Browsing by Author "Zheng, Jie"
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Item Activity and Pharmacology of Homemade Silver Nanoparticles in Refractory Metastatic Head and Neck Squamous Cell Cancer(Wiley, 2018-12-11) Singh, Jasmine; Moore, William; Fattah, Farjana; Jiang, Xingya; Zheng, Jie; Kurian, Pamela; Beg, Muhammad S.; Khan, Saad A.; 0000-0001-8546-1882 (Zheng, J); 22147423113244881679 (Zheng, J); Jiang, Xingya; Zheng, JieBackground Silver nanoparticles (AgNP) show efficacy in cancer cell lines. We present the first in-human outcome of AgNP in a cancer patient. Methods Homemade AgNP solution is manufactured using online instructions by a 78-year old male. He started consuming AgNP while on hospice after he developed nasal cavity squamous cell cancer metastatic to liver and lung. Results Electron microscopy of AgNP solution revealed bimodal nanoparticle size distribution: 3 and 12 nm. Inductively coupled plasma mass spectrometry showed basal silver ion concentrations of 32 ng/g, rising to 46 ng/g 1 hour after ingesting 60 mL of AgNP solution. Urine showed no AgNP. No toxicities were observed and he had complete radiographic resolution of his cancer. He remains without evidence of cancer 18 months later. Conclusions AgNP ingestion was associated with sustained radiographic resolution of cancer. Further testing of AgNP should be done to confirm its efficacy in head and neck cancer.Item Algorithms to Compute Discrete Residues of a Rational Function(August 2023) Sitaula, Hari Prasad 01-27-1985-; Zheng, Jie; Arreche, Carlos; Williams, Nathan; Dabkowski, Mieczyslaw K.; Arnold, MaximThe classical notion of residue, for a rational function with complex coefficients, is a powerful and ubiquitous tool, having applications in many different areas. For example: Complex Analysis, Physics, Number Theory, Differential Equations, and Combinatorics, to name a few. In the last decade several new notions of discrete residues have been developed by different researchers, all of which have in common the following obstruction-theoretic feature: a given rational function f (x) is “special” (e.g., rationally integrable, or rationally summable, or rationally q-summable) if and only if all of its corresponding residues are zero. All of these notions of residue (both the classical one and also its discrete variants) are originally defined in terms of a complete partial fraction decomposition of the given rational function f (x), which is too expensive to carry out in practice due to the high computational cost of finding the complete factorization of the denominator. The main contribution of this dissertation is the development of an efficient factorization-free algorithm to compute the discrete residues of a rational function.Item Biochemical and Biophysical Characterization of Bacterial Transition Metal Transporters by Functional Reconstitution in Artificial Lipid Bilayers(2022-05-01T05:00:00.000Z) Abeyrathna, Nisansala Sandamali; Meloni, Gabriele; Williams, Nathan; Nielsen, Steven O; Zheng, Jie; Pantano, PaulTransition metals play a vital role in all living organisms due to their key structural and functional properties central to diverse metabolic processes. However, because of their high reactivity organisms have evolved sophisticated biomolecular protein networks to control intercellular metal ion homeostasis, without reaching toxic intracellular levels. Transmembrane transporter proteins play a gate-keeper role in maintaining the dynamic flux of these transition metal ions across biological membranes, thereby finely tuning metal delivery and availability in cells and subcellular organelles. P-type ATPases are a superfamily of transmembrane primary active transporters involved in translocating substrates against an electrochemical gradient which play a key role in maintaining homeostasis of cellular concentrations of essential ions. They are classified into 5 classes (P1, P2, P3, P4 and P5) based on their substrate selectivity. This dissertation is focused on studying the substrate selectivity and mechanism of translocation in the P1B class of P-type ATPases which are involved in transition metal transport for both essential and toxic transition metals. P1B-type ATPases are classified into 7 sub families (P1B-1 - P1B-7 types) based on conserved amino acid motifs in their transmembrane helices that appear to control each sub-family’s substrate selectivity, resulting in the existence of pumps that can selectively translocate 1st, 2nd and 3rd row transition metals across the lipid bilayer. Considering their central role in controlling cellular metal levels and extrusion in cells they are also acting as virulence factors in pathogenic bacteria. Studies towards their characterization could therefore help in establishing them as new potential therapeutic targets to develop novel antibiotics to overcome the bacterial resistance observed with traditional antibiotics. However, the substrate transport across lipid bilayers, the overall mechanism for cargo translocation, and kinetics of these transporters remain elusive to a significant extent, due to lack of molecular tools to study putative metal substrate transport across membranes in real-time