Abstract

Melanoma represents one of the most aggressive and lethal forms of skin cancer, with annually rising incidences throughout the world. Although chemotherapy modalities remain the mainstay of treatment, the therapeutic potential of chemotherapy typically is hampered by multidrug resistance (MDR) and nonspecific drug distribution that causes side-effects. To surmount such limitations, novel nanoformulations of low band-gap poly ({4,8-bis [(2-ethylhexyl) oxy] benzo [1,2-b:4,5-b?] dithiophene-2,6-diyl}{3-fluoro-2-[(2-ethylhexyl) carbonyl] thieno [3,4-b] thiophenediyl}) (PTB7) and poly [2,1,3-benzothiadiazole- 4,7- diyl [4,4-bis (2-ethylhexyl)- 4H-cyclopenta [2,1-b:3,4-b'] dithiophene-2,6-diyl]] (PCPDTBT) were fabricated by a reprecipitation method. These conjugated polymer nanoparticles were functionalized with the polypeptide endothelin-3 (EDN3-CPNPs) to target melanoma. The combination of EDNRB and EDN3 is unique to melanoma's endothelin axis in an otherwise healthy body. Therapeutic effects were studied in vitro for photodynamic (PDT) and chemodynamic (CDT) therapy applications. The PTB7 derived EDN3-CPNPs showed limited PDT effect and were difficult to handle due to challenges with preparation and poor colloidal stability. We, therefore, moved forward with PCPDTBT as an alternative polymer. Here, we serendipitously discovered that the PCPDTBT derived EDN3-CPNPs efficiently and specifically kill tumor cells that overexpress the endothelin B receptor agonized by EDN3. We found that tumor cell killing proceeds through ferroptosis, a reactive oxygen species (ROS) mechanism that is not dependent on external activation by, for example, light, as is the case in PDT. The EDN3-CPNPs obtained from PCPDTBT are loaded with iron (Fe3+) that is a residual catalyst of the polymer synthesis. This iron content catalyzes ferroptosis in the cells. The ferroptosis mechanism is also not heavily reliant on oxygen availability and is, therefore, promising for the treatment of hypoxic tumors. The resulting hydroxyl radicals (•OH) can rapidly oxidize bio-macromolecules, cause damage to DNA, and reduce tumor cell population. The results reported in this dissertation demonstrate that melanoma targeted EDN3-CPNPs present a new therapeutic avenue. In the future, this approach can be broadened to other tumors by replacing the targeting ligand to address cases where conventional methods are not feasible or no longer effective.

Notes

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Graduation Date

2019

Semester

Fall

Advisor

Gesquiere, Andre

Degree

Doctor of Philosophy (Ph.D.)

College

College of Sciences

Department

Chemistry

Degree Program

Chemistry

Format

application/pdf

Identifier

CFE0008280; DP0023651

Language

English

Release Date

June 2020

Length of Campus-only Access

None

Access Status

Doctoral Dissertation (Open Access)

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