Development of contrast agents for molecular imaging of hipoxia in the heart

Abstract

Background: Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease (when an artery is occluded) and stroke when oxygen demand is greater than oxygen supply (Sinusas, 1999). Currently, most non-invasive approaches to detect myocardial hypoxia measure either the level of myocardial oxygen supply or the downstream effects of myocardial hypoxia such as altered mechanical function or electric instability, and few studies have reported on imaging of hypoxic myocardium directly. Therefore, the aim of this project was to design and synthesize a highly sensitive Contrast Agent capable of selectively bind to hypoxic cells/tissues, relying on the magnetic properties of iron oxide nanoparticles (IONPs) to deliver a high and sensitive contrast in Magnetic Resonance Imaging (MRI). Methods: 2-nitroimidazole has been shown to accumulate on hypoxic tissues, being the organic complement of the IONPs, responsible for the magnetic distortion of the field, hence, the contrast. These iron oxide particles were firstly synthetized and then functionalized with bioactive coatings, so they could interact, organically, with the hypoxia tracer. The chemical group 2-imido-2-methoxy-ethyl (IME) linker, previously used and tested in similar reactions (van Kasteren et al, 2009; Pearce et al, 2005) was chosen for a stable and safe linkage between the two complements of the final Contrast Agent. Results: Hypoxia tracer modified particles were successfully developed, with a 10-30 % modification level, which was proven to be enough to deliver a detectable contrast, in the cell tests. The ability to detect and to quantify the area of hypoxic tissue is of extreme relevance and it may open the field for numerous applications, e.g. the assessment of novel cardio-protective agents. It may also serve as a pre-asymptomatic diagnosis of several pathologies such as strokes, heart attacks or even cancer.

Date of Award	2014
Original language	English
Awarding Institution	Universidade Católica Portuguesa
Supervisor	Jürgen Schneider (Supervisor) & Benjamin G. Davis (Co-Supervisor)