in a native-like environment. In light of this, metal-stimulated ATPase activity assays were coupled with an experimental platform based on multiple fluorescence sensor probes, to study substrate selectivity, transport mechanism, including counterion transport and electrogenicity, and translocation kinetics in realtime with recombinantly expressed proteins belonging to P1B-1 (CopA from E. coli) and P1B-5 (Nia from S. meliloti) classes reconstituted in artificial lipid bilayer vesicles known as proteoliposomes. The proteoliposomes were used as an in-vitro tool to determine metal selectivity and the kinetic parameters for metal transport by encapsulating fluorescent detector probes featuring turn-on florescence signal upon substrate ion binding and translocation. However, the use of the proteoliposomes is challenging due to their intrinsic structural instability and susceptibility to stressors like temperature, aging, and chemicals, which limits their shelf life. Therefore, an experimental approach was developed to stabilize membrane proteins and proteoliposomes by encapsulating them in a sheddable metal organic framework, which reduces their susceptibility to external stressors. This platform sheds light on developing methods to utilize proteoliposomes in biochemical and biophysical investigation of transmembrane proteins and in drug delivery applications. In addition, this approach would help to overcome the challenges of cold-chain therapeutic transport of liposomal vaccine formulations.Item B–type Catalan States of Lattice Crossing(2021-08-01T05:00:00.000Z) Rakotomalala, Diarisoa Mihaja Andriamanisa; Dabkowski, Mieczyslaw K.; Zheng, Jie; Tran, Ahn; Hooshyar, M. Ali; Ramakrishna, Viswanath; Dragovic, VladimirM. K. Dabkowski and J. H. Przytycki defined for any realizable Catalan state C with no bottom returns, the rooted plane tree with a delay function, (TC, f), and the partially ordered set (B(C), 4) of some Kauffman states that realize C. In this dissertation, we study the properties of (B(C), 4) and establish an important relation between its rank generating function and the plucking polynomial of (TC, f). Furthermore, we show that the rank generating function of (B(C), 4) is unimodal for any realizable A–type Catalan state with no bottom returns of an A–type lattice crossing LA(m, n), where n ≤ 4. In the last part of this dissertation, we study B–type Catalan states. We show which crossingless connection between 2(m + n) outer boundary points of an annulus can be realized as Kauffman states of the B–type Lattice crossing LB (m, n). Furthermore, we give a closed-form formula for the number of realizable B–type Catalan states, and find coefficients of those obtained as Kauffman states of LB(m, 1) and LB(m, 2).Item Carrier Recombination in Perovskites 3D Through 0D(2022-05-01T05:00:00.000Z) Zheng, Yangzi; Campbell, Zachary; Malko, Anton V.; Gartstein, Yuri; Lv, Bing; Shi, Xiaoyan; Zheng, JieLead-halide perovskites have long been demonstrated as materials with exceptional structural and optoelectronic properties. As an important crystalline material, lead-halide perovskites have potential applications in lasers, light-emitting diodes (LEDs), photovoltaic solar cells, photon detectors and biosensors, etc. By tailoring the morphological dimensionality, low-dimensional possessed distinct properties from their bulk (3D) counterparts. Due to the strong quantum confinement and octahedral site isolation, these low dimensional metal halide hybrids at the molecular level exhibit remarkable and unique properties that are significantly different from those of ABX3 perovskites. Considering the rapid development of low dimensional metal halide perovskites, we will discuss the synthesis, characterization, application, computational studies and compare various metal halide perovskites ranging from 3D through 0D. Finally, we show that a modified atomic layer deposition technique may be successfully used to protect 0D perovskite against external environment.Item Chemically Tuned Virus Like Particles: From Cancer Therapy to Targeted Delivery(December 2021) Shahrivarkevishahi, Arezoo; Gassensmith, Jeremiah J.; Slinker, Jason D.; Zheng, Jie; Ahn, Jung-Mo; Dodani, SheelIn recent years, nanoparticle-based therapeutics have been increasingly applied in broad range of clinical applications from diagnosis to treatment of many diseases such as cancer, diabetes and neurodegenerative disorders. A wide range of synthetic and naturally occurring materials such as polymers, metal oxides, silicate, liposome, and carbon nanotubes have been developed to overcome some of the key barriers in free therapeutics including intracellular trafficking, cell/tissue targeting, poor biodistribution, and low efficiency. However, despite all achievements in creating these nanomaterials with different chemical and physical properties such as size, shape and surface properties, developing a nanoparticle to surmount these limitations all in one is a big challenge. Virus like particle (VLP) as protein-based nanomaterials that closely mimic the highly symmetrical and polyvalent conformation of viruses while lack the viral genomes have emerged as a solution for these limitations. Their