Melanoma incidence is increasing faster than any other cancer in the world today. Disease detected early can be cured by surgery, but once melanoma progresses to the metastatic stage it is lethal, with an overall median survival of less than one year. The poor prognosis for late stage melanoma patients is attributed to the intrinsic resistance of melanoma to all Federal Drug Administration approved melanoma therapies. Therefore, there is a critical need for novel treatment approaches that circumvent melanoma therapy resistance. Emerging evidence suggests that differences in melanoma metabolism relative to non-malignant cells represents a potential target for therapeutic intervention. The research presented here demonstrates the potential for using triphenylphosphonium-based compounds as a new therapeutic platform for metastatic melanoma that is designed to take advantage of these metabolic differences. In vitro experiments demonstrate that triphenylphosphonium-based compounds modified with an aliphatic side chain target melanoma cell mitochondria and promote melanoma cell death via mitochondria metabolism inhibition and subsequent reactive oxygen species production. Increased reactive oxygen species production results in decreased glutathione levels and an oxidized cellular state. There is also a structure-activity relationship between side chain length, metabolic disruption, and melanoma cell cytotoxicity. Further, results demonstrate that traditional in vivo triphenylphosphonium drug administration routes such as oral gavage, intraperitoneal injection, and intravenous injection do not result in significant tumor accumulation of triphenylphosphonium drugs. However, the use of a thermosensitive hydrogel delivery system localizes triphenylphosphonium drugs directly at the melanoma tumor site and decreases melanoma tumor growth rate. These results suggest that a hydrogel-based triphenlyphosphonium delivery system could potentially be a therapeutic strategy that circumvents melanoma resistance mechanisms in order to provide durable therapy for an increasing number of metastatic melanoma patients worldwide.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-7439 |
| Date | 15 December 2015 |
| Creators | Kloepping, Kyle Christohper |
| Contributors | Schultz, Michael K. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright © 2015 Kyle Christohper Kloepping |
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