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Molecular Probes for Cancer Imaging and Therapy

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thesis
posted on 2018-04-04, 00:00 authored by Felicia M. Roland

The clinical need for more advanced disease detection and therapy has propelled the biomedical field towards creating highly sophisticated multifunctional probes, which exhibit high specificity for a disease and avoid limitations that accompany traditional methods. Many of these probes unite the capabilities of therapy and diagnostics, which has given rise to the term “theranostics”.

This thesis explores theranostic probes for cancer. It begins by providing a detailed review of supramolecular probes for medical imaging. These probes have three core structural components: a targeting unit, a linker, and a reporter group, which work together to target a biomolecule and report functional information used to better-understand a disease. The following two chapters describe molecular imaging probes based on squaraine dyes linked to zinc(II) dipicolylamine (ZnDPA) for fluorescence imaging of anionic lipids on membranes of cancer cells and pathogens. The first probe was prepared using Synthavidin self-assembly technology, where ZnDPA targeting units were appended to a macrocycle that threaded with high affinity onto a fluorescent squaraine dye. Studies compared two constructs having different numbers of targeting units to reveal that a hexavalent probe is preferred for mammalian cell imaging while a dodecavalent probe is favored for microbial imaging. The second probe was based on an unsymmetrical squaraine dye conjugated to one or two ZnDPA targeting ligands. This probe exhibited solvatochromic properties that were useful for no-wash fluorescence imaging of anionic membranes of cells undergoing programmed cell death in Xenopus laevis embryonic development.

The last two chapters focus on theranostic nanoparticle probes for photothermal therapy (PTT) using novel croconaine dyes. PTT is a treatment strategy that employs a photoabsorbing agent that is activated using laser light to create localized temperature that results in selective destruction of cancer cells. First, lipid-based nanoparticles were used to encapsulate the croconaine dyes and their efficacy was demonstrated in cell culture and animal models. Furthermore, the theranostic applications of croconaine dyes were explored as contrast agents for photoacoustic imaging. Lastly, theranostic gold-silica core-shell NPs were used for 1) covalent loading of croconaine dyes within the silica shell for PTT and 2) targeting cancer cells using Arg-Gly-Asp attached to the silica surface.

History

Date Created

2018-04-04

Date Modified

2018-10-30

Defense Date

2018-03-26

Research Director(s)

Bradley D. Smith

Committee Members

Ryan K. Roeder Basar Bilgicer

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Program Name

  • Chemistry and Biochemistry

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