Exploring potential of auger emitting radionuclides for targeted therapy

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My proposed research program aims at the systematic in vitro evaluation of Auger-electron emitting radionuclides with different physical half-lives, Auger electron emission energies, and accompanying emissions in combination with various delivery systems (placing radionuclides within different proximities to DNA) to explore the potential of Auger emitting radionuclides for targeted radionuclide therapy (TRT). This research aims to understand the processes of interaction of cell nuclei with Auger electrons on single cell level and will allow to design effective radiopharmaceuticals based on Auger-emitting radionuclides. This will involve experimental work in parallel with theoretical calculations. Further, we will compare the in vitro therapeutic efficacy of Auger electrons from 119Sb, 125I, 103mRh, 67Ga, 111In and 197m+gHg to alpha (225Ac/213Bi) and beta (177Lu) emitting radionuclides to possibly combine several emission types for targeted therapy. Some of the proposed isotopes (111In, 67Ga and 125I) are commercially available which allows us to start in vitro experiments immediately. However, some of the most promising isotopes (119Sb, 103mRh and 197Hg) will require development of production, radiochemistry and radiolabeling before starting in vitro evaluation. We will take advantage of TRIUMF's unique facilities and its established collaboration network to produce and study the proposed repertoire of isotopes for TRT. We will utilize TRIUMF's cyclotrons with energies from 13 to 500 MeV, enabling production of all proposed Auger candidates. Radiochemical processing of research candidates will be done in shielded fumehood and hot cell facilities at TRIUMF. Another crucial component of this proposal is the multi-institutional and multidisciplinary collaboration aspect. The chelation aspects will be performed in collaboration with the University of British Columbia (C. Orvig, Chemisry). In vitro evaluation and cell experiments will be performed in collaboration with the British Columbia Cancer Agency (F. Benard, Radiology, Molecular Oncology). This program also includes several international collaborations: Southern University of Denmark (H. Thisgaard), Cornell U., USA (J. Wilson) and Erasmus MC, The Netherlands (J. Nonnekens) on in vitro evaluation of Auger emitting candidates as well as comparison with β- emitters and alpha emitters; Joint Institute for Nuclear Research, Russia (D. Filosofov) on theoretical calculation of toxicity effects and support on radiochemistry of proposed candidates; U. of Wisconsin, USA (J.W. Engle) on production, radiochemical aspects and in vitro evaluation of proposed research candidates. By building on TRIUMF's advanced isotope production capabilities, and emerging efforts in therapeutic (alpha-, beta- and Auger-) isotope production, this research proposal aims to solidify Canada as a center of excellence in TRT.