Date of Graduation

5-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Cell & Molecular Biology

Advisor/Mentor

Thompson, Audie K.

Committee Member

Beitle, Robert R. Jr.

Second Committee Member

Millett, Francis S.

Third Committee Member

McNabb, David S.

Keywords

Cancer; Drug delivery; Hydrogels; Materials science; Nanoparticles; Polymer; Polysaccharide

Abstract

Drug delivery systems (DDS) have highly evolved in the last decades with the development of hydrogels and nanoparticles. However, high systemic uptake, side effects, low bioavailability, and encapsulation efficiency continue to be a major hurdle faced by such DDSs.

Nanoparticles and hydrogels can be specifically designed for targeted DDSs to mitigate some of the problems. This dissertation aimed to design two DDSs for ocular drug delivery and one for cancer treatment. The first project sought to develop chitosan nanoparticles (Cs-NP) using PEGDA as a copolymer to encapsulate gentamicin (GtS) for ocular drug delivery. Cs-NPs contain positive charges that can interact with negatively charged ocular proteins to increase the NP residence time. Simultaneously, ocular enzymes degrade the chitosan β-(1→4)-glycosidic bonds to release GtS at the eye's surface, therefore, preventing premature release of GtS. PEGDA was used to increase drug encapsulation by shielding the repelling forces of like charges between Cs and GtS. The data shows PEGDA does not hinder enzymatic degradation while increasing drug encapsulation efficiency and producing more stable and homogeneous particles.

The second project utilized Michael's reaction to crosslink Cs, Cs-NPs, and PEGDA to produce a film designed for ocular drug delivery. The film serves as an anchor for the NPs to prevent drug removal by tears and blinking. The data shows that crosslinking of Cs and PEGDA does not affect lysozyme activity, and NPs could successfully release GtS without affecting GtS activity.

Finally, the third project sought to compare the cytotoxicity of the polysaccharide fucoidan (FU) encapsulated into chitosan nanoparticles (CFU) and without encapsulation (free-FU) and their effects on two cancer cell lines. The results indicate that free-FU has very little toxicity to MDA-MB-231 cancer cells compared to MCF-7. However, cytotoxicity to MDA-MB-231 cells was increased by delivering encapsulated FU. Free-FU can enter MCF-7 cells using surface receptors that are not present in MDA-MB-231 cells. Therefore, by encapsulating FU into Cs-NPs, cytotoxicity can be increased as Cs-NPs containing FU are endocytosed into the MDA-MB-231 cells.

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