DEVELOPMENT OF OPTICAL SENSOR BASED ON COLORIMETRIC DYE ARRAY AND DIVERSITY ORIENTED FLUORESCENCE LIBRARY APPROACH

Ph.DDOCTOR OF PHILOSOPH

PET/MRI: a frontier in era of complementary hybrid imaging

Abstract With primitive approaches, the diagnosis and therapy were operated at the cellular, molecular, or even at the genetic level. As the diagnostic techniques are more concentrated towards molecular level, multi modal imaging becomes specifically essential. Multi-modal imaging has extensive applications in clinical as well as in pre-clinical studies. Positron Emission Tomography (PET) has flourished in the field of nuclear medicine, which has motivated it to fuse with Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) for PET/CT and PET/MRI respectively. However, the challenges in PET/CT are due to the inability of simultaneous acquisition and reduced soft tissue contrast, which has led to the development of PET/MRI. Also, MRI offers the better soft tissue contrast over CT. Hence, fusion of PET and MRI results in combining structural information with functional image from PET. Yet, it has many technical challenges due to the interference between the modalities. Also, it must be resolved with various approaches for addressing the shortcomings of each system and improvise on the image quantification system. This review elaborates on the various challenges in the present PET/MRI system and the future directions of the hybrid modality. Also, the different data acquisition and analysis techniques of PET/MRI system are discussed with enhanced details on the software tools

A colorimetric pH indicators and boronic acids ensemble array for quantitative sugar analysis

The colorimetric response patterns of pH indicators and boronic acids ensemble array were used to analyze serial concentrations of mono-, disaccharides quantitatively. Furthermore, this ensemble array was successfully applied to quantify the sugar content in clinically used saline solutions.1113sciescopu

Dealing with PET radiometabolites

Positron emission tomography (PET) offers the study of biochemical, physiological, and pharmacological functions at a cellular and molecular level. The performance of a PET study mostly depends on the used radiotracer of interest. However, the development of a novel PET tracer is very difficult, as it is required to fulfill a lot of important criteria. PET radiotracers usually encounter different chemical modifications including redox reaction, hydrolysis, decarboxylation, and various conjugation processes within living organisms. Due to this biotransformation, different chemical entities are produced, and the amount of the parent radiotracer is declined. Consequently, the signal measured by the PET scanner indicates the entire amount of radioactivity deposited in the tissue; however, it does not offer any indication about the chemical disposition of the parent radiotracer itself. From a radiopharmaceutical perspective, it is necessary to quantify the parent radiotracer's fraction present in the tissue. Hence, the identification of radiometabolites of the radiotracers is vital for PET imaging. There are mainly two reasons for the chemical identification of PET radiometabolites: firstly, to determine the amount of parent radiotracers in plasma, and secondly, to rule out (if a radiometabolite enters the brain) or correct any radiometabolite accumulation in peripheral tissue. Besides, radiometabolite formations of the tracer might be of concern for the PET study, as the radiometabolic products may display considerably contrasting distribution patterns inside the body when compared with the radiotracer itself. Therefore, necessary information is needed about these biochemical transformations to understand the distribution of radioactivity throughout the body. Various published review articles on PET radiometabolites mainly focus on the sample preparation techniques and recently available technology to improve the radiometabolite analysis process. This article essentially summarizes the chemical and structural identity of the radiometabolites of various radiotracers including [11C]PBB3, [11C]flumazenil, [18F]FEPE2I, [11C]PBR28, [11C]MADAM, and (+)[18F]flubatine. Besides, the importance of radiometabolite analysis in PET imaging is also briefly summarized. Moreover, this review also highlights how a slight chemical modification could reduce the formation of radiometabolites, which could interfere with the results of PET imaging.Nanyang Technological UniversityPublished versionThe authors acknowledge the support from Lee Kong Chian School ofMedicine, Nanyang Technological University, Singapore, Austrian Institute ofTechnology and Medical University of Vienna internal Grant (NAM/15006)and LKCMedicine Imaging Probe Dev. Platform, Singapore

