Radiotheranostic agents targeting the tumor microenvironment

The genesis and evolution of the tumor microenvironment is a key determinant in the proliferation and dissemination of cancer and ultimately, patient outcomes. The C-X-C chemokine receptor 4 (CXCR4) is a key player in shaping the tumor microenvironment, attracting stromal and immune cells, and propagating metastasis of expressing cells. As such, its expression is associated with a poor prognosis and therefore, this protein is a promising therapeutic target. An emerging approach involves the design of molecular probes for non-invasive imaging and radionuclide therapy, through vectors that target the desired protein and carry a radioisotope with imaging or treatment properties. We use this approach to design positron emission tomography (PET) imaging and radionuclide therapeutic pharmaceuticals by modifying a known potent antagonist of CXCR4 called LY2510924. Through careful design of the linker and radioprosthetic group necessary to confer favorable properties for a pharmacological agent to be used as a molecular probe, I developed a series of radiopharmaceutical ligands that showed high-contrast imaging properties and high accumulation in cancers expressing CXCR4. These radiopharmaceuticals have the capacity to carry a variety of radioisotopes, including ⁶⁸Ga, ¹⁸F and ¹⁷⁷Lu, for imaging and therapeutic purposes. Furthermore, by modifying the LY2510924 pharmacophore, I further enhanced its affinity to CXCR4, developing one of the most potent pharmacophores of CXCR4 to date. Based on this new pharmacophore, BL34, a novel CXCR4-targeting radiopharmaceutical, showed excellent accumulation in CXCR4-expressing tissue, while clearing rapidly from non-target organs. The PET images and biodistribution data show the promise of BL34 as a clinically viable radiopharmaceutical. Due to the global COVID19 pandemic, I developed one of the first specific inhibitors of transmembrane protease serine 2 (TMPRSS2), a serine protease implicated in SARS-CoV-2 viral entry. By leveraging the substrate specificity and catalytic mechanism of TMPRSS2, I designed and evaluated an electrophilic inhibitor with nanomolar potency. This inhibitor showed broad inhibition of wild-type and mutant spike protein processing by TMPRSS2. This work further delineated a novel diazomethane-free route in the synthesis of an irreversible inhibitor of TMPRSS2, enabling further proteomic and structural studies of TMPRSS2 and streamlining the design of other covalent probes for serine proteases.Medicine, Faculty ofGraduat