Novel approaches for the measurement of tumoral pO2 by magnetic resonance methods

Resumen

Increasing evidence supports a strong relationship between tumor hypoxia and tumor aggressiveness, poor outcome and resistance to therapies. Tumor hypoxia results from the negative balance between the oxygen demands of the tissue and the capacity of the neovasculature to deliver satisfactory oxygen provisions. A plethora of treatments have been proposed recently to overcome specifically the hypoxic burden (photodynamic therapy, hyperoxic gas breathing during radiotherapy, hypoxia sensitive the¿;¿W¿¿¿I¿ ¿¿¿ aimed to improve the results of oncotherapy. However, the lack of suitable methods to assess tumor hypoxia in the clinic, makes it not possible to identify a priori those tumors potentially sensitive to the hypoxic directed treatment and, thus, those patients that could benefit from these novel therapies. Magnetic Resonance (MR) methods are well endowed to fulfill these needs. On these grounds, the aim of this thesis is to develop and implement novel strategies to measure tumor hypoxia using MR methods. To this end, we followed two independent approaches; 1) The development and implementation of novel exogenous contrast agents revealing tissue hypoxia and 2) The development and implementation of new and advanced methods of endogenous imaging contrast sensitive to the environmental oxygen tension. In our first approach, we synthesized and characterized new 2-nitromidazole derivatives as exogenous hypoxia markers. Their potential use was investigated both in vitro and in cell cultures, and the results obtained compared with those generated by commercial hypoxia markers. We characterized the main determinants of the metabolism of nitroimidazole derivatives proposing a new mechanism for their bioreduction and sensitivity to hypoxia, implementing a new method to obtain hypoxia maps from the bioreduction of nitroimidazoles as detected non invasively by 1H Magnetic Resonance Spectroscopy Imaging (MRSI). In our second approach, we exploited the sensitivity of the relaxation times of endogenous tissue water to physiological oxygen concentrations. The paramagnetic nature of oxygen, induced appreciable, concentration dependent, T1 shortening in vivo, as revealed by T1 weighted MRI, an approached named Tissue Oxygenation Level Dependent (TOLD). Based on these images, we designed and tested a new MRI methodology to identify those tumors that could benefit from a hypoxia directed therapy as breathing gas mixtures with high oxygen content. Taken together, our results provide a new frame for the non invasive measurement of tumor hypoxia by Magnetic Resonance methods.