Masters Theses

Keywords and Phrases

Antisense oligonucleotide; polyamidoamine (pamam) dendrimer; targeted gene delivery; triple-negative breast cancer (tnbc); urokinase-type plasminogen activator receptor (upar)

Abstract

"Around 15% of breast cancers are triple-negative breast cancer (TNBC), which is characterized by the absence of three common receptors—ER, PR, and HER2, and therefore do not respond to hormonal or anti-HER2 therapies. It is urgent to explore targeted therapeutic strategies for TNBC due to its poor prognosis and rare effective targeted therapy. In this study, we developed a polyamidoamine (PAMAM) dendrimer-based targeted gene delivery system—GDP-uPA, to utilize urokinase-type plasminogen activator (uPA) to target uPA receptor (uPAR), which is highly expressed in both TNBC cells and cancer-associated stromal cells. Our results of 1H NMR spectrum, TEM imaging, and MTT assay showed characterization of functionalized dendrimers (16.45 nm) and their high biocompatibility (25 µg/ml) in MDA-MB-231 TNBC cell line. Results of flow cytometer and confocal microscopy showed that GDP-uPA improved the delivery of GTI-2040 (GTI), an anticancer oligonucleotide, in MDA-MB-231 cell line and HCC2218 fibroblast cell line up to 6-fold compared to the GTI only group. GDP-uPA/GTI killed cells by ~30% through knock-downing human ribonucleotide reductase component (R2) by 35%. In addition, biodistribution and therapeutic studies showed a significant inhibition of tumor growth in the TNBC orthotopic xenograft mice model with GDP-uPA/GTI administration for 14 days. Collectively, GDP-uPA improved the transfection efficiency of anticancer nucleic acids in both breast cancer cells and cancer-associated stromal cells, showing the targeted capacity and attenuated tumor growth in mice model. GDP-uPA has great potential in developing efficient targeted delivery systems to treat TNBC"-- Abstract, p. iv

Advisor(s)

Huang, Yue-Wern
Yang, Hu

Committee Member(s)

Shannon, Katie
Convertine, Anthony J.

Department(s)

Biological Sciences

Degree Name

M.S. in Biological Sciences

Publisher

Missouri University of Science and Technology

Publication Date

Spring 2024

Pagination

x, 66 pages

Note about bibliography

Includes_bibliographical_references_(pages 60-65)

Rights

© 2023 Hsin-Yin Chuang, All rights reserved

Document Type

Thesis - Open Access

File Type

text

Language

English

Thesis Number

T 12330

Electronic OCLC #

1426863714

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Biology Commons

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