Activating molecules and complexes for diagnosis and therapy

Thesis

Development of new molecules for cancer imaging, for diagnosis and prognosis evaluation, is crucial to expand the information available to clinicians. The formation of activatable profluorophores is desirable to enable imaging of disease and upregulation of enzymes or biological molecules in certain regions, such as in the presence of hypoxia (low oxygen concentration) in cancerous tissues.

In hypoxic tissue, found in solid tumours, the effects of both chemotherapy and radiotherapy are reduced, therefore selective delivery of a compound which is activated in the presence of both hypoxia and X-ray irradiation is a route to overcome this. Chapter II highlights the design of a series of profluorophores, based on known fluorophores and the tetrafluoroaryl azide group, as proof-of-concept work to determine whether activation of a profluorophore under hypoxia and X-ray irradiation is orthogonal or can be used advantageously in combination. The chapter explores profluorophore design and the poor activation of the novel profluorophores under reductive chemical and enzymatic conditions and X-ray irradiation, highlighting the need for development of new moieties which can be activated at lower, clinically relevant doses of X-ray irradiation to further investigate the orthogonality of activation.

Investigation of lanthanide complexes as imaging agents, due to their advantages over organic fluorophores, is an expanding field and these complexes have utility for both optical imaging and MRI, based on the lanthanide metal employed (Eu, Tb or Gd). Chapter III discusses the synthesis, spectroscopy and activation of complexes which contain ester linkages to common hypoxia-activated groups and highlights the change in luminescence and relaxivity between the profluorophores and known LnDOTA complexes. It is proposed that these complexes release LnDOTA in the presence of chemical and enzymatic reductants via a hydrolysis mechanism, therefore they do not exhibit the desired selectivity profile for biological applications and emphasise the need to balance activity and selectivity. However, these novel probes act as a proof-of-concept for activatable optical imaging and MRI complexes and give insight into the design considerations needed for their future development.

Chapter IV builds on the drawbacks from chapter III, involving the design of leucine and alkyl appended azobenzene bimetallic lanthanide complexes, aiming for improved cell permeability and emission intensity for biological application of reductively activated lanthanide complexes in vivo. However, derivatised azobenzene bimetallic complexes were synthetically challenging to make and further work is needed to expand on approaches to overcome the problem of cell permeability.

Chapter V summarises the work carried out in this thesis and chapter VI describes the experimental synthetic and assay procedures utilised to obtain the results in chapters II-IV.

Authors: Foster, CA

• DOI: 10.5287/ora-o1xqvwwbo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: optical imaging; hypoxia; lanthanide; profluorophore; cancer imaging; MRI
• Subjects: Chemistry, Inorganic; Chemistry, Organic; Imaging systems in chemistry; Magnetic resonance imaging