unique features such as high biocompatibility, biodegradability, monodisperisty, intrinsic immunogenicity, and safety combined with interior and exterior modification capability offer new tool to scientists for careful design and engineering of multi-component therapeutic agent with intended biological behavior and pharmacological profiles. Herein, various chemistry strategies are introduced in combination with biology and immunology to turn virus like particle to a favorable engineered biomaterial for several functions such as cancer therapy and intracellular delivery. We showed how by modifying surface of VLP Qβ with NIR organic molecule we can make a highly efficient and stable photothermal agent that can cause thermal ablation of tumor while simultaneously activating the immune response. We found this immunophotothermal agent, suppress primary tumor, control metastasis, and prolong survival time in mice bearing breast cancer. We also addressed one of the biggest challenges in biologic delivery which is direct delivery of therapeutic cargo into cell cytoplasm. Using organic chemistry we designed a cytosolic targeting linker that when attached to surface of VLP Qβ, helps to escape endosomes and be released into cytoplasm, Moreover, this proteinaceous material is shown to have a great potential in combination with other materials such as metal organic framework to construct a multimodal cancer therapeutic agent enabling delivering mulit therapeutic agents such as immunotherapeutic drugs while taking advantage of all unique features of virus like particles. These works clearly show the significant potential of VLP in design and modification of new therapeutic platform.Item Effects of Flux Type and Molar Ratio in the Synthesis of Cerium Germanides(2022-08-01T05:00:00.000Z) Ortega, Juan Luis; Nielsen, Steven O; Smaldone, Ronald A.; Meloni, Gabriele; Zheng, JieWith the discovery of a new homologous series An+1BnX3n+1 (A = Ce, B = Co, X = Ge), the low melting main group elements, indium, tin, and bismuth, were evaluated to determine how different concentrations will influence the outcome of intermetallics syntheses. Different flux molar ratios were evaluated, and the systematic synthetic approach led to a fresh perspective on the flux role in the growth of intermetallic compounds of the series An+1BnX3n+1, including the new series members Ce3Co2Ge7 and Ce4Co3Ge10. The structure determination by powder and single crystal X-ray diffraction methods are discussed.Item Glutathione-Mediated Biotransformation in the Liver Modulates Nanoparticle Transport in Vivo(2019-07-11) Jiang, Xingya; Zheng, JieGlutathione-mediated biotransformation in the liver is a key and well-known detoxification process for the body to eliminate small xenobiotics but its impacts on nanoparticle retention, targeting and clearance are much less understood than liver macrophage uptake even though both processes are involved in the liver detoxification function. This dissertation aims to fundamentally understand how glutathione-mediated biotransformation in the liver impacts the in vivo transport of nanoparticles at the chemical level and how this unique physiological process could be exploited to enhance the disease targeting and/or minimize potential toxicity of nanomedicines. In Chapter 1, the current status on understanding of nanoparticle clearance in vivo through the kidneys and liver was reviewed and glutathione-mediated biotransformation as a key hepatic detoxification function was also discussed. In Chapter 2, the kidney transport and elimination of glutathione-protected Au25 nanoclusters (GS-Au25) in vivo were noninvasively imaged by photoacoustic tomography at high temporal and spatial resolution, which for the first time enabled the accurate quantification of single kidney glomerular filtration rate (GFR) by an engineered nanoparticle. Combining other evidences suggests that GS-Au25 was eliminated in vivo through free glomerular filtration and could serve as an excellent exogenous glomerular filtration marker. In Chapter 3, the mechanism of hepatic glutathione-mediated biotransformation of the model nanoparticle, ICG4-GS-Au25, was unraveled at the chemical level. It was found that glutathione efflux from hepatocytes resulted in high local concentrations of not only glutathione but also cysteine in liver sinusoids, which transformed the surface chemistry of nanoparticles, reduced their affinity to serum proteins and significantly altered their blood retention, targeting and clearance. In Chapter 4, the fundamental discovery of hepatic glutathione-mediated biotransformation of nanoparticles was extended to other nanosystems with distinct sizes and surface chemistries. The biotransformation rate of solid gold nanoparticles was found to exponentially decrease with the increase in their core sizes, which is likely due to more reactive surface gold atoms on the smaller gold nanoparticles. This liver glutathione-mediated biotransformation function was exploited to enhance the targeting of small-molecule prodrugs as well as reduce the nonspecific accumulation of large thiol-degradable nanoparticles in the body. In Chapter 5, future work and outlook were discussed.Item