Mitochondrial Reactive Oxygen Species in Infection and Immunity

Reactive oxygen species (ROS) contain at least one oxygen atom and one or more unpaired electrons and include singlet oxygen, superoxide anion radical, hydroxyl radical, hydroperoxyl radical, and free nitrogen radicals. Intracellular ROS can be formed as a consequence of several factors, including ultra-violet (UV) radiation, electron leakage during aerobic respiration, inflammatory responses mediated by macrophages, and other external stimuli or stress. The enhanced production of ROS is termed oxidative stress and this leads to cellular damage, such as protein carbonylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and base modifications. This damage may manifest in various pathological states, including ageing, cancer, neurological diseases, and metabolic disorders like diabetes. On the other hand, the optimum levels of ROS have been implicated in the regulation of many important physiological processes. For example, the ROS generated in the mitochondria (mitochondrial ROS or mt-ROS), as a byproduct of the electron transport chain (ETC), participate in a plethora of physiological functions, which include ageing, cell growth, cell proliferation, and immune response and regulation. In this current review, we will focus on the mechanisms by which mt-ROS regulate different pathways of host immune responses in the context of infection by bacteria, protozoan parasites, viruses, and fungi. We will also discuss how these pathogens, in turn, modulate mt-ROS to evade host immunity. We will conclude by briefly giving an overview of the potential therapeutic approaches involving mt-ROS in infectious diseases

Coordination chemistry of ligands: insights into the design of amyloid beta/tau-PET imaging probes and nanoparticles-based therapies for Alzheimer's disease

The diagnosis and therapy of neurodegenerative diseases are highly indispensable. In particular, the definitive clinical diagnosis and therapy of Alzheimer's disease (AD) remains a challenge. Despite the use of amyloid beta (Aβ) positron emission tomography (PET) gold standard [11C]-PiB, other approved benzothiazole ([18F]-flutemetamol) and stilbene derivative ([18F]-florbetaben and [18F]-florbetapir) based probes have been extensively studied and advocated as potential early Aβ PET radioligands for AD. Recent years have witnessed a burgeoning research activity in the development of radiotracers for tau neurofibrillary tangles (NFTs) binding using PET imaging, while monitoring the progression of disease. Notably, several tau PET ligands (e.g. [18F]-THK5351, [18F]-MK-6240, and [18F]-AV-1451, [18F]-RO-6958948, [18F]-JNJ-64326067, [18F]-PI-2620) showed high affinity and selective binding to tau pathology. Although early detection and progression of AD have been studied extensively using PET imaging, therapeutic approaches to the disease are scarce. Recently, nanoparticles (NPs) based therapeutic approaches have emerged. Coordination of ligands to the surface of organic NPs (e.g., flavonoids: green tea polyphenol- EGCG, curcumin), and inorganic NPs (e.g. Au, ZnO, CeO2) have been explored to decrease/inhibit the amyloid aggregation and tau hyperphosphorylation. This review focuses on (i) the importance of coordination chemistry of ligands in the design of PET imaging probes with specific binding affinities to Aβ and tau NFTs in AD, and (ii) the role of surface ligands and their coordination to NPs and functional molecules for the rational design of novel anti-AD reagents for therapeutic interventions.Nanyang Technological UniversityS.T.S., B.G., P.P. thank the support from Lee Kong Chian School of Medicine, Imaging Probe Development Platform, and Cognitive Neuro Imaging Centre (CONIC) at Nanyang Technological University (NTU) Singapore

Surface ligand influences the Cu nanoclusters as a dual sensing optical probe for localized pH environment and fluoride ion

Functional metal nanomaterials, especially in the nanocluster (NC) size regime, with strong fluorescence, aqueous colloidal stability, and low toxicity, necessitate their application potential in biology and environmental science. Here, we successfully report a simple cost-effective method for red-/green-color-emitting protein/amino-acid-mediated Cu NCs in an aqueous medium. As-synthesized Cu NCs were characterized through UV-Vis absorption spectroscopy, fluorescence spectroscopy, time-resolved photoluminescence, dynamic light scattering, zeta potential, transmission electron microscopy and X-ray photoelectron spectroscopy. The optical properties of both Cu NCs responded linearly to the variation in pH in the neutral and alkaline ranges, and a robust pH reversible nature (between pH 7 and 11) was observed that could be extended to rapid, localized pH sensor development. However, a contrasting pH response nature between protein-Cu NCs and amino acid-Cu NCs was recorded. The alteration in protein secondary structure and strong binding nature of the surfactants were suggested to explain this behavior. Furthermore, we investigated their use as an efficient optical probe for fluoride ion detection. The limit of detection for protein-Cu NCs is 6.74 µM, whereas the limit of detection for amino acid-Cu NCs is 4.67 µM. Thus, it is anticipated that ultrasmall Cu NCs will exhibit promise in biological and environmental sensing applications.Published versionSC thank SRM University, AP research funding (SRMAP/URG/E&PP/2022-23/014) for financial support

