X-ray Radiation Enabled Cancer Detection And Treatment With Nanoparticles

Despite significant improvements in medical sciences over the last decade, cancer still continues to be a major cause of death in humans throughout the world. Parallel to the efforts of understanding the intricacies of cancer biology, researchers are continuously striving to develop effective cancer detection and treatment strategies. Use of nanotechnology in the modern era opens up a wide range of possibilities for diagnostics, therapies and preventive measures for cancer management. Although, existing strategies of cancer detection and treatment, using nanoparticles, have been proven successful in case of cancer imaging and targeted drug deliveries, they are often limited by poor sensitivity, lack of specificity, complex sample preparation efforts and inherent toxicities associated with the nanoparticles, especially in case of in-vivo applications. Moreover, the detection of cancer is not necessarily integrated with treatment. X-rays have long been used in radiation therapy to kill cancer cells and also for imaging tumors inside the body using nanoparticles as contrast agents. However, X-rays, in combination with nanoparticles, can also be used for cancer diagnosis by detecting cancer biomarkers and circulating tumor cells. Moreover, the use of nanoparticles can also enhance the efficacy of X-ray radiation therapy for cancer treatment. This dissertation describes a novel in vitro technique for cancer detection and treatment using X-ray radiation and nanoparticles. Surfaces of synthesized metallic nanoparticles have been modified with appropriate ligands to specifically target cancer cells and biomarkers in vitro. Characteristic X-ray fluorescence signals from the X-ray irradiated nanoparticles are then used for detecting the presence of cancer. The method enables simultaneous detection of multiple iv cancer biomarkers allowing accurate diagnosis and early detection of cancer. Circulating tumor cells, which are the primary indicators of cancer metastasis, have also been detected where the use of magnetic nanoparticles allows enrichment of rare cancer cells prior to detection. The approach is unique in that it integrates cancer detection and treatment under one platform, since, X-rays have been shown to effectively kill cancer cells through radiation induced DNA damage. Due to high penetrating power of X-rays, the method has potential applications for in vivo detection and treatment of deeply buried cancers in humans. The effect of nanoparticle toxicity on multiple cell types has been investigated using conventional cytotoxicity assays for both unmodified nanoparticles as well as nanoparticles modified with a variety of surface coatings. Appropriate surface modifications have significantly reduced inherent toxicity of nanoparticles, providing possibilities for future clinical applications. To investigate cellular damages caused by X-ray radiation, an on-chip biodosimeter has been fabricated based on three dimensional microtissues which allows direct monitoring of responses to X-ray exposure for multiple mammalian cell types. Damage to tumor cells caused by X-rays is known to be significantly higher in presence of nanoparticles which act as radiosensitizers and enhance localized radiation doses. An analytical approach is used to investigate the various parameters that affect the radiosensitizing properties of the nanoparticles. The results can be used to increase the efficacy of nanoparticle aided X-ray radiation therapy for cancer treatment by appropriate choice of X-ray beam energy, nanoparticle size, material composition and location of nanoparticle with respect to the tumor cell nucleus

MODELING OF AQUEOUS EQUILIBRIUM: THREE-DIMENSIONAL TREND SURFACES (TOPOS)

