Theranostic gold nanoshells and nanomatryoshkas for cancer therapy

Abstract

This dissertation describes the synthesis of multifunctional gold nanoparticles designed for therapy and diagnosis of cancer (theranostics), and the evaluation of their therapeutic efficacy and bioimaging of tumors in mice. The design of these metallic nanoparticles is aimed to incorporate imaging agents (MRI contrasts and fluorophores) in compact structures with dimensions below 100 nm while keeping their NIR-light-absorbing properties and optimum surface chemistry to enhance accumulation in tumor. The therapeutic response of these metallic nanoparticles is derived from the photoexcitation of their plasmon resonance, the collective oscillation of the conduction band electrons, which was advantageously utilized to enhance the quantum yield of fluorophores resonant in the NIR where the penetration of light is maximal in biological tissue and minimally destructive. Gold nanoshells as absorbers of NIR light can convert the absorbed light into heat consequently causing hyperthermia in the surrounding medium which leads to tumor cell death. To extent the application of previously developed theranostic nanoshells to the highly lethal pancreatic cancer, chapter 2 describes a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase associated lipocalin (NGAL) receptor in pancreatic cancer. Gold nanoshells (SiO2-Au core-shell nanoshell) resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the NIR dye ICG, resulting in a theranostic gold nanoshells, which provided contrast for both T2 weighted MRI and NIR fluorescence optical imaging. The large size of this complex (200 nm) potentially can hinder the accumulation in tumor. Seeking to reduce the size of the theranostic nanoparticles, chapter 3 presents the sub-100 nm Au nanomatryoshkas (Au/SiO2/Au). Au nanomatryoshkas are strong light absorbers with 77% absorption efficiency while the nanoshells are weaker absorbers with only 15% absorption efficiency. After an intravenous injection of Au nanomatryoshkas followed by a single NIR laser dose of 2 W/cm2 for 5 min, 83% of the tumor-bearing mice appeared healthy and tumor free >60 days later, while only 40% of mice treated with nanoshells survived the same period. The smaller size and larger absorption cross section of Au nanomatryoshkas combine to make this nanoparticle more effective than Au nanoshells for photothermal cancer therapy. Chapter 4 presents the therapeutic efficacy in mice bearing large (>1000 mm3) and highly aggressive triple negative breast tumors. To equip the Au nanomatryoshkas with imaging contrast agents, fluorophores were encapsulated in the internal SiO2 layer of the Au/SiO2/Au matryoshkas as described in chapter 5. We observed strong fluorescence enhancements of the NIR dyes Cy7 and IR800. This behavior can be understood by taking into account the near field enhancement induced by the Fano resonance of the nanomatryoshka, which is responsible for enhanced absorption of the fluorophores incorporated into the nanocomplex. The combination of compact size and enhanced light emission with internal encapsulation of the fluorophores for increased biocompatibility suggests outstanding potential for this type of nanoparticle complex in biomedical applications as it is investigated and presented in chapter 6