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In an effort to design near-infrared (NIR), water soluble glucose sensors, several pH sensitive NIR cyanine derivates were designed and synthesized to provide insight into the viability of the cyanine platform as the fluorophore core for performing minimally invasive long term glucose monitoring in vivo. Many previous efforts to build effective fluorescent sensors for glucose have provided guidance towards the architecture of binding groups and fluorescent response required to achieve this goal, but have not provided appropriate solubility, or excitation and emission characteristics for in vivo sensing. In an effort to address the aqueous solubility of the highly rigid cyanine platform, a tetra sulfonated core was chosen for this work. Though fully water soluble, pH sensitive derivates still showed some aggregation characteristics. Simple sugarbinding boronic acid derivatives showed appropriate fluorescent responses, but poor binding. Efforts to improve binding through synthesis of bis-boronic acid compounds proved elusive.
With the advent of chemical biosensing, a wide variety of biomolecules endogenous to the body are detected in vivo using a number of different methods. Most fluorescent based chemical sensing is primarily done as a form analytical diagnostics, however, recently this technology is being applied to continuous data collection. This work focuses on the translation and usage of fluorescent sensing in vivo, primarily using corona phase molecular recognition (CoPhMoRe) single walled carbon nanotube (SWNT) sensors. These sensors were developed for the lab bench but their translation to in vivo required a number of advances to overcome the method error involved with fluorescent sensor usage in vivo. The goal of this work was to create a framework for the implantation and imaging of intensity modulated sensors to be used in vivo with confidence. This work explored a diverse range of topics in nanosesnsor development and biomedicine. The theoretical and experimental tools developed for this work were then applied to a number of different topics. We initially used pharmacokinetic modeling to predict adipose analyte concentrations for sensor optimization. However, pharmacokinetic model was then adapted to predict glucose responsive insulin (GRI) dynamics. A GRI is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient’s dynamic glucose concentration. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. We use well developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI to determine the desired kinetic parameters and dosing for optimal glycemic control. Our model shows there exists an optimal parameter space that results in successful glycemic control within prescribed constraints over a 24-hour period that persists through a skipped meal. Our results show how tools developed for the sensing space can be applied to adjacent fields. Experimentally, we applied the concept of ratiometric fluorescent sensing to account for the myriad of confounding artifacts that occur while imaging in vivo: from light scattering to mechanical perturbations. The CoPhMoRe technique was applied to find a poly(styrene p-styrenesulfonate) polymer wrapped nanotube for use as a reference and was combined with a DNA SWNT sensor for riboflavin in a hydrogel. The encapsulating hydrogel was shown to preserve the riboflavin sensor response after exposure to 10% mouse serum and after three days of implantation in vivo. Combining the sensor with the invariant reference into a single hydrogel to ratio the modulated signaling, we show that it corrects for in vivo errors, such as breathing and heart-beats, resulting in an order of magnitude increase in confidence signal detection. This works shows the ratiometric hydrogel strategy improves in vivo sensing, enabling SWNT and potentially other fluorescent nanosensor constructs. Even with ratiosensing there is the issue of optimizing the orientation, implantation location, and analyte administration for in vivo imaging of fluorescent sensors, as ratiometric sensing cannot account for all sources of error. We show that subcutaneous implantation and local injection involves significantly more method error compared to intraperitoneal implantation and analyte administration. In combination with hydrogel implants, bottom up imaging, and retro-orbital injections, we show that it is possible to administer analyte systemically while having a stable fluorescent signal. This work has shown the ability to detect local analyte concentrations in vivo with confidence, a potential application of the detection of any generic analyte is introduced as the concept of chemical tomography. Chemical tomography is a technique where a sensor and a tracer analyte can be injected and used to characterize the 3D mass transfer characteristics of a volume. We show proof of concept for using fluorescent nanosensors for vitamins as a way to characterize properties of an environment. In this work we use HUVEC cells adhered to a porous membrane beneath a layer of MoS2 sensors that change fluorescence in response to riboflavin. By adding riboflavin to this space, we can characterize the 2D diffusivity profile across the porous membrane. Using riboflavin in combination with the sensor we can characterize the decreases in diffusivity as the HUVEC cells contract the space between the pores. Finally, as SWNT sensors are applied to a variety of environments they will inherently experience different laser excitations. Exposing fluorescent SWNT sensors to varying laser fluence [mW/area] can alter their responses to analytes significantly. As the laser fluence increases the nanotube response to certain analytes increases. However, this effect is corona phase dependent as corona phases like sodium cholate and phospholipid-PEG wrapped SWNTs are immune to the range of laser fluences tested. Additionally, we show that increasing the SWNT residence time under laser exposure by encapsulating the sensors in a hydrogel amplifies the effect. Mathematical modeling, Raman G peak shifting studies, fluorescent wavelength shifts all suggest that this effect is not due to laser heating of a single nanotube. We show the importance of testing and accounting for the changes in laser fluence as novel SWNT sensors are developed for new applications.
