Date on Master's Thesis/Doctoral Dissertation
Nantz, Michael H.
Committee Co-Chair (if applicable)
Burns, Christopher T.
Maurer, Muriel C.
Nanostructured materials--Health aspects; Biomedical engineering; Drug delivery devices
The development of nanomaterials as medical diagnostic and therapeutic agents is a rapidly expanding field. A brief search of the literature revealed that roughly half of all articles related to nanoparticle-based drug delivery were published after the onset of this thesis research, over the past 4 years. A few nano-based formulations have entered into clinical use, including liposomal drug formulations, protein-linked drugs, and nanoparticle-based MRI contrast agents. The chemistry that enables conjugation of a functional cargo, whether a drug, a targeting element, or a radionucleotide, to a nanocarrier is thus a critical component for development. Oximation is one of the simplest and most efficient chemical conjugation methods. It entails condensation of an aminooxy group with an aldehyde or ketone carbonyl yielding an oxime ether. The versatility of oximation is highlighted and exploited in this thesis. Chapter 1 provides an overview of the application of iron oxide nanoparticles in medicine, and more specifically, to nanoparticles as delivery agents for the anticancer drug doxorubicin. Chapter 2 describes an oximation methodology for cellular metabolite derivatization to enhance the detection of carbonyl analytes using mass spectrometry (MS). Integration of carbonyl-selective aminooxy functionality with a quaternary ammonium moiety for MS electrospray enhancement and a hydrophobic domain for sample cleanup led us to design reagent QDA (quaternary dodecyl aminooxy) and its 13CD3 isotopologue *QDA. Analysis of QDA/*QDA-treated lung adenocarcinoma A549 cells established a profile of carbonyl metabolites spanning multiple structural classes showing capability for global carbonyl profiling. In Chapter 4, hydroxylated cationic oxime ether lipids are described for coating core-shell Fe3O4-SiO2 nanoparticles. Formulation of the nanoparticles produced lipid-coated, highly ζ–potential–positive assemblies: a new form of cationic magnetoliposomes (CML). The CMLs were evaluated as potential drug carriers by integrating into the bilayer a hydrophobically modified analog of doxorubicin. On treatment of MCF-7 breast cancer cells with the drug-loaded CMLs, the assemblies were rapidly internalized and exhibited higher toxicity than treatments with doxorubicin alone. In a separate assessment of the oxime ether lipids, complexation with nucleic acids to form cationic lipoplexes similarly showed high cellular uptake and marked them as viable candidates for siRNA delivery. Chapter 5 provides all experimental procedures for the aforementioned science.
Mattingly, Stephanie, "Aminooxy reagents in nanomedicine and bioanalysis." (2014). Electronic Theses and Dissertations. Paper 1751.