Development of targeted radiopharmaceuticals for the treatment of melanoma : a tale of lutetium-177 and terbium-161

Abstract

Despite recent developments and the progress made in providing clinical solutions for the management of disease, melanoma continues to be a disease with a high mortality rate. In recent years, advances in clinical options for diagnosing and treating the disease have greatly improved patient management and improved patient survival. Targeted radiopharmaceutical therapy (TRT), which involves systemic delivery of radiation via a tumor-selective biological agent, has shown great promise for cancer treatment, with increasing clinical adoption seen in recent years. Compared to conventional external beam radiation therapy, TRT reduces potential damage to healthy cells and enables dosage delivery to distant metastases by specifically binding tumor targets or accumulating them within them. The radionuclides emit radiation that is both cytotoxic to these diseased cells and suitable for non-invasive diagnostic imaging. Additionally, there is the possibility of developing a "theranostic pair," using diagnostic and therapeutic radioisotope companions, which enables pre-therapy imaging to support patient-specific dose selection and treatment of the disease. The recent FDA approvals of radiopharmaceuticals like Pluvicto[trademark] and LUTATHERA[trademark] represent great progress towards the promise of TRT. Analogous to lutetium-177 both in chemical and radiochemical properties, terbium-161 represents a potential alternative for lutetium-177-based therapies. However, terbium-161 emits a higher fraction of Auger and conversion electrons, which provide the potential of impacting a higher level of cellular damage through the production of an increased amount of radical oxygen species (ROS), which are lethal to cellular components like the cell wall and cytosolic processes. When applied in proximity to the nucleus, terbium-161 has the potential to damage DNA components to bring about cell death through other intrinsic cellular pathways. Albumin binders have long been explored for their ability to increase the circulatory time of pharmaceuticals in a bid to improve their cellular activity and the effect of the pharmaceutical to which they are tagged Here, I present work centered on a comparison between lutetium-177 and terbium-161 labeled radiotracers evaluated through in vitro studies in B16F10 cells, as well as in vivo using mice bearing tumors of the same cell line. Comparisons are also made between albumin-binding and non-albumin-binding radiotracers, as well as between the commercially available chelator DOTAGA and the novel HOPO-1,2-based chelator L804. Radiochemical yields, saturation binding assays, biodistribution studies, and efficacy/toxicity studies were evaluated using both radionuclides. The data presented in this dissertation provide us with insights into potential clinical translations and explorations of terbium-161, as well as providing answers to the question of which chelator is better suited for the complexation of terbium-161 for future preclinical and clinical explorations.