DESIGN, SYNTHESIS, AND CHARACTERIZATION OF ULTRASMALL FLUORESCENT CORE-SHELL SILICA NANOPARTICLES FOR BIOLOGICAL IMAGING AND SENSING APPLICATIONS
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2024-06-02
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Nanoparticles have shown great promise in the field of biological imaging as well as in vivo diagnostics and therapy, due to their small size and ability to be specifically engineered for targeting sites of disease and drug release applications. Thorough understanding of the fundamental structure, as well as the in situ intracellular behavior, of a nanoparticle facilitate optimized design and control of its features, ultimately maximizing its desired capabilities, and yielding optimal results in its final application, enabling e.g. clinical translation. In this dissertation, the core structure of clinically-translated C’ dots, a class of ultrasmall fluorescent core-shell silica nanoparticles, was first studied in detail by advanced high performance liquid chromatography (HPLC) methods. Experimental as well as modeling results suggested a core structure consisting of ~2 nm sized silica clusters loosely bound together via silicon-oxygen-silicon bridges. An alternative core surface functionalization chemistry was identified to eliminate surface chemical heterogeneities induced in post-synthesis surface functionalization with amines while retaining high conjugation efficiency. Next, a NIR-window-II-emitting fluorophore was encapsulated into sub-10 nm C dots, potentially enabling high penetration depth in vivo imaging due to their small size and enhanced optical properties. Multiple synthetic challenges were overcome, and insights were obtained on fluorophore molecular design for the purpose of efficient encapsulation during ultrasmall silica nanoparticle synthesis. Brightness and photostability were both substantially enhanced by over an order of magnitude after encapsulation into C dots as compared to free dye in solution, while the originally barely water-soluble NIR-II-emitting fluorophore encapsulated in C dots became colloidally stable in aqueous solution. Finally, a ratiometric pH sensor enhanced in spatial resolution capability by live-cell optical super-resolution microscopy (OSRM) was developed to obtain new insights into C dot processing by cells in the intracellular environment. Analysis and data processing methods were established to integrate sub-diffraction-limit localization information from OSRM with diffraction-limited ratiometric pH sensing. To that end, single-particle-based compositional heterogeneity in reference and sensor dyes of solution chemistry-based probes was separately characterized in detail, and resulting information was used to enable reliable pH sensing down to the single particle level. The insights provided by the results of this thesis should enable the design, synthesis, and application of next generation ultrasmall silica nanoparticle probes and drug delivery vehicles with improved biological properties for applications ranging from bioimaging and biosensing all the way to nanomedicine.
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186 pages
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2022-05
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Wiesner, Uli B.
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Putnam, David A.
Estroff, Lara A.
Estroff, Lara A.
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Materials Science and Engineering
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Ph. D., Materials Science and Engineering
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Doctor of Philosophy
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dissertation or thesis