Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Paula Foster

Abstract

Purpose: This thesis uses magnetic resonance imaging (MRI) techniques to study natural killer (NK) cell therapy in a nude mouse model of prostate cancer. Cellular MRI, anatomical MRI and hyperpolarized 13C spectroscopy were used to study various aspects of the model. Methods: The cells used were KHYG-1 NK cells and PC-3M prostate cancer cells. Imaging was performed on a clinical 3T GE MR 750 scanner, using a high-performance gradient insert for acquisition with the balanced steady state free precession (bSSFP) sequence, and using the built-in gradients for 13C pyruvate spectroscopy. Pyruvate was hyperpolarized by dynamic nuclear polarization. Results: KHYG-1 were toxic to PC-3M in vitro and were successfully labeled with MoldayRhodamine, a superparamagnetic iron oxide nanoparticle (SPIO). A subcutaneous PC-3M tumour model was used to investigate tracking of KHYG-1 in vivo using the bSSFP sequence. Four days after administration, KHYG-1 accumulation in the tumours was detected by histology but not by MRI, although labeled KHYG-1 at high density were visible in MR images. The bSSFP sequence was then optimized for imaging the mouse prostate and the whole mouse body. Tumour development in an orthotopic prostate cancer model was characterized by MRI and histology for tumour growth, metastasis and tumour metabolism. Tumours were visible by MRI day 9 after injection. Using histology, metastasis was detected in the lymph nodes and spleen of the mice. Necrotic regions in the tumours were detected on day 22 by both anatomical imaging and pyruvate spectroscopy and were confirmed by histology. Conclusions: KHYG-1 cell therapy shows promise as a treatment of prostate cancer. A mouse model that developed lymph node metastases was characterized. Based on the accumulation of KHYG-1 in SC tumours 4 days after administration, and the consistent presence of MRI-visible tumours on day 9-13, a treatment time point of 9-13 days is proposed for future NK cell tracking experiments.

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