Graduation Year

2020

Document Type

Thesis

Degree

M.S.

Degree Name

Master of Science (M.S.)

Degree Granting Department

Medicine

Major Professor

Shyam Mohapatra, Ph.D.

Co-Major Professor

Subhra Mohapatra, Ph.D.

Committee Member

Eleni Markoutsa, Ph.D.

Keywords

Actinomycin D (ACD), Cancer Stem Cells (CSC), Chitosan-Terephalaldehyde (CS-TPA), Acetazolamide (ATZ), Tumor Microenvironment (TME)

Abstract

Out of all cancer diagnosis’s, lung cancer has the highest mortality in both sexes making it the leading cause of cancer deaths. Current therapeutic and clinical methods fail to successfully treat the disease, contributed to the development of multi-drug resistance (MDR). Hence, new therapies are needed that can exploit the tumor microenvironment (TME) to target Cancer Stem Cells (CSC). CSCs constitute a key population of the TME, promoting hypoxia, low intracellular pH, and angiogenesis. Actinomycin D (ACD) is a potent CSC inhibitor, but due to its high toxicity and lack of specificity towards cancer cells presents a need for a targeted nano-delivery system. This project focuses on the synthesis of a novel pH-responsive nanoparticle for controlled release of ACD. Chitosan (CS) nanoparticles crosslinked with Terephalaldehyde (TPA) to form a stable Schiff-base at neutral pH. CS-TPA form relatively homogenous nanoparticles in aqueous phase with a Z-average size of 195nm±1.6. Acidosis and hypoxia are coupled within the TME due to high Carbonic Anhydrase IX (CA-IX) expression; Acetazolamide (AZT), a CA-IX inhibitor, is conjugated on to the surface of CS-TPA as a targeting moiety to potentially enhance solid tumor penetrance. The study demonstrates successful synthesis, characterization, and imaging of CS-TPA and CS-TPA-AZT along with in-vitro analysis of pH response with ACD-loaded CS-TPA nanoparticles.

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