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Nanodelivery of Novel Inhibitors of ERCC1/XPF for sensitizing colorectal cancer cell to platinum drugs
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- Author / Creator
- Mehinrad, Parnian
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This project's long-term goal is to increase the efficacy of genotoxic therapeutics through thesensitization of cells to DNA-damaging therapy ahead of the treatment. The focus of this projectwas on the enhancement of platinum-based chemotherapeutics in colorectal cancer usingcolorectal cancer cell lines as models of the disease. For this purpose e, novel inhibitor of a DNArepair enzyme involved in the repair of DNA caused by platinum-based chemotherapeutics, i.e.,small molecule inhibitors of ERCC1-XPF heterodimerization, namely A4 and pyronaridine wereused. To reduce the systemic effect of ERCC1-XPF inhibitors, that can lead to the sensitization ofnormal cells as well as cancer cells to DNA-damaging chemotherapeutics nano delivery systemsof A4 and pyronaridine were also developed. Inhibition of ERCC1/XPF, a heterodimeric enzymecomplex with endonuclease activity that participates in the repair of DNA inter-and intra-strandcrosslinks, by A4, pyronaridine, and their nano-formulations was hypothesized to make cellssensitive to DNA damage by platinum-based chemotherapeutics. The results of our studies ledto the development of optimum polymer and lipid-based nano-formulations for delivery of A4and pyronaridine, respectively, showing maximum encapsulation efficiency, <50 % drug releasewithin 24 hrs, and average diameter of < 150 nm. Free and particularly encapsulated inhibitorsof ERCC1/XPF were able to sensitize colorectal cancer cells to the cytotoxic effects of platinumbased chemotherapeutics under study at specific dose ratios. The sensitizing effect of ERCC1/XPFinhibitors and their encapsulated counterparts was more noticeable for carboplatin
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- Graduation date
- Spring 2023
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.