Date of Award

6-21-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Applied Science

First Advisor

Nawab Ali

Abstract

Breast cancer is a significant cause of cancer-associated deaths, with over 13% of women in the U.S. estimated to develop invasive breast cancer in their lifetime. The human epidermal growth factor receptor (HER2/neu) is a growth-promoting protein that is overexpressed in 15-20% of breast cancers (HER2-positive breast cancer). HER2- positive breast cancer generally grows and spreads more quickly than other breast cancers but can be targeted therapeutically. Drug targeting methods have been developed to stop the growth and spread of cancer. These methods include using specific antibodies to target overexpressed cancer cell surface antigens and delivering drugs via nanoparticles. However, the need for better-targeted therapies still exists. In this dissertation, a nanomaterial-based application was developed to target HER2-positive breast cancer cells and deliver a potent therapy to inhibit cell proliferative signaling pathways. We aimed to synthesize and characterize gold nanorods with an aspect ratio of 3 to target HER2-positive breast cancer cells and deliver Rapamycin, an FDA-approved drug shown to inhibit cell proliferation. In addition to the synthesis, characterization, and functionalization of the nanodrug itself, we worked to understand cellular interactions with the gold nanorods, both bare and functionalized, particularly cellular uptake mechanisms and intracellular localization. The cytotoxicity profile of the nanorods alone and with surface modifications was evaluated, along with the ability of the nanodrugs to both target HER2-positive breast cancer cells and deliver Rapamycin for therapeutic effect. We used spectrophotometry and flow cytometry assays for cytotoxicity analysis, inductively coupled plasma mass spectrometry and transmission electron microscopy for cellular uptake and localization analysis, and spectrophotometry and western blotting analysis for analyzing the nanodrug efficacy. Results show successful synthesis and characterization of the gold nanorods and successful functionalization for targeting HER2-positive breast cancer cells. The cytotoxicity analysis helped determine doses for studies and the cytotoxic effects of modifying the nanorod surfaces. Further, we quantified cellular uptake, delineated the endocytosis mechanism, and track the intracellular localization of bare and functionalized gold nanorods in SKBR-3 cell lines. Results show successful targeting and growth suppression of HER2-positive breast cancer cells treated with the nanodrug.

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