Positron emission tomographic imaging in drug discovery

Positron emission tomography (PET) is an extensively used nuclear functional imaging technique, especially for central nervous system (CNS) and oncological disorders. Currently, drug development is a lengthy and costly pursuit. Imaging with PET radiotracers could be an effective way to hasten drug discovery and advancement, because it facilitates the monitoring of key facets, such as receptor occupancy quantification, drug biodistribution, pharmacokinetic (PK) analyses, validation of target engagement, treatment monitoring, and measurement of neurotransmitter concentrations. These parameters demand careful analyses for the robust appraisal of newly formulated drugs during preclinical and clinical trials. In this review, we discuss the usage of PET imaging in radiopharmaceutical development; drug development approaches with PET imaging; and PET developments in oncological and cardiac drug discovery.Nanyang Technological UniversityAuthors acknowledge support from Lee Kong Chian School of Medicine, NTU Austrian Institute of Technology and Medical University of Vienna internal grant (NAM/15006), the LKC Medicine Imaging Probe Development Platform, Singapore, and the Cognitive Neuroimaging Centre (CONIC) at Nanyang Technological University, Singapore

Surface Ligand Influences the Cu Nanoclusters as a Dual Sensing Optical Probe for Localized pH Environment and Fluoride Ion

Functional metal nanomaterials, especially in the nanocluster (NC) size regime, with strong fluorescence, aqueous colloidal stability, and low toxicity, necessitate their application potential in biology and environmental science. Here, we successfully report a simple cost-effective method for red-/green-color-emitting protein/amino-acid-mediated Cu NCs in an aqueous medium. As-synthesized Cu NCs were characterized through UV-Vis absorption spectroscopy, fluorescence spectroscopy, time-resolved photoluminescence, dynamic light scattering, zeta potential, transmission electron microscopy and X-ray photoelectron spectroscopy. The optical properties of both Cu NCs responded linearly to the variation in pH in the neutral and alkaline ranges, and a robust pH reversible nature (between pH 7 and 11) was observed that could be extended to rapid, localized pH sensor development. However, a contrasting pH response nature between protein–Cu NCs and amino acid–Cu NCs was recorded. The alteration in protein secondary structure and strong binding nature of the surfactants were suggested to explain this behavior. Furthermore, we investigated their use as an efficient optical probe for fluoride ion detection. The limit of detection for protein–Cu NCs is 6.74 µM, whereas the limit of detection for amino acid–Cu NCs is 4.67 µM. Thus, it is anticipated that ultrasmall Cu NCs will exhibit promise in biological and environmental sensing applications

Enhancement of upconversion emission of LaPO<SUB>4</SUB>: Er@Yb core−shell nanoparticles/nanorods

We demonstrated the synthesis of LaPO<SUB>4</SUB>:Er:Yb-doped nanoparticles/nanorods and LaPO<SUB>4</SUB>:Er@Yb core−shell nanoparticles/nanorods by a solution-based technique. The mechanism related to morphology control of LaPO<SUB>4</SUB>:Er:Yb nanorods/nanoparticles is proposed and discussed. Bright-green (550 nm) and red (670 nm) emission were observed due to the transitions <SUP>2</SUP>H<SUB>11/2</SUB> + <SUP>4</SUP>S<SUB>3/2</SUB> → <SUP>4</SUP>I <SUB>15/2</SUB> and <SUP>4</SUP>F<SUB>9/2</SUB> → <SUP>4</SUP>I<SUB>15/2</SUB>, respectively. The experimental data for 550- and 670-nm emission bands of doped nanoparticle/nanorod and core−shell nanoparticles/nanorods have been fit with a straight line with a slope of ∼2, which confirms the two-photon absorption process. The enhancement of upconversion emission of LaPO<SUB>4</SUB>:Er:Yb-doped nanoparticles and LaPO4:Er@Yb core−shell nanoparticles/nanorods are mainly due to modifications of surface-related effects. It is found that the tensile strain increases from +1.0% to +1.9% with changing the shape from nanoparticle to nanorod and reversal of the lattice strain (compressive) is obtained for coated nanoparticle/ nanorod. It is worth mentioning that the lattice strain varies with changing the shape and surface coating on nanocrystals and the upconversion emission intensity increases with decreasing the tensile lattice strain and it increases with increasing compressive strain. Analysis suggests that the lattice strain plays an important role in modification of the upconversion properties of the rare-earth-doped nanocrystals