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Date of Award

2-2009

Document Type

Campus Access

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemical Engineering

First Advisor

Neil S. Forbes

Second Advisor

Michael A. Henson

Third Advisor

Vincent M. Rotello

Subject Categories

Biomedical Engineering and Bioengineering | Chemical Engineering

Abstract

Heterogeneous tumor microenvironments reduce the efficacy of cancer therapeutics because associated heterogeneous tumor cell populations respond differently to treatments. Tumor cells develop altered metabolism to meet the increased energy demand for rapid proliferation and cell survival in unfavorable microenvironments. Using 13 C-isotope labeling and flux analysis, intracellular metabolism of tumor cells in nutrient-limited and hypoxic microenvironment was quantified using in vitro 3-dimensional tumor model, spheroids. The effects of, hypoxia-inducible-factor-1α (HIF-1α), a factor promoting cell survival in hypoxic microenvironments, on cell growth and metabolism were investigated by using spheroids of wild type and HIF-1α-null cells. Quiescent cells in the inner region of spheroids have reduced carbon flux through the biosynthetic pentose phosphate and pyruvate carboxylase pathways. Cell survival and intracellular metabolism were not different between wild-type and HIF-1α-null tissues. These suggest that the metabolic microenvironment should be taken into account in the development and clinical application of HIF-1α targeted therapies.

A microscopy technique was developed to measure cellular DNA and RNA contents in 3-dimensional tumor model using thin cylindroids and acridine orange staining. This technieque identified heterogeneous cell populations and their distribution in cylindroids and will be useful to determine the effectiveness of chemotherapies on different cell populations. Inefficient interstitial transport hampers the efficacy of tumor therapeutics against cells distant from blood vessels, including quiescent and hypoxic cells. Gold nanoparticles have a great potential as drug vehicles due to their unique size and functionality. For clinical applications, surface charge affecting transport and cellular uptake should be carefully tuned for efficient delivery. Intercellular diffusion and cellular uptake/release of cationic and anionic gold nanoparticles in cylindroids were measured. A descriptive mathematical model based on diffusion-coupled reaction system was developed to determine the parameters governing intercellular diffusion and cellular uptake/release of gold nanoparticles. Cationic gold nanoparticles were better for fast cellular uptake and negative nanoparticles were advantageous for intercellular diffusion.

These studies demonstrate the heterogeneity in cell metabolism, populations, and transport of nanoparticles in 3-dimensional tumor model and their therapeutic implications. Because distinctive biological and biochemical characteristics collectively define tumor physiology, these results will be valuable for the development and clinical applications of cancer therapeutics.

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