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Studies on Synthesis and Properties of Physio-Responsive Molecular Materials for Bioimaging
바이오이미징을 위한 생리활성감응 분자소재의 합성과 그 특성에 관한 연구

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Authors
Jeongyun Heo
Advisor
Soo Young Park
Major
공과대학 재료공학부
Issue Date
2016-08
Publisher
서울대학교 대학원
Keywords
Bioimaging agentsFluorescent probesNear-infrared spectroscopyKinetics controlResonance Raman probeReactive oxygen speciesBio-orthogonal Raman scatteringUltrasound imaging
Description
학위논문 (박사)-- 서울대학교 대학원 : 재료공학부, 2016. 8. 박수영.
Abstract
Bioimaging is a technique that is used for visualizing anatomical areas, as well as visualizing at the molecular level, and it is an effective tool for accurate diagnoses. For an early and accurate diagnosis, precise detection methods are necessary. To improve diagnostic selectivity and specificity, it is important to select a specific marker, which is only expressed in pathological conditions and that has changed compared to the normal biological state. It is also important to develop a probe that responds to this marker sensitively and selectively. In this thesis, various physio-responsive molecular materials are introduced as contrast agents into in the image modalities of optical imaging (fluorescence), Resonance Raman imaging and sonography in order to control for the pathology-related physio-responsive properties of material and to establish its diagnostic test accuracy thereafter. Furthermore, while utilizing the unique and beneficial properties of the newly designed probes, novel and innovative concepts are demonstrated, which can make a breakthrough for challenging issues in various bioimaging modalities.
In Chapter 2, we introduce a method of a spatiotemporal detection for endogenous H2O2, which is known to cause pathological conditions, as well as fluorophores for in vivo fluorescence bioimaging. First, a reactor-like nanoassembly probe for tailoring H2O2-sensing kinetics is produced, with an H2O2-responsive fluorogenic molecule and a catalytic additive that are co-incorporated. The nanoscopic sensing kinetics are reasonably tailored over a wide range by adjusting the types and loading amounts of the catalysts. When compared to the uncatalyzed nanoprobe, the base catalysis shows an unprecedented sensing rate that is increased by ten orders of magnitude along with significantly improved H2O2 selectivity. With burst kinetics and high structural integrity, the base-catalyzed probe enables spatiotemporally resolved mapping of the low-level H2O2 that is generated at the very beginning of epidermal growth factor stimulation in A431 cells. The enzyme-like rate of sensing kinetics also allows for visualizing the subcellular responses of β-cells under lipotoxicity as well as their proliferation and autophagy, demonstrating potential as a bioprobe for studying low-level H2O2-implicated cell processes. Secondly, the utility of 1,3-bis(dicyanomethylidene)indan, which turns blue in polar media by self-deprotonation, shows potential as a minimal anionic polymethine dye for probing biomolecules in cells and in vivo through non-covalent complex formation and near-infrared fluorescence signaling.
In Chapter 3, we develop a new generation of RR molecular probes to analyze and monitor the molecular content of specific cellular compartments that are related to disease and to specifically respond to ROS and generate an RR signal. First, the specific cellular compartment-targeting molecular RR probes are designed for applications in live cells. This probe shows unprecedented detection sensitivity through RR enhancement and produces spectrally distinct and intense signals. The probe also allows simultaneous mapping of macromolecules such as membranes and mitochondria in live cells. Second, we demonstrate a novel design concept for a molecular-sensing platform that specifically generates a signal by non-toxic visible laser excitation, with resonant Raman nitrile signatures (~2200 cm-1) in response to ROS. The sensing principle employs a ROS-triggered oxidative chromogenic reaction that activates resonant Raman enhancement through chemical transformation of a non-resonant hydrazo molecule into a resonant azo dye with extended p-conjugation. Experimental studies as well as DFT calculations demonstrate that this design strategy for activatable resonant Raman sensors is applicable for the selective detection of highly oxidative ROS, namely hypochlorite ions, down to 100 ppm.
In Chapter 4, we adapt a non-enzymatic peroxyoxalate-based Chemiluminescence (POCL) reaction for use as an H2O2-responsive ultrasound (US) contrast agent. POCL undergoes a highly sensitive and selective CL reaction for detecting H2O2 and produces a 1,2-dioxetanedione intermediate. The intermediate decomposes into to two carbon dioxide (CO2) molecules. Researchers have demonstrated that colloidal POCL nanoreactors show enhanced CL sensitivity toward H2O2. However, in this chapter we direct our attention to the carbon dioxide byproduct as a potential core gas of microbubbles for use as an H2O2-responsive ultrasound (US) contrast agent. The oxamide-rich bPEI-oxamide nano-formulation was successfully synthesized and examined by CL in optical imaging with the formation of microbubbles under microscopic observation with intense US contrast in phantom US experiments upon addition of H2O2. The nano-formulation was administered to disease-model mice and exhibited enhanced contrast in US images.
Language
English
URI
https://hdl.handle.net/10371/118075
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College of Engineering/Engineering Practice School (공과대학/대학원)Dept. of Materials Science and Engineering (재료공학부)Theses (Ph.D. / Sc.D._재료공학부)
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