High Performance Diesel Oxidation Catalysts Using Ultra-Low Pt Loading on Titania Nanowire Array Integrated Cordierite Honeycombs(Elsevier Science B.V., 2017-11-15) Hoang, Son; Lu, Xingxu; Tang, Wenxiang; Wang, Sibo; Du, Shoucheng; Nam, Chang-Yong; Ding, Yong; Vinluan, Rodrigo D., III; Zheng, Jie; Gao, Pu-Xian; Vinluan III, Rodrigo D.High performance of an ultra-low Pt loading diesel oxidation catalyst can be achieved by using a combination of novel nano-array structured support, precise control of ultrafine active Pt particles, and an addition of H₂ as a promoter into the exhausts. Highly stable mesoporous rutile TiO₂ nano-array was uniformly grown on threedimensional (3-D) cordierite honeycomb monoliths using a solvothermal synthesis. Atomic layer deposition was employed for precise dispersion of ultrafine Pt particles (0.95 ± 0.24 nm) on TiO₂ nano-array with a Pt loading of 1.1 g/ft³. Despite low Pt loading, the Pt/TiO₂ nano-array catalyst shows impressive low-temperature oxidation reactivity, with the conversion of CO and total hydrocarbon (THC) reaching 50% at 224 and 285°C, respectively, in the clean diesel combustion (CDC) simulated exhaust conditions. The excellent activity is attributed to the unique nano-array structure that promotes gas-solid interaction and ultra-small Pt particle dispersion that increase surface Pt atoms. We also demonstrate that addition of more H₂ into the exhaust can lower light-off temperature for CO and THC by up to ~60 °C and ~30 degrees °C, respectively.Item In Vivo Transport of Renal Clearable Nanomedicines in Diseased Kidneys(December 2021) Li, Siqing; Zheng, Jie; Rachinskiy, Dmitry; Stefan, Mihaela; Nielsen, Steven; Meloni, GabrieleRenal clearable nanomaterials have been considered promising nanomedicines for disease diagnosis and therapeutics. Understanding the in vivo transport of renal clearable nanomedicines under various diseased conditions is not only fundamentally important to unravelling pathophysiology in the nano regime, but also critical to successful translations of nanomedicines into the clinics. Since kidney disease as a silent killer influence more than 10% people in the world, understanding the transport mechanisms of renal clearable nanoparticles in the diseased kidneys will lay down a foundation for developing new disease diagnostics as well as treatments. This dissertation aims to unravel the in vivo transport of renal clearable nanomaterials in various kidney disease conditions, which includes seven chapters as follows. In Chapter 1, an overview is given to the current understandings of nanomedicines and their in vivo transport in normal and diseased kidney, which are classified into different categories according to its injury sites and pathologic mechanisms. In Chapter 2, we investigated the in vivo transport of PEG nanoparticles with different elimination pathways including glomerular filtration and renal tubular secretion in a well-known kidney disease model, cisplatin-induced kidney injury. In Chapter 3, we did a head-to-head comparison of the renal tubular secretion of PEG nanoparticle and small molecule, para-amino hippuric acid (PAH) in cisplatin-induced renal tubular injuries, and correlation between transport of the exogeneous probes and biomarkers was also investigated. In Chapter 4, we explored the feasibility of transcutaneous detection of cisplatin-induced acute kidney injury by combining fluorescent ICG-PEG45 and IRDye-PEG45 with a commercially available device. In Chapter 5, we studied the in vivo behaviors of various exogenous probes including the glomerular filtrated FITC-inulin and Au25SG18 and the renal tubular secreted PAH in cisplatin-injury acute kidney injury. In Chapter 6, we discussed the transport of nanoparticles in other types of kidney disease models including primary glomerular injuries induced by doxorubicin and tubular obstructions caused by folic acid. In Chapter 7, an outlook was given based on our current understandings of in vivo transport and interactions of nanomedicines in kidney diseases.Item Incorporating Novel Functionality on In Vitro Microelectrode Arrays(2018-05) Hammack, Audrey Sue; 0000-0001-5620-1993 (Hammack, AS); Gnade, Bruce E.; Pantano, Paul; Sherry, A. Dean; Zheng, JieThe microelectrode array (MEA) is an inexpensive, high throughput platform for measuring and recording extracellular electrical potentials from a culture of electrogenic tissues. However, this technology is not without drawbacks, which this work seeks to address. On conventional MEAs, stimulation of a culture is achieved via electrical stimulation through the electrodes, which may introduce recording artifacts. Optogenetics is a molecular biology technique that can be used to decouple the recording and stimulation functions of the MEA electrode, but hardware required to utilize optogenetics in combination with an MEA is a barrier that prevents utilization of this technique. One project presented here seeks to integrate an MEA with an array of organic light-emitting diodes (OLEDs) driven by thin film transistors (TFTs), to create a multifunctional MEA with optical stimulating capabilities, in order to streamline the hardware required for an in vitro