A thorough, accessible, and general overview of chemosensors Providing a comprehensive overview of chemosensors organic molecules designed to bind and sense small molecules or metal ions and their applications, Chemosensors: Principles, Strategies, and Applications is an accessible one-stop resource for analysts, clinicians, and graduate students studying advanced chemistry and chemosensing. Chemosensors function on a molecular level, generating a signal upon binding. The book reviews their synthesis, design, and applications for detecting biological and organic molecules as well as metal ions. The text highlights applications in drug discovery and catalyses that have not been well covered elsewhere. Covering such topics as molecular recognition, detection methods, design strategies, and important biological issues, the book is broken into four sections that examine intermolecular interactions, strategies in sensor design, detection methods, and case studies in metal, saccharide, and amino acid sensing. An indispensable source of information for chemical and biomedical experts using sensors, Chemosensors includes case studies to make the material both accessible and understandable to chemists of all backgrounds.
Part A.: Overviews of biological inorganic chemistry : 1. Bioinorganic chemistry and the biogeochemical cycles -- 2. Metal ions and proteins: binding, stability, and folding -- 3. Special cofactors and metal clusters -- 4. Transport and storage of metal ions in biology -- 5. Biominerals and biomineralization -- 6. Metals in medicine. -- Part B.: Metal ion containing biological systems : 1. Metal ion transport and storage -- 2. Hydrolytic chemistry -- 3. Electron transfer, respiration, and photosynthesis -- 4. Oxygen metabolism -- 5. Hydrogen, carbon, and sulfur metabolism -- 6. Metalloenzymes with radical intermediates -- 7. Metal ion receptors and signaling. -- Cell biology, biochemistry, and evolution: Tutorial I. -- Fundamentals of coordination chemistry: Tutorial II.
This volume explores developments in techniques in diagnostics, DNA sequencing, bioanalysis of immunoassays, and single-molecule detection. It promotes the measurement, identification, monitoring, analysis, and application of near-infrared spectroscopy (NIR) to medical and pharmaceutical advances. The text also considers noninvasive methods of NIR for successful, cost-effective, and prompt diagnoses of diseases.
(cont.) The total uptake of both SWNT and Au nanoparticles is maximal at a common radius of 25 nm when scaled using an effective capture dimension for membrane diffusion. The ability to understand and predict the cellular uptake of nanoparticles quantitatively should find utility in designing nanosystems with controlled toxicity, efficacy and functionality. The development of such single molecule detection technologies for ROS motivates their application to many other unexplored signaling pathways both in vitro and in vivo.
Discover how metal-enhanced fluorescence is changing traditional concepts of fluorescence This book collects and analyzes all the current trends, opinions, and emerging hot topics in the field of metal-enhanced fluorescence (MEF). Readers learn how this emerging technology enhances the utility of current fluorescence-based approaches. For example, MEF can be used to better detect and track specific molecules that may be present in very low quantities in either clinical samples or biological systems. Author Chris Geddes, a noted pioneer in the field, not only explains the fundamentals of metal-enhanced fluorescence, but also the significance of all the most recent findings and models in the field. Metal-enhanced fluorescence refers to the use of metal colloids and nanoscale metallic particles in fluorescence systems. It offers researchers the opportunity to modify the basic properties of fluorophores in both near- and far-field fluorescence formats. Benefits of metal-enhanced fluorescence compared to traditional fluorescence include: Increased efficiency of fluorescence emission Increased detection sensitivity Protect against fluorophore photobleaching Applicability to almost any molecule, including both intrinsic and extrinsic chromophores Following a discussion of the principles and fundamentals, the author examines the process and applications of metal-enhanced fluorescence. Throughout the book, references lead to the primary literature, facilitating in-depth investigations into particular topics. Guiding readers from the basics to state-of-the-technology applications, this book is recommended for all chemists, physicists, and biomedical engineers working in the field of fluorescence.