This dissertation establishes a comprehensive approach to looking at aqueous equilibria phenomena over essentially all feasible compositions of two component solutions - acid-base titrations, metal-ligand complexation, oxidation-reduction couples and solubility of binary ionic compounds. Fundamental to this method is the definition of a composition grid above which numerous system properties can be plotted as three-dimensional trend surfaces to visualize important aspects of system behavior. These have been named topos because their appearance is similar to topographic maps. In each case Microsoft ExcelTM worksheets have been designed with embedded Visual BasicTM macros that provide an easy means for anyone to generate surfaces of interest. The only inputs required are thermodynamic values such as acid dissociation constants (Ka), overall formation constants (βs), standard reduction potentials (Eo) or solubility product constants (Ksp). Once the macro is started, the software generates equilibrium values for system parameters at every composition grid point and then constructs 3-D surfaces in plotting windows. The resultant plots can be rotated in any direction to enhance viewing of surface features. Several new chemical phenomena have been identified in the course of this project: 1) in acid-base systems buffering against dilution effects has been characterized more thoroughly than previously found in the literature. 2) New equations relating buffer capacity to titration procedures have been derived and visualized as topos. 3) Anti-buffering, a new behavior in metal-ligand complexation systems has been identified; it was confirmed experimentally with a Cu2+-ethylenediamine system where the activity of free Cu2+ ion increased more than 100-fold as the system was diluted more than 1300 times. 4) Overall trends in cell potentials have been clarified and utilized in describing why batteries supply a nearly constant voltage until suddenly dying. 5) A composition grid has been designed for future studies on the solubility of ionic compounds. The interactive Excel spreadsheets are easily adapted to use in pedagogic settings. Suggested PowerPoint teaching resources and explanations of the numerical methods used to solve the equilibrium calculations have been supplied as examples in the acid-base studies

Nanotalade võnkumise numbriline analüüs

Väitekirja elektrooniline versioon ei sisalda publikatsiooneKäesolevas väitekirjas uuritakse nanomaterjalist valmistatud talade omavõnkumisi mitmesuguste kinnitusviiside korral. Väitekirjas on välja töötatud meetodid nanotalade omavõnkesageduse määramiseks astmelise nanotala jaoks erinevate kinnitustingimuste korral; kusjuures astmete nurkades asuvad stabiilsed praod või prao-tüüpi defektid. Prao mõju võnkesagedusele modelleeritakse nn kaalutu väändevedru meetodil. Selle meetodi kohaselt tuleb reaalne astmega tala asendada kahest elemendist koosneva süsteemiga, kus elemendid on omavahel ühendatud väändevedruga, mille jäikus on pöördvõrdeline pinge intensiivsuse koefitsiendiga prao tipu juures. Kuna pinge intensiivsuse koefitsiendi väärtused on leitavad kataloogidest, siis see meetod võimaldab omavahel siduda nanotala omavõnkesageduse ning prao pikkuse ja laiuse. Väitekiri koosneb sissejuhatusest, viiest peatükist ning kirjanduse loetelust, mis sisaldab 82 nimetust. Sissejuhatus kujutab endast esimest peatükki. Teises peatükis on toodud põhivõrrandid ning põhieeldused. Esimesed kaks peatükki on referatiivsed, ülejäänutes esitatakse originaalseid tulemusi. Kolmandas peatükis esitatakse nanotalade võnkumise võrrandid, mis arvestavad tala elementide pöördeinertsi. Need on Euler-Bernoulli võrrandite üldistuseks juhule, kui pöördeinertsi arvestamine on kohustuslik. See süsteem on lahendatav ka muutujate eraldamise teel. Neljandas peatükis lahendatakse põhivõrrandite süsteem numbriliselt. Näidatakse muuhulgas, et süsteemi saab hõlpsasti lahendada Maclaurini rea abil. Viies peatükk on pühendatud nanotalade võnkumise uurimisele juhul, kui nanotala on kinnitatud elastsete tugede abil st. toed ei ole jäigad. Kuuendas peatükis uuritakse pragudega nanotalade võnkumisi arvestades termilisi mõjutusi st. temperatuuripingeid. Väitekirjas saadud tulemusi on võrreldud erijuhtudel kirjandusest leitavate tulemustega ning veendutud, et väitekirjas esitatud tulemused on heas kooskõlas teiste uurijate poolt saadud tulemustega. Väitekirjas saadud tulemuste põhjal on avaldatud koos juhendajaga 10 teadusartiklit.In this dissertation, an analysis of the dynamic behavior of nanobeams with different physical and geometrical properties using several numerical techniques is presented. Euler-Bernoulli beam theory and nonlocal theory of elasticity are used to simulate the nanobeam. Nanobeams are considered with some special requirements such as tapered, axially graded, and double beams. First of all, in a tapered beam, the width of the beam is varying exponentially along the x-axis from one end to another end. The properties of the tapered beam are to reduce material consumption and provide the cross-sectional area according to the moment distribution. Secondly, in an axially graded beam, material properties such as elasticity and density are varying exponentially from one end to another end. The axially graded beam can be considered as a non-homogeneous as well as a composite beam. In this beam, the material properties can be distributed according to the requirement. The axially graded beam overcomes the limitation of conventional composite. Finally, in a double beam, two identical nanobeams are connected by a Winkler-type spring layer. Double beams are used for absorbing the vibration. It reduces deflection and vibration. The double beam is modeled by the coupled differential governing equations. Some adverse effects such as cracks and the influence of the temperature are considered. Cracks are common defects in nanostructures. Single and multiple cracks are considered in this analysis. According to the model, the crack is replaced by a rotational spring where the crack divides the beam into two segments that are connected to each other by the spring at the crack position. Cracks reduce the overall stiffness of the beam. The effect of temperature is significant for the vibration of nanobeams. The thermal load is compatible with the mechanical load where the thermal load is modeled as an axial load. It reduces the natural frequency. The main objective of this research is to find suitable techniques for a reliable, cost-effective design that is able to fulfill the desired requirements. That is why the important feature of this research is to apply numerical techniques for solving these problems. Three different approximation techniques such as homotopy perturbation technique, power series method, and Maclaurin series method are used for solving these problems. These techniques are useful for solving linear and non-linear differential equations. However, these techniques are rare to analyze the nano-material. These techniques are applied effectively to scrutinize the model of nanobeams. Obtained results are verified with the results of other researchers in the existing literature. This analysis can be used to design nano-electromechanical devices effectively.https://www.ester.ee/record=b550871