optogenetics recording experiment. Discreet functional components are demonstrated and a proof of concept integrated substrate is presented. Another project presented in this dissertation seeks to insulate the MEA electrodes with polystyrene. The vast set of organic and inorganic materials used to insulate MEA electrodes present challenges to users who must modify cell culture protocols for cell adhesion to the surface of the MEAs. An MEA that features a patterned film of polystyrene, a material that is far more common to cell culture work, as electrode insulation is presented. Viable cell culture on this MEA and recordings that are comparable to other MEA substrates are demonstrated.Item Interactions of Renal Clearable Gold Nanoparticles with the Kidneys in Vitro and in Vivo(2018-08) Xu, Jing; 0000-0001-6602-7335 (Xu, J); Zheng, JieThe emergence of renal clearable inorganic nanoparticles (NPs) offers a great opportunity to address the health concern raised by nonspecific accumulation of conventional inorganic NPs in the macrophage system, mostly in the liver and spleen. In recent decades, we have dedicated a remarkable amount of research in developing renal clearable gold nanoparticles (AuNPs) and investigating their biointeractions. Our group discovered that glutathione-coated renal clearable AuNPs (GS-AuNPs) can be efficiently excreted through the urinary system resulting in significantly reduced accumulation in the liver and spleen. By integrating the near-infrared fluorescence, GS-AuNPs can sensitively probe kidney clearance kinetics and indicate renal dysfunction. Future clinical translation requires a fundamental understanding of nano-bio interactions in the kidneys and the biocompatibility of GS-AuNPs. In this dissertation, Chapter 1 covers the status of renal clearable inorganic NPs and the current understanding of their biointeractions in the kidneys. Chapter 2 describes using X-ray imaging to visualize the transport of GS-AuNPs in the kidney components under both normal and pathological conditions. The unique deposition of GS-AuNPs in the diseased kidney offers a great chance to diagnose renal injury noninvasively. Chapter 3 focuses on the blood transport and biocompatibility of GS-AuNPs. The dose effect on the blood transport and renal clearance efficiency of GS-AuNPs is unraveled which results in high biocompatibility. Chapter 4 describes an in vitro study on the surface-ligand-density effect on interactions between GS-AuNPs and human kidney proximal tubular cells. The results demonstrate precise responses of proximal tubular cells to GS-AuNPs with different ligand densities in membrane affinity, cytotoxicity and the mechanism of cell death. Finally, a summary of the obtained understanding and future perspective are presented in Chapter 5.Item Molecular Basis for Chaperone Control of Rtt109 Acetylation of Histone H3-H4(2021-08-01T05:00:00.000Z) Akhavantabib, Noushin; D'Arcy, Sheena; Cao, Yan; Meloni, Gabriele; Zheng, Jie; Pantano, PaulAcetylation is one of many protein post-translational modifications (PTMs) that frequently occurs in the cell. One type of acetylation is when the acetyl group from acetyl-coenzyme A (Ac-CoA) is transferred onto the ε-amino group of lysine sidechains. Histones are highly basic proteins that associate with genomic DNA and compact it into chromatin in the nucleus of the cell. They are often accompanied by a group of histone-binding proteins called histone chaperones in events such as nucleosome assembly/disassembly, histone transport and nuclear import. Being rich in lysine content, histones are frequently acetylated and therefore influence chromatin structure. Enzymes that carry out histone acetylation are termed histone acetyltransferases (HATs). Rtt109 is one such HAT that is found in fungal species, and requires association with histone chaperones to efficiently acetylate histones. Vps75 and Asf1 are the two known histone chaperones that when bound to Rtt109, enhance its enzymatic activity significantly. They also play a role determining Rtt109 selectivity and specificity towards different lysine residues in histones H3-H4. Cells deleted for Rtt109, Asf1 or both, are highly sensitive to genotoxic exposure; and it has been shown that Rtt109 acetylation of K56 is required for a cell to maintain its genomic integrity. This has made Rtt109 and its chaperone-containing complexes attractive anti-fungal therapeutic targets. The structure, dynamics and function of Rtt109 complexes are the focus of this dissertation. Utilizing comprehensive biophysical and biochemical analysis, we first investigate molecular interactions between Vps75 and H3-H4. We report the stoichiometry of binding in multiple ionic conditions and compare their interactions to a homologous complex containing Nap1. We identify the interface between Vps75 and H3-H4, and reveal how specific structural elements are tailored for Vps75 chaperoning activity with Rtt109. Next, we add Rtt109 to the Vps75-(H3-H4) complex and extensively characterize complex homogeneity and absolute stoichiometry. We define a detailed step-by-step Rtt109-Vps75 co-expression and purification protocol that maximizes yield and purity. We show the stoichiometry