All ETDs from UAB

Advisory Committee Chair

Sergey Mirov

Advisory Committee Members

Paul Castellanos

Renato Camata

William Grizzle

Ho-Wook Jun

Eben Rosenthal

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

This dissertation describes how the mastery of active tumor targeting and subsequent tumor regression is a great challenge for cancer therapy. Near infrared (NIR) photothermal therapy (PTT) as a localized minimally invasive therapy utilizes nanoparticles (NPs) as a physical contrast agent. The NIR laser irradiation, transparent to normal tissue, overlaps with plasmon resonance absorption of gold nanoparticles (AuNPs). The AuNPs convert the absorbed NIR light energy into thermal energy and cause localized destruction of surrounding tissue. To improve efficiency for targeting of AuNPs to malignant tumors, we developed a technique for conjugating gold nanoparticles to tumor-specific antibodies. We demonstrated that the binding efficiency of the antibodies conjugated to the polyethylene glycol coated (PEGylated) gold nanorods (AuNRs) is 33.9% greater than PEGylated antibody-GNR conjugates as reported by Liao "Gold Nanorod Bioconjugates" in Chem. Mater., 2005, 17, pp 4636-4641. We report the in vivo feasibility of a minimally invasive modality that combines active targeting, fluorescent imaging, and NIR photothermal treatment of malignant tumors as a potential approach for a variety of cancer types that over-express the epidermal growth factor receptor (EGFR). The anti-EGFR antibody was labeled with a NIR fluorescent dye and conjugated to PEGylated AuNRs (dye-antibody-AuNR). The optimal molar ratio determination and conjugation of dye-antibody-AuNR facilitated the targeted delivery of the nanorods to the tumor site. The conjugation did not reduce the binding affinity of the antibody to the EGFR, the fluorescence of the IRDye, or the therapeutic qualities of the AuNRs. NIR photothermal treatment with the dye-antibody-nanorod conjugate sufficiently killed approximately 90% of tumor cells in vitro and provided a reduction in tumor size in vivo post intravenous tail injection. Intratumoral injections of AuNRs followed by a one-time 10-minute near infrared laser treatment resulted in ~100% tumor regression as monitored grossly and confirmed by histology. The change of tumor volume was dramatically different for the combination AuNR and laser treatment group as compared to the control groups: no treatment, laser only, and nanorods only.

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