Chapter 3.1: Visualization of the Nernst Equation Via 3-D Topo Surfaces: E⁰ Plateaus, Left-Hand Bluffs, Front Cliffs and Reaction Paths

A new 3-D graphical representation of oxidation–reduction (redox) processes in aqueous solutions has been developed utilizing a composition grid for which the x-axis carries the activity of the reduced form of the redox couple and the y-axis carries the activity of the oxidized form. The Nernst equation potential corresponding to the redox couple’s activities at each grid point is plotted above it as a z-coordinate. This creates a 3-D trend surface (a topo) over the grid. The topos typically have a steep left-hand bluff and a precipitous front cliff that are encountered when one or the other of the redox couple species is near depletion. In between these two features, much of the topo is a broad plateau with an elevation near the E0 for the half-reaction. Discharge paths during the operation of a galvanic cell appear as oppositely-trending, angled paths across a pair of vertically-separated surfaces. The cell dies when the two reaction paths achieve the same potential, i.e., identical z-coordinates. Redox TOPOS, a free downloadable Microsoft Excel workbook, generates 1681-point (41 x 41) 3-D topos once a redox couple has been identified and all Nernst equation parameters have been entered. Also included are a set of PowerPoint lecture slides and a document “Teaching with Redox TOPOS” containing sections for use in lecture and exercises for homework or discussion for introductory college courses and upper division or graduate physical chemistry, analytical chemistry, biochemistry, and geochemistry courses.https://scholarworks.umt.edu/topos/1007/thumbnail.jp

Chapter 1.3: 3-D Topo Surface Visualization of Acid-Base Species Distributions: Corner Buttes, Corner Pits, Curving Ridge Crests and Dilution Plains