of binding is 1:2, with a second Rtt109 binding only at high concentration and readily replaced with H3-H4. We show that Rtt109-Vps75-(H3-H4) has a 1:2:1 unit that can self-associate to become a 2:4:2 complex through the H3-H3 contacts in a H3-H4 tetramer. Our large-scale reconstitution methods for various Rtt109 complexes paved the way for acquiring high-resolution structures via crystallography or cryo-electron microscopy. It also facilitated solution characterization via hydrogen-deuterium exchange mass spectrometry (HDXMS). Finally, we added Asf1, the last binding partner to reconstitute the double-chaperone complex − Rtt109-Vps75-(H3-H4)-Asf1. This allows for a comprehensive comparative HDX-MS experiment to uncover the mechanism behind chaperone activation of Rtt109. We purified and reconstituted eleven relevant protein complexes for analysis. We identify direct binding sites between each member of the complex and compare them to existing structures, and show different conformations upon addition of each chaperone. These results elucidate the acetylation mechanisms facilitated by cross-talk between two histone chaperones Vps75 and Asf1.Item Nano-biothiol Interactions of Engineered Nanoparticles(December 2021) Zhou, Qinhan; Zheng, Jie; Kesden, Michael; Gnade, Bruce E.; Nielsen, Steven O.; Meloni, Gabriele; D'Arcy, SheenaNanomedicines have been extensively studied in the past decades at the fundamental level because they could potentially make a paradigm shift in human healthcare. Nano-bio interactions play a central role in the precise control of the benefit and hazards of nanomedicines, but current studies mainly focus on how nanoparticles are taken up by cells and interact with different receptors. There is still not enough investigation of how the physiological environment transforms engineered nanoparticles through a variety of biochemical reactions. This dissertation aims to fundamentally understand the nanoparticle-biochemical interactions and the in vivo transport of engineered nanoparticles modulated by these interactions. In Chapter 1 of this dissertation, an overall review is given on the current understanding of nanobio interactions at the molecular and chemical levels, particularly. In Chapter 2, we systematically investigated how the nanoparticle size, the thiols species, and the protein binding affect the interactions between the nanoparticles and thiols at the in vitro level. In Chapter 3, we focused on unraveling the relation between the nanoparticle-biothiol interactions in vitro and the nanoparticle-biothiol interactions in vivo. In Chapter 4, we explored the nanoparticle-biothiol interactions in the diseased mice model and illustrated the application of nanoparticle-biothiol interactions in disease diagnosis. Finally, in Chapter 5, we present the summary and outlook. These new understanding on nano-biochemical interactions at both in vitro and in vivo levels will help further advance physiology at the nanoscale as well as open new pathways to early disease diagnosis and treatment.Item PH-Responsive MRI Agents that can be Activated Beyond the Tissue MT Window(2017-05) Wang, Xiaojing; Sherry, A. Dean; Kiefer, Garry E.; Sibert, John W.; Zheng, JieChemical Exchange Saturation Transfer (CEST) has emerged as a novel Magnetic Resonance Imaging (MRI) contrast mechanism and gained increasing attention in applications. The image contrast is obtained by utilizing slow exchange properties of CEST agents that contain protons in exchange with bulk water protons. And continuous transfer of saturation makes the solutes at low concentration indirectly observable. In CEST, application of a pre-saturation pulse results in an extra signal called the Magnetization Transfer (MT) effect, arising from immobile protons bound in proteins and other large macromolecules. It is worthwhile to note that the MT effects always accompany CEST in tissue; as a result, measuring the pure CEST contribution that is separated from MT effect becomes somewhat difficult. Up to now, for the CEST data processing, the most commonly method used is the MTratio (MTR) asymmetry analysis with respect to the water frequency. Good asymmetry analysis requires that the MT profile is symmetric around water. However, over the past few years, several studies have found that in tissue, the z-spectra associated with semi-solid molecular pool are slightly asymmetric around the water proton resonance frequency, probably due to the chemical shift center mismatch between bulk water and semi-solid macromolecules. Thus, the validity of the MTR asymmetry analysis has been compromised. The goal of the present work is to develop CEST-based pH sensors that can be activated without simultaneous activation of the tissue MT signal. Our research efforts are focused under the theme to develop CEST-based pH sensors with large hyperfine shifts, putting them well outside the range of the MT profile. Thus they can be activated via selective RF irradiation without MT interference. Terbium-based complexes were developed, which displayed a water exchange CEST resonance located in the range of -500 to -600 ppm, well-outside the normal MT frequency range of tissues. By using this type of