Improving Prostamide Anti-Cancer Activity Through Derivatization and Micellar Delivery
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Date
2023-04-28
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Authors
Halatek, David James
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East Carolina University
Abstract
Colorectal cancer is the fourth most common cancer diagnosis per year as well as the fourth highest rate of death per year according to the Centers for Disease Control. Approximately 1/3rd of the diagnosed colorectal cancer cases per year will result in death. Prior research from our group has shown that the prostaglandin-ethanolamide 15-deoxy, D12,14 prostamide J2 (15d-D12,14-PMJ2) is selectively toxic to murine melanoma cells (B16F10) and murine colorectal cells (CT-26) both in vitro and in vivo and significantly reduces tumor growth. Further, 15d-D12,14-PMJ2 induces cell death in primary patient melanoma cells and thus may be a promising therapeutic. As 15d-D12,14-PMJ2 can be made by the condensation of ethanolamine with 15-deoxy, D12,14 prostaglandin J2 (15d-D12,14-PGJ2), we sought to test the cytotoxicity of other prostamide derivatives to determine the structural features required for activity. Based on prior results in a study of related prodrugs, 15d-D12,14-PMJ2-Arvanil was selected as the top candidate for testing anti-cancer activity. After testing in both a human and murine cell line, it was determined that 15d-D12,14-PMJ2-Arvanil was not as cytotoxic as 15d-D12,14-PMJ2. It is possible that the bulkier functional group on the α-chain of the prostamide prevents transport into the cell the same way or to the same degree 15d-D12,14-PMJ2 enters. In an effort to test this hypothesis, and to develop an improved means for systemic delivery for this class of hydrophobic prostamides, engineered micelles composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] and D-α-tocopherol polyethylene glycol 1000 succinate were investigated as drug carriers