DESIGNING NEW SENSORS FROM CITRATE-BASED FLUORESCENT MATERIALS

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Author:
Kim, Jimin P
Graduate Program:
Bioengineering
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
July 14, 2018
Committee Members:
  • Jian Yang, Dissertation Advisor
  • Jian Yang, Committee Chair
  • Siyang Zheng, Committee Member
  • Pak Kin Wong, Committee Member
  • Zhiwen Liu, Outside Member
Keywords:
  • fluorescence
  • chloride
  • sensors
  • antimicrobial
  • polymers
Abstract:
Novel fluorescent biomaterials are needed to match the rapid advances in optics and fluorescence-based instrumentation, not only for intracellular labeling and drug delivery systems, but also for the detection of many metabolites and biomolecules that currently lack viable and selective sensors. We herein describe the findings of a new class of fluorescence chloride sensors synthesized from a facile, low-cost reaction of citric acid and an amino thiol. The resulting thiozolopyridine molecular sensors exhibited strong fluorescence properties including high quantum yield and photostability, along with unique chloride sensitivity that switched on at low pH, enabling a selective sensing strategy for the simultaneous detection of multiple halides. We next determined the sensing mechanism to be of fluorescence quenching from the heavy atom effect, and applied molecular modeling to identify the main substituents involved, serving to expand this class of fluorescence sensors with improved chloride sensitivities. To translate this technology into point-of-care diagnostics, we designed a smartphone operated chloridometer in which the visible emission of the molecular sensor corresponds to sweat chloride levels for the diagnosis of Cystic Fibrosis. Moreover, our previously reported biodegradable photoluminescent polymers (e.g. BPLP-Cysteine) exhibited chloride sensitivity, prompting future work in the development of thin-film chloride sensors for real-time sweat monitoring in athletes. Next, we further expanded the citrate-based synthesis platform to include other amino alcohols and amino acids, resulting in a new class of fluorescent molecular rotors with a diverse array of turn-on responses to solvent polarity and viscosity. Appropriate selection of amine-containing monomers enabled the formation of a dioxopyridine ring possessing various auxochromic groups, thereby guiding structure-function studies to elucidate the fluorescence mechanisms governing polarity or viscosity sensitivity. By incorporating the fluorescent small molecules into our BPLP polymers, we then designed self-setting materials with built-in polarity probes to monitor the setting reaction in real-time. Therefore, in this dissertation we identified two distinct classes of fluorescent sensors from the citrate-based synthesis platform: a thiozolopyridine family of fluorescent chloride quenchers and a dioxopyridine family of fluorescent molecular rotors. Further work is needed to translate citrate-derived chloride and viscosity sensors towards intracellular applications to further our understandings of transmembrane chloride flux and regulation of membrane viscosity. To conclude this dissertation, we report the design of fluorescent antimicrobial polymers derived from anacardic acid (e.g. BPLP-Anacardic Acid), extracted from cashew nut shell liquid. The introduction of citric acid and anacardic acid into a renewable polymer design offered several significant advantages: 1) mild reaction conditions enabled poly-condensation of anacardic acid without destroying its antimicrobial function, 2) antibiotic synergy was herein demonstrated between citrate and anacardic acid, enabling lower antibiotic dosage and combination therapy from dual antimicrobial sources within the polymeric network, 3) The intrinsic fluorescence of anacardic acid was demonstrated herein, enabling fluorometric determination of antibiotic potency in anacardic acid-derived polymeric materials. The resulting family of BPLP-anacardic acid polymers is scalable, low-cost, and inherently antibacterial.