agents, the macromolecule MT effect has no impact on contrast-to-noise ratios in biological systems and MTratio (MTR) asymmetry analysis is not considered as necessary as other agents, thus opening a new way of circumventing the MT contamination and complication. Deprotonation of the phenolic proton resulted in a frequency shift of about 60 ppm in a bound water molecule exchange peak between pH 5 and 8. This allows direct imaging pH without prior knowledge of the agent concentration. A new model for simultaneous measurement of pH and temperature parameters was also proposed. The chemical shift information extracted from imaging data could be used to obtain the local temperature and pH values by simultaneously solving equations in our established model.Item Photoacoustic Imaging of Nanoparticle Transport in the Kidneys at High Temporal Resolution(Wiley-VCH Verlag) Jiang, Xingya; Du, Bujie; Tang, Shaoheng; Hsieh, J. -T; Zheng, Jie; 0000-0001-8546-1882 (Zheng, J); 22147423113244881679 (Zheng, J); Jiang, Xingya; Du, Bujie; Tang, Shaoheng; Zheng, JieNoninvasive monitoring of kidney elimination of engineered nanoparticles at high temporal and spatial resolution will not only significantly advance our fundamental understandings of nephrology on the nanoscale, but also aid in the early detection of kidney disease, which affects more than 10 % of the worldwide population. Taking advantage of strong NIR absorption of the well-defined Au₂₅(SG)₁₈ nanocluster, photoacoustic (PA) imaging was used to visualize its transport in situ through the aorta to the renal parenchyma and its subsequent filtration into the renal pelvis at a temporal resolution down to 1 s. High temporal and spatial resolution imaging of Au₂₅(SG)₁₈ kidney elimination allowed the accurate quantification of the glomerular filtration rate (GFR) of individual kidneys in normal and pathological conditions, broadening the biomedical applications of engineered nanoparticles in preclinical kidney research. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimItem Physiological Stability and Renal Clearance of Ultrasmall Zwitterionic Gold Nanoparticles: Ligand Length Matters(American Institute of Physics, 2017-03-15) Ning, Xuhui; Peng, Chuanqi; Li, Eric S.; Xu, Jing; Vinluan, III,Rodrigo D.; Yu, Mengxiao; Zheng, Jie; 0000-0001-8546-1882 (Zheng, J); 22147423113244881679 (Zheng, J); Ning, Xuhui; Peng, Chuanqi; Li, Eric S.; Xu, Jing; Vinluan, III,Rodrigo D.; Yu, Mengxiao; Zheng, JieEfficient renal clearance has been observed from ultrasmall zwitterionic glutathione-coated gold nanoparticles (GS-AuNPs), which have broad preclinical applications in cancer diagnosis and kidney functional imaging. However, origin of such efficient renal clearance is still not clear. Herein, we conducted head-to-head comparison on physiological stability and renal clearance of two zwitterionic luminescent AuNPs coated with cysteine and glycine-cysteine (Cys-AuNPs and Gly-Cys-AuNPs), respectively. While both of them exhibited similar surface charges and the same core sizes, additional glycine slightly increased the hydrodynamic diameter of the AuNPs by 0.4 nm but significantly enhanced physiological stability of the AuNPs as well as altered their clearance pathways. These studies indicate that the ligand length, in addition to surface charges and size, also plays a key role in the physiological stability and renal clearance of ultrasmall zwitterionic inorganic NPs.Item Renal Clearable Luminescent Gold Nanoparticles for In-Vitro Bioimaging(2017-05) Jacobe, Jessica L; Zheng, JieRenal clearable fluorescent gold nanoparticles (AuNPs) have potential to become tumor imaging and drug delivery agents because of their minimized accumulation in the body. However, they cannot actively target tumor receptors at both in vitro and in vivo levels. Since transferrin, a proliferative protein, has been widely used for targeted delivery of nanoparticles, in this thesis, we investigated targeting of transferrin after being conjugated with renal clearable fluorescent gold nanoparticles at the in vitro cellular level. Our results show that transferrin lost its targeting functionality due to the conjugation renal clearable AuNPs while it still can retain targeting capabilities after being conjugated onto organic dyes. Our further studies use a well-known ligand, biotin, also lost its binding affinity to avidin. Renal clearable AuNPs effect on the functionality of active targeting ligands are highly complicated, which demands extensive efforts in the future studies.Item Renal-Clearable Gold Nanoparticle-Based Drug Delivery Systems(2019-07-19) Peng, Chuanqi; Zheng, JieEngineered nanoparticles (NPs) have demonstrated unprecedented physiological understandings and versatile biomedical applications. However, clinical translation of cancer nanomedicines remains slow due to limited tumor targeting but elevated body retention of off-target therapeutics. With decreased size and surface passivation, the engineered, ultrasmall NPs have shown not only efficient body elimination through renal pathway, but also high targeting efficiency to the disease tissues as tumors. Therefore, such renal-clearable NPs could possibly address the many challenges