This chapter adds 3-D species distribution topos to earlier surfaces that showed pH (Chapter 1.1) and buffer capacity behavior (Chapter 1.2) during titration and dilution procedures. It constructs trend surfaces by plotting computed alpha distribution coefficients above a composition grid with “mL of NaOH” as the x-axis and overall system dilution (log C) as the y-axis. The systematic shift from protonated to deprotonated forms is clearly visualized on a linear z-axis. Because pH and buffer capacity surfaces accompany the species topos, it is easy to see their interrelationships. On the basis of their graphical appearance, features on species topo surfaces have been named corner buttes, corner pits, curving ridge crests, curving canyons and dilution plains. Ramps connecting surface features are linear when tied to additions of NaOH and logarithmic when followed on the log C dilution axis. The amphiprotic behavior of water is demonstrated through dilution procedures. Systems examined include acetic acid, CH3COOH (a weak monoprotic acid); carbonic acid, H2CO3 (a weak diprotic acid), and phosphoric acid, H3PO4 (a weak triprotic acid). For comparative purposes, species topos are depicted for a set of three acids with hypothetical pKas of 4.0, 7.0, and 10.0. Supplementary files include the Species TOPOS software, a macro-enabled Excel workbook that quickly generates pH, buffer capacity and alpha surfaces for any mono-, di-, or triprotic acid desired. Only the acid dissociation constants, the Ka values, are needed as inputs. Also included are a set of PowerPoint lecture slides and a document “Teaching with Species TOPOS” with sections for lecture, practice exercises, and suggested laboratory activities for introductory college courses and upper-division or graduate courses in analytical chemistry, biochemistry and geochemistry.https://scholarworks.umt.edu/topos/1003/thumbnail.jp

Chapter 4.1: Visualizing the Solubility of Salts Via 3-D Topo Surfaces: Pyramids with Ridges and Plateaus

A new 3-D graphical representation for the solubility of sparingly soluble salts in aqueous solutions has been developed utilizing a new composition grid. In this case, the x-axis carries the concentration of the salt’s cation (usually a metal) and the y-axis holds the concentration of the salt’s anion. Plotted above the grid are a salt’s solubility, individual species concentrations or distribution coefficients. Three levels of sophistication in the descriptive chemistry are discussed. In Case 1, the only dissolved species included are the cation and anion present in the salt’s solubility product expression, the Ksp. Case 2 adds the possibility of ion pairs or neutral complexes. Finally, Case 3 encompasses all complexes for which thermodynamic constants are available. Example systems include the 1:1 AgCl and the 1:2 PbI2 salts. The composition grid approach addresses not only the solubility of a solid salt in pure water, but essentially all other feasible conditions in which one or the other of the component ions is present in the dissolving liquid phase. Case 1 gives rise to 3-D solubility surfaces (topos) that have a pyramidal shape. Case 2 possesses plateaus under saturated conditions where the concentration of the ion pair or neutral complex dominates. Case 3 can add extra ramps under saturated conditions when other complexes become important. A comparison of the topos from all three cases for a given salt allows the user to see the effects of incompletely capturing the possible chemical processes that contribute to solubility. The Case 3 solubility maximum can be significantly larger than that for Case 1. In the AgCl system, for example, the maximum solubility was 12.5 times greater than that predicted for Case 1. Included as supplementary files for the chapter are the downloadable Solubility TOPOS software (an Excel workbook), a PowerPoint lecture, teaching materials, a detailed description of the formulas and algorithms used to solve for solubility, and a Visual Basic code listing.https://scholarworks.umt.edu/topos/1009/thumbnail.jp

Prologue: An Overview to Water Topos: A 3-D Trend Surface Approach to Viewing and Teaching Aqueous Equilibrium Chemistry

The “topo” approach to viewing and teaching aqueous equilibrium through 3-D trend surfaces is introduced. A list of the pedagogical resource categories that accompany each chapter is provided. We describe the “composition grids” that form the foundation for the trend surfaces. A roadmap for the subsequent chapters follows. Finally, a brief statement about the Excel-based computer software is provided.https://scholarworks.umt.edu/topos/1000/thumbnail.jp

Chapter 1.2: Visualization of Buffer Capacity with 3-D Topos: Buffer Ridges, Equivalence Point Canyons and Dilution Ramps

