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UBC Theses and Dissertations

Radiotheranostic agents targeting the tumor microenvironment Kwon, Daniel


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.

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