Hypoxia-selective Compounds for Boron Neutron Capture Therapy

Boron neutron capture therapy (BNCT) is a biochemically targeted form of radiotherapy for cancer. In BNCT, a compound labeled with the stable isotope boron-10 is systemically administered, and tumor cells selectively uptake the boron-10 containing compound at higher concentrations than normal cells. A general problem with the tumor seeking compounds is that drug delivery is dependent upon sufficient vascularization within the tumor. To investigate the possibility of delivering boron to hypoxic regions of tumor, a new boronated nitroimidazole delivery agent has been synthesized as a carrier of boron-10 for BNCT. It is expected that this will be used in combination with the existing boron carrier boronophenylalanine-fructose to treat solid tumors. An immunohistochemical protocol to visualize hypoxia was tested and refined to confirm the suitability of two tumor models established in the lab for hypoxia related uptake studies. The immunohistochemical protocol is used to detect pimonidazole, which localizes at hypoxic regions in tissue and is the parent compound for the new hypoxia-selective boron carrier. The protocol was used to test and confirm the suitability of a hypoxic in vivo tumor model. Two tumor lines were tested: SCCVII squamous cell carcinoma and EMT-6 murine mammary carcinoma. Both exhibited hypoxia. Finally, quantitative studies using Inductive Coupled Plasma Atomic Emission Spectrum demonstrated that the synthesized boronated nitroimidazole reaches suitable concentrations in SCCVII and F98 tumor. Future therapeutic studies are required to empirically confirm the effectiveness of this compound. Thesis Supervisor: Jeffrey A. Coderre Title: Associate Professor of Nuclear Science & Engineering Acknowledgements Many people have contributed to this work in a wide variety of ways. I would first like to express my gratitude to my research supervisor, Dr. Peter Binns, who has given me the opportunity to pursue research on a unique topic that lies at the crossroads of my dual interests in nuclear engineering and biology. It has been a very rewarding experience. Prof. Jeffrey Coderre, who provided support and a kind ear throughout the duration of my project, is deserving of many thanks. I would also like to express my gratitude to Prof. Harling, through which I first became interested in the BNCT project. Kent Riley also deserves a very special mention for being the first to explain to me the intricacies of BNCT, as well as the technical difficulties. Dr. Arlin Rogers of the MIT DCM obliged to many meetings and consultations regarding immunohistochemistry, because of which I was able to complete my project in half of the time it probably would have taken otherwise. Kathy Cormier of the MIT DCM, who provided quick and professional turnaround of both paraffin-embedded slides and sound advice, deserves thanks. Dr. David Lee of McLean Hospital synthesized and gratefully provided the compounds, because of which I was able to have a project in the first place. I would like to express my gratitude to the faculty and staff in the Department of Nuclear Science & Engineering that have contributed to my education development. Prof. Yanch has been a kind, caring, and wonderful advisor to me throughout the years. Spending time in lab has been made easier because of the friendly staff and students in our group. Yoonsun Chung helped me tremendously with handling mice. I am grateful to Rachel Batista, a true friend who never failed to radiate her pleasantness to her surroundings. Vered Anzenberg also deserves a special mention for all of the lab bench conversations, academic, political or otherwise. Special thanks go to all of my friends, who I will truly miss next year. To my parents, and my sister Yesha, I give thanks for the everlasting encouragement and love.