Abstract : In the past twenty years, fluorescence sensing and imaging based on fluorescent probes has been developed as an imperative technique due to the merits including excellent sensitivity, operational simplicity, instant time effectiveness and outstanding selectivity in the research areas such as mineralogy, gemology, biological medicine, materials and environmental engineering. Protons act as a significant role in a variety of pathological and physiological processes, and there are obvious differences in the pH among organelles: the pH in lysosomes is acid within the range of 4.5-5.5, whereas mitochondrial pH is basic that can be as high as 8.0. Abnormal intracellular pH is always an indication of a disrupted pH homeostasis in the whole cell. Furthermore, intracellular bio-thiols are vital to cell metabolism, which by either elevated or deficiency levels of bio-thiols will lead to some diseases. Possessing the advantages of avoiding systematic errors and undesirable photophysical properties of certain fluorophores, novel near-infrared ratiometric fluorescent sensors for the accurately monitoring intracellular pH and biothiols have become the spotlight in research topics. Throughout this dissertation, we firstly have designed and synthesized two novel rhodamine-based dyes with high fluorescence quantum yield, good pH stability large Stokes shifts and excellent photostability by introducing an additional amino residue with fused rings into a classic rhodamine skeleton. We also have constructed a fluorescent sensor by incorporating a receptor to one of these dyes and applied it as an effective sensor for the quick and sensitive monitoring of lysosomal pH fluctuations. Then, we have prepared two sets of ratiometric fluorescent probes for the sensitive detection of lysosomal pH values. The former series were based on π-conjugation modulation strategy, which was accomplished by conjugating a visible coumarin motif to a classic near-infrared hemicyanine skeleton via a vinyl linker. The lysosome-targeting goal was reached by introducing a morpholine ligand or a o-phenylenediamine group to the hemicyanine acceptor. For the latter series, we have obtained three near-infrared ratiometric fluorescent sensors containing a TPE as a donor and a rhodamine as an acceptor for the quantitative, sensitive and comparative analysis of lysosomal pH alterations through FRET and TBET approaches. Furthermore, we have prepared two near-infrared hybrid rhodol dyes for the ratiometric and sensitive visualization of pH value alterations in mitochondria taking advantage of conjugating typical hemicyanine fluorophores into a classic rhodol motif. Upon pH changes, a rhodol hydroxyl group in the probe acts as a spiropyran switch, resulting in the change of π-conjugation and the appearance of a new fluorescent peak. Due to the positive charge, these two novel rhodol dyes possessed the mitochondria-targeting property. In the end, besides the ratiometric fluorescent pH probes, we have reported a FRET-based fluorescent sensor for the ratiometric, selective and accurate detection of cysteine (Cys), which was achieved by linking a visible coumarin skeleton and a near-infrared rhodamine motif through a piperazine spacer. This probe could be used to monitor the intracellular cysteine concentration ratiometrically and be further applied for imaging of Drosophila melanogaster larvae to detect cysteine concentration alterations in vivo.
This book focuses on the latest fluorescent materials for cell imaging. Cell imaging is a widely used basic technique that helps scientists gain a better understanding of biological functions through studies of cellular structure and dynamics. In the past decades, the development of a variety of new fluorescent materials has significantly extended the applications of cellular imaging techniques. This book presents recently developed fluorescent materials, including semiconductor quantum dots, carbon dots, silicon nanoparticles, metal nanoclusters, upconversion nanoparticles, conjugated polymers/polymer dots, aggregation-induced emission (AIE) probes, and coordination compounds, used for various cellular imaging purposes. It will appeal to cell biologists and other researchers in academia, industry and clinical settings who are interested in the technical development and advanced applications of fluorescence imaging in cells, tissues and organisms to explore the mechanisms of biological functions and diseases.