Molecularly-Targeted Gold-Based Nanoparticles for Cancer Imaging and Near-Infrared Photothermal Therapy
Day, Emily S
West, Jennifer L.
Doctor of Philosophy
This thesis advances the use of nanopartic1es as multifunctional agents for molecularly-targeted cancer imaging and photothermal therapy. Cancer mortality has remained relatively unchanged for several decades, indicating a significant need for improvements in care. Researchers are evaluating strategies incorporating nanopartic1es as exogenous energy absorbers to deliver heat capable of inducing cell death selectively to tumors, sparing normal tissue. Molecular targeting of nanopartic1es is predicted to improve photothermal therapy by enhancing tumor retention. This hypothesis is evaluated with two types of nanopartic1es. The nanopartic1es utilized, silica-gold nanoshells and gold-gold sulfide nanopartic1es, can convert light energy into heat to damage cancerous cells. For in vivo applications nanopartic1es are usually coated with poly(ethylene glycol) (PEG) to increase blood circulation time. Here, heterobifunctional PEG links nanopartic1es to targeting agents (antibodies and growth factors) to provide cell-specific binding. This approach is evaluated through a series of experiments. In vitro, antibody-coated nanopartic1es can bind breast carcinoma cells expressing the targeted receptor and act as contrast agents for multiphoton microscopy prior to inducing cell death via photoablation. Furthermore, antibody-coated nanopartic1es can bind tissue ex vivo at levels corresponding to receptor expression, suggesting they should bind their target even in the complex biological milieu. This is evaluated by comparing the accumulation of antibody-coated and PEG-coated nanoparticles in subcutaneous glioma tumors in mice. Contrary to expectations, antibody targeting did not yield more nanoparticles within tumors. Nevertheless, these studies established the sensitivity of glioma to photothermal therapy; mice treated with PEG-coated nanoshells experienced 57% complete tumor regression versus no regression in control mice. Subsequent experiments employed intracranial tumors to better mimic the clinical setting. These tumors are highly vascularized, so nanoparticles were addressed toward receptors abundantly expressed on tumor vessels using growth factors as a novel targeting strategy. Photothermal therapy with these vascular-targeted nanoparticles disrupted tumor vessels, leading to a 2.2-fold prolongation of median survival versus control mice. This work confirms that nanoparticle surface coating can affect biodistribution and therapeutic efficacy. With continued optimization of molecular targeting strategies, imaging and photothermal therapy mediated by nanoshells and gold-gold sulfide nanoparticles may offer an effective alternative to conventional cancer management.
Engineering; Biomedical engineering; Oncology