Award Date

8-2010

Degree Type

Thesis

Degree Name

Master of Science in Health Physics

Department

Health Physics and Diagnostic Sciences

First Committee Member

Steen Madsen, Chair

Second Committee Member

Phillip Patton

Third Committee Member

Ralf Sudowe

Fourth Committee Member

Henry Hirschberg

Graduate Faculty Representative

Merrill Landers

Number of Pages

125

Abstract

The current median survival of patients with glioblastoma multiforme (GBM), the most common type of glioma, remains at 14.6 months despite multimodal treatments (surgery, radiotherapy and chemotherapy). This research aims to study the feasibility of photothermal ablation of glioma using gold nanoshells that are heated upon laser irradiation at their resonance wavelength. The novelty of our approach lies in improving nanoshell tumor delivery by loading them in macrophages, which are known to be recruited to gliomas via tumor-released chemoattractive agents. Ferumoxides, superparamagnetic iron oxide (SPIO) nanoparticles, are needed as an additional macrophage load in order to visualize macrophage accumulation in the tumor with magnetic resonance imaging (MRI) prior to laser irradiation. The feasibility of this approach was studied in an in vitro model of glioma spheroids with the use of continuous wave (CW) laser light for ablation.

The optimal loading of both murine and rat macrophages with Ferumoxides was determined using inductively coupled plasma atomic emission spectroscopy (ICP-AES). Higher concentrations of SPIO were observed in rat macrophages, and the optimal concentration was chosen at 100 μg Fe/ml. Macrophages were found to be very sensitive iv to near infra-red (NIR) laser irradiation, and their use as vehicles was thus not expected to hinder the function of loaded nanoshells as tumor-ablating tools.

The intracellular presence of gold nanoshells in macrophages was confirmed with TEM imaging. Next, the loading of both murine and rat macrophages with gold nanoshells was studied using UV/Vis spectrophotometry, where higher nanoshell uptake was found in rat macrophages.

Incubation of loaded murine and rat macrophages with rat C-6 and human ACBT spheroids, respectively, resulted in their infiltration of the spheroids. Subsequent laser irradiation at 55 W/cm2 for 10 min and follow-up of spheroid average diameter size over 14 days post-irradiation showed that ACBT, but not C-6, spheroids responded to laser-activated nanoshell therapy starting from Day 12. The lack of C-6 response was attributed primarily to the lower nanoshell loading of murine macrophages.

Finally, the attempt to double-load macrophages with both Ferumoxides and nanoshells failed under both simultaneous and sequential co-incubation. However, in vivo tracking of nanoshell-loaded macrophages with Ferumoxide is likely feasible using injections containing a mixture of Ferumoxide-loaded and nanoshell-loaded macrophages. Overall, the proof-of-principle studies suggest that photothermal ablation of gliomas via macrophage-mediated delivery of nanoparticles is a promising approach and the work described herein establishes the guidelines and experimental parameters for subsequent in vivo trial.

Keywords

Glioblastoma multiforme – Treatment; Gliomas – Treatment; Gold nanoshells; Lasers; Macrophages; Photothermal ablation; Superparamagnetic iron oxide nanoparticles

Disciplines

Analytical, Diagnostic and Therapeutic Techniques and Equipment | Nanoscience and Nanotechnology | Oncology

Language

English