The BufCap TOPOS software generates 3-D topographic surfaces for acid-base equilibrium studies that portray pH and buffer capacity behavior during titration and dilution procedures. Topo surfaces are created by plotting computed pH and buffer capacity values above a composition grid with volume of NaOH as the x-axis and overall system dilution as the y-axis. What emerge are surface features that correspond to pH and buffer behaviors in aqueous solutions. Topo surfaces are created for pH, log buffer capacity and linear buffer capacity. Equivalence point breaks become pH cliffs and logarithmic buffer capacity canyons that grow shallower with dilution. Areas of high buffer capacity become rounded ridges. Dilution alone generates 45° ramps. Example systems include acetic acid, CH3COOH (a weak monoprotic acid); hydrochloric acid, HCl (a strong acid); oxalic acid, HOOCCOOH (a weak diprotic acid) and L-glutamic acid hydrochloride, C5H9NO4·HCl (a weak triprotic acid). The Supplementary files include a copy of the interactive BufCap TOPOS program as a downloadable Excel workbook. Its macro-enabled spreadsheets quickly generate surfaces for any mono-, di-, or triprotic acid. Only acid dissociation constants, Ka values, need be changed. Other materials include a PowerPoint lecture, materials/suggested laboratory activities for teaching with BufCap TOPOS, and derivation of new equations that permit the calculation of buffer capacities for titration/dilution composition grid points.https://scholarworks.umt.edu/topos/1002/thumbnail.jp

Chapter 2.1: Visualization of Metal Ion Buffering Via 3-D Topo Surfaces of Complexometric Titrations

This chapter examines 1:1 metal-ligand complexometric titrations in aqueous media. It presents surfaces that plot computed equilibrium parameters above a composition grid with titration progress (mL of ligand) as the x-axis and overall system dilution (log C ) as the y-axis. The sample systems in this chapter are restricted to EDTA as a ligand. Other chelating ligands that form exclusively 1:1 complexes could also be modeled with this software. The surfaces show the quality of the equivalence point break under various conditions. More importantly, they develop the phenomenon of metal ion buffering. They clearly distinguish the difference between “pseudo-buffering” and “true buffering”. They introduce terminology for two different forms of metal ion buffering: 1) mass action metal ion buffering under excess ligand conditions; and 2) precipitate metal ion buffering when hydroxide precipitates are present under excess metal ion conditions. Systems modeled are EDTA titrations of Cu2+, Ca2+ and Mg2+. A final section demonstrates a second type of topo that helps evaluate the optimal pH for an EDTA titration. Supplemental files include the Complexation TOPOS software, an Excel workbook that generates topo surfaces in under 20 seconds, and teaching suggestions. Required inputs are: 1) stability constants for the metal-ligand complex; 2) acid dissociation constants for the ligand, 3) stability constants for hydroxy complexes from of the metal cation; and 4) a Ksp value and stoichiometry for hydroxide precipitates. Many of these constants are contained in a workbook tab. Also included are a PowerPoint lecture and teaching materials (for lecture, homework, and pre-laboratory activities) that are suitable in general chemistry courses or third-year and graduate courses in analytical chemistry, biochemistry and geochemistry.https://scholarworks.umt.edu/topos/1004/thumbnail.jp

Multiplexed biomarker detection using x-ray fluorescence of composition-encoded nanoparticles

Multiple DNA and protein biomarkers have been detected based on characteristic x-ray fluorescence of a panel of metal and alloy nanoparticles, which are modified with ligands of biomarkers to create a one-to-one correspondence and immobilized on ligand-modified substrates after forming complexes with target biomarkers in three-strand or sandwich configuration. By determining the presence and concentration of nanoparticles using x-ray fluorescence, the nature and amount of biomarkers can be detected with limits of 1 nM for DNA and 1 ng/ml for protein. By combining high penetrating ability of x-rays, this method allows quantitative imaging of multiple biomarkers