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Studies of novel targeted drug delivery systems and molecular probes of cancer biology
Knewtson, Kelsey Erin
Knewtson, Kelsey Erin
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Abstract
Cancer is a complex family of diseases. As our understanding of cancer biology has improved, so has our ability to treat the pathology associated with this condition. Traditional anticancer therapeutics lack selectivity and cause many side effects. These side effects can reduce the quality of life of the patient and limit the doses of drugs that need to be used to fully eradicate cancer cells. In recent years, a deeper understanding of cancer has led to the development of targeted therapies that exploit molecular differences between cancer cells and healthy cells. These newer targeted therapies often have reduced side-effects compared with traditional drugs, to the great benefit of patients. Sections of this dissertation focus on a specific class of targeted anticancer therapeutics called antibody drug conjugates (ADCs). ADCs combine the targeting power of antibodies with the cell killing mechanisms of potent toxins. These therapies can overcome some of the resistance that can emerge against therapeutic antibodies, and the low therapeutic index of associated toxins, but there is still room for improvement. Many patients treated with ADCs experience severe side effects. Additionally, most ADCs are generated by attaching the toxins to the antibody in a random manner, generating very heterogenous mixtures of therapeutics. In this dissertation, a system that combines ADCs with endosome disruptive peptides is explored as a possible method to improve the therapeutic index of ADCs. This system employs ADCs composed of poorly membrane permeable toxins whose toxicity is triggered by endosome disruptive peptides that allow these toxins to reach the cytoplasm. A novel approach to generate more homogenous ADCs is also described. This method takes advantage of the binding of Protein A from Staphylococcus aureus to human antibodies to direct the labeling of the antibody with small molecules. This dissertation also describes basic cancer biology research related to the cellular production of reactive oxygen/nitrogen species. Control of the levels of oxidants and reductants is very important for the normal function of cells and imbalances are linked to many disease states including cancer. We describe the development and use of novel fluorescent sensors of the important biological oxidant peroxynitrite. These sensors are able to detect endogenous production of peroxynitrite by macrophages upon phagocytosis of opsonized beads, a process that previously reported sensors are unable to detect. Better sensors of peroxynitrite such as those discussed here could aid the study of this oxidant and its role in cancer and other diseases.
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Date
2019-05-31
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University of Kansas
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Keywords
Chemistry, Biology, antibody drug conjugate, endosome disruption, fluorescence, peroxynitrite