faced by non-renal-clearable nanocarriers, once the efficient and stable drug loading as well as systematic physiological understandings of such ultrasmall delivery systems were achieved. In Chapter 1, we prepared the delivery vector by using the renal-clearable gold nanoparticles (AuNPs) with high tumor targeting efficiency. By rational design and modification, we firstly loaded the widely used anticancer drug, doxorubicin (DOX), on the renal-clearable AuNPs at high loading capacity, and then investigated the physiological stability, drug release and in vitro cytotoxicity studies. In addition, this ultrasmall AuNPs can also load many other small-molecule therapeutic or imaging agents as well as small-interfering RNAs for gene therapy. In Chapter 2 and 3, we systematically investigated blood circulation, tumor targeting, intratumoral transport, as well as body elimination of the renal-clearable 5-nm AuNP-based drug delivery system (DDS). The renal-clearable DDS not only significantly enhanced delivery efficiency and intratumoral transport of drug but also accelerated the renal clearance and body elimination of offtarget drug compared to both free drug (DOX) and the non-renal-clearable 30-nm DDS. As a result, the therapeutic index was improved by both enhanced efficacy and safety. In Chapter 4, we investigated the targeting and imaging of poorly permeable brain tumors (gliomas) by using the renal-clearable zwitterionic 3-nm AuNPs. The renal-clearable AuNPs increased tumor targeting efficiency and specificity compared to non-renal-clearable 18-nm counterpart. The effective NP penetration in brain tumorssuggeststhat renal-clearable AuNPs may achieve early brain tumor detection once integrated with nuclear imaging techniques used in the clinics. In Chapter 5, we investigated the ligand-directed in situ growth of AuNPs in biological tissues and the possible biological interaction of biomolecules. The results indicate that the ligand-directed AuNP growth can serve as a novel tool for tissue imaging via nanoparticle labeling with multimodality and multi-scale characterization. Herein, we not only report the design and practice of renal-clearable AuNP-based DDS as well as tissue targeting and imaging with AuNPs, we also conclude the outlook and future work for the renal-clearable AuNPs. We believe the renal-clearable AuNPs can shift the paradigm in drug delivery and expedite the clinical translation of cancer nanomedicines once some critical challenges are further addressed in the near future.Item Size-Dependent in Vivo Transport and Interactions of Ultrasmall Nanoparticles(2019-07-10) Du, Bujie; Zheng, JieThe past decade has witnessed the accelerating development of ultrasmall nanoparticles (NPs) in disease diagnosis and treatment. Fundamental understanding of the in vivo transport and nano-bio interactions of ultrasmall nanoparticles not only advances their biomedical applications but also is important for understanding physiology at nano scale. Among many factors, size of NPs is known to play a key role in determining their elimination and targeting. For elimination, NPs with size larger than 6 nm are easily accumulated in the liver, spleen etc. while NPs with size smaller than 6 nm are readily eliminated through the kidneys into urine. Subtle differences, even a several-atom difference in size can result in dramatically distinct renal clearance efficiency. For targeting, it has been conventionally deemed that only NPs within the size range of 10-100 nm can efficiently target tumors through the enhanced permeability and retention (EPR) effect, but in recent years, we have witnessed that ultrasmall nanoparticles (<6 nm) not only retain the EPR effect but also display deeper and more homogenous distribution in solid tumors than larger ones. Moreover, subtle differences of ultrasmall NPs in size also can result in their distinct accumulation and interactions in tumors. This dissertation aims to fundamentally understand the size-dependent elimination and targeting of ultrasmall nanoparticles in the body. In this dissertation, Chapter 1 reviews the current understanding of in vivo transport and interactions of nanoparticles in the kidneys and tumors in terms of nanoparticle size. Chapter 2 describes the size-dependent glomerular filtration of sub-nm gold nanoclusters and illustrates a unique size scaling law which shows that the glomerular barrier behaves as an atomically precise bandpass filter in a sub-nm regime. Chapter 3 focuses on the accumulation and interaction of subnm gold nanoclusters in solid tumor at the cellular level and illustrates that smaller nanoclusters display higher cellular uptake efficiency in solid tumors than larger counterparts. In addition to metal-based nanomaterials, Chapter 4 describes the in vivo transport and nano-bio interactions of ultrasmall organic materials. By utilizing PEGylated (<10,000 Da) organic dyes, we not only found a general molecular weight dependent scaling law in renal clearance but also observed the renal tubular secretion of indocyanine green after PEGylation, which in turn greatly enhanced its targeting to primary and metastatic tumors. Finally, Chapter 5 presents conclusion and outlook.