothelial cells in vitro produced a circular area of cell death after laser irradiation. A tumor-bearing mouse model further validated the vascular targeting when VEGF nanoshells induced tumor regression after systemic nanoshell delivery and laser irradiation. Both in vivo and in vitro studies confirmed the ability to selectively induce cell death with the photothermal interaction of immunonanoshells and NIR light. Immunonanoshells exposed to laser irradiation produced targeted cell death of cancer cells even when cancer cells were in close proximity to normal healthy cells. Immunonanoshells are a promising minimally invasive cancer therapy due to their biocompatibility, selective cell specific binding, and NIR-assisted photothermal destruction of tumor tissue.