Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Collaborative Specialization

Molecular Imaging

Supervisor

Bartha, Robert

Abstract

The response of tumor intracellular pH (pHi) to a pharmacological challenge could help identify aggressive cancer. In addition, tumor pHi may influence cell proliferation, apoptosis, chemotherapy resistance, and thermosensitivity. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is sensitive to cellular pH. More specifically, a CEST method called amine and amide concentration-independent detection (AACID) produces images weighted by intracellular pH (pHi) and can be used to study pharmacologic pH modulation in tumours.

The overall goal of this thesis was to maximize the magnitude of intracellular tumour acidification using pharmacologic agents. Several different drugs were studied, and we hypothesized that simulatenously blocking multiple pH regulatory mechanisms while also providing glucose as an energy substrate would increase the acute pH modulation effect. AACID CEST images were acquired in mice with glioblastoma using a 9.4T MRI scanner to measure acidification in tumours within the first two hours after treatment with dichloroacetate (DCA), cariporide, and five different drugs plus glucose.

Intravenous DCA injection produced a significant 0.04±0.01 increase in tumor AACID level corresponding to a 0.16 decrease in pHi. Intraperitoneal cariporide injection produced a significant 0.12±0.03 increase in tumor AACID value corresponding to a 0.48 decrease in pHi. Intraperitoneal injection of five drugs, plus glucose produced a 0.18±0.03 increase in AACID value corresponding to a 0.72 decrease in pHi.

Combination treatment produced the greatest tumour acidification. pH-weighted MRI in combination with a drug challenge represents a unique approach to cancer detection does not require injection of an imaging contrast agent.

Download

Share

COinS