Date Available
8-20-2027
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Engineering
Department/School/Program
Biomedical Engineering
Faculty
Samuel Gorman Awuah
Faculty
Mark Suckow
Faculty
Sunderam Sridhar
Abstract
Breast cancer is the most prevalent form of cancer diagnosed in women with about 2.3 million cases worldwide. The causes of breast cancer formation are still being debated, with hypothesized causes including environmental, genetic, lifestyle, and many other conditions. The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), where all these molecular receptors estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) are lacking. The prognosis of TNBC remains uncertain, and treatment options remain underexplored. Further research is needed to better develop targeted therapies that can improve patient outcomes. Chemotherapy treatment causes systemic toxicity and unwanted side effects. My dissertation expounds on the potential use of nanotechnology using a drug delivery system to deliver these chemotherapeutic agents directly to the cells to eliminate limitations associated with chemotherapy treatment, such as off-target effects causing toxicity, poor selectivity between drugs and cancer cells, poor cellular uptake of these drugs by cells, and potential drug resistance. Metal-based gold complexes have received considerable attention due to their potential in demonstrating anticancer activity. Specifically, gold complexes are known to possess distinctive chemical and physical features that impact reactivity and biocompatibility. Notwithstanding the attractive attributes of gold complexes, they suffer from physicochemical and physiological limitations such as poor solubility, leading to poor bioavailability, poor cellular uptake, and off-target effects, reducing their effectiveness and lethality towards TNBC cells. The development of nanodevices and nanoparticles as a drug delivery system for these chemotherapeutics offsets most limitations of currently approved chemotherapeutics. Here, we synthesize chitosan derivatives as a potential drug delivery system to deliver anticancer agents to TNBC cells with the goal of improving the lethality and efficacy of these agents. Chitosan biopolymer has been approved by the FDA for wound dressing and as a supplement. It has unique properties such as biocompatibility, biodegradability, mucoadhesion properties, and enhanced cellular uptake and selectivity towards cancer cells. The limitation with chitosan is its solubility only in lower pH and not in neutral pH, which reduces biomedical applications.
This dissertation is focused on the synthesis of chitosan derivatives as a drug delivery system to extend chitosan's application in cancer research, specifically by improving the solubility and bioavailability of the chitosan polymer, which in turn increases the lethality of anticancer agents when used as a drug delivery system. The first work focused on the synthesis of chitosan polyethylene glycol (PEG) copolymers through the formaldehyde linkage method to form chitosan PEG nanoparticles as a drug delivery system for auranofin, which was FDA-approved initially for treating rheumatoid arthritis and is now being repurposed to treat ovarian, breast, and lung cancers. The second work focused on the synthesis of thiolated chitosan polymer into nanoparticles with the goal of
improving the solubility of chitosan in neutral pH through the conjugation of thiol groups to chitosan. The chitosan thiolated nanoparticle was conjugated to with our potent anticancer agent, AuDNC1, which is a cyclometalated gold (III) dithiocarbamate complex. The final work focuses on the design of chitosan hyperbranched polyglycerol nanoparticles and comparing that to our gold phosphate anticancer agent to test efficacy in vitro and in vivo. We believe these findings highlight the importance of nanodevices in cancer treatment, demonstrating improved selectivity and anticancer activity when anticancer gold agents are delivered with nanoparticles compared to when they are not. The selectivity of chitosan nanoparticle derivatives toward triple-negative breast cancer cells enhances the therapeutic indices of anticancer agents, with the potential for clinical application.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.419
Recommended Citation
Afrifa, Maame Abena O., "The Delivery of Gold-Based Anticancer Agents Using Polymeric Drug Delivery Systems Toward Triple Negative Breast Cancer" (2025). Theses and Dissertations--Biomedical Engineering. 86.
https://uknowledge.uky.edu/cbme_etds/86
