Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)



Committee Chair

Philip Low

Committee Member 1

David Thompson

Committee Member 2

Nikolai Skrynnikov

Committee Member 3

Angeline Lyon


Carbonic anhydrase IX (CAIX) is a membrane-spanning zinc metalloenzyme that catalyzes the reversible consumption of CO2 and water to form H+ + HCO3- in hypoxic and acidic environments. Many human cancers upregulate CAIX to help control their pH in hypoxic microenvironments. The consequent overexpression of CAIX on malignant cells and low expression on normal tissues renders CAIX a particularly attractive target for small molecule inhibitors, antibody drug conjugates, and ligand-targeted drugs. In this study, CAIX-targeted fluorescent reporter molecules were initially exploited to investigate CAIX-specific binding to multiple cancer cell lines in vitro and were shown to exhibit potent, selective in vitro binding characteristics. A small molecule CAIX-targeted tubulysin B conjugate was then synthesized and examined for its ability to kill CAIX-expressing tumor cells in vitro and in vivo. These therapeutic conjugates were shown to be efficacious in several xenograph models without exhibiting signs of gross toxicity. Because most solid tumors contain hypoxic regions where CAIX is over-expressed, development of a method to selectively deliver drugs to these hypoxic regions could aid in the therapy of otherwise difficult to treat tumors.