scispace - formally typeset
Search or ask a question
Author

Angelo J. M. Lubag

Other affiliations: University of Texas at Dallas
Bio: Angelo J. M. Lubag is an academic researcher from University of Texas Southwestern Medical Center. The author has contributed to research in topics: In vivo & Molecular sieve. The author has an hindex of 14, co-authored 16 publications receiving 1083 citations. Previous affiliations of Angelo J. M. Lubag include University of Texas at Dallas.

Papers
More filters
Journal ArticleDOI
TL;DR: This review describes examples of imaging extracellular pH in brain tumors, ischemic hearts, and pancreatic islets with Gd(3+)-based pH sensors and discusses the potential of CEST and PARACEST agents as metabolic imaging sensors.
Abstract: Magnetic resonance imaging (MRI) has inherent advantages in safety, three-dimensional output, and clinical relevance when compared with optical and radiotracer imaging methods. However, MRI contrast agents are inherently less sensitive than agents used in other imaging modalities primarily because MRI agents are detected indirectly by changes in either the water proton relaxation rates (T(1), T(2), and T(*)(2)) or water proton intensities (chemical exchange saturation transfer and paramagnetic chemical exchange saturation transfer, CEST and PARACEST). Consequently, the detection limit of an MRI agent is determined by the characteristics of the background water signal; by contrast, optical and radiotracer-based methods permit direct detection of the agent itself. By virtue of responding to background water (which reflects bulk cell properties), however, MRI contrast agents have considerable advantages in "metabolic" imaging, that is, spatially resolving tissue variations in pH, redox state, oxygenation, or metabolite levels. In this Account, we begin by examining sensitivity limits in targeted contrast agents and then address contrast agents that respond to a physiological change; these responsive agents are effective metabolic imaging sensors. The sensitivity requirements for a metabolic imaging agent are quite different from those for a targeted Gd(3+)-based T(1) agent (for example, sensing cell receptors). Targeted Gd(3+) agents must have either an extraordinarily high water proton relaxivity (r(1)) or multiple Gd(3+) complexes clustered together at the target site on a polymer platform or nanoparticle assembly. Metabolic MRI agents differ in that the high relaxivity requirement, although helpful, is eased because these agents respond to bulk properties of tissues rather than low concentrations of a specific biological target. For optimal sensing, metabolic imaging agents should display a large change in relaxivity (deltar(1)) in response to the physiological or metabolic parameter of interest. Metabolic imaging agents have only recently begun to appear in the literature and only a few have been demonstrated in vivo. MRI maps of absolute tissue pH have been obtained with Gd(3+)-based T(1) sensors. The requirement of an independent measure of agent concentration in tissues complicates these experiments, but if qualitative changes in tissue pH are acceptable, then these agents can be quite useful. In this review, we describe examples of imaging extracellular pH in brain tumors, ischemic hearts, and pancreatic islets with Gd(3+)-based pH sensors and discuss the potential of CEST and PARACEST agents as metabolic imaging sensors.

239 citations

Journal ArticleDOI
TL;DR: Exchange rates derived from omega plots using either high‐resolution CEST NMR data or CEST data obtained by imaging agree favorably with exchange rates measured by the more commonly used Bloch fitting and line‐width methods, potentially allowing access to a direct measure of exchange rates in vivo, where the agent concentration is typically unknown.
Abstract: The efficiency of chemical exchange dependent saturation transfer (CEST) agents is largely determined by their water or proton exchange kinetics, yet methods to measure such exchange rates are variable and many are not applicable to in vivo measurements. In this work, the water exchange kinetics of two prototype paramagnetic agents (PARACEST) are compared by using data from classic NMR line-width measurements, by fitting CEST spectra to the Bloch equations modified for chemical exchange, and by a method where CEST intensity is measured as a function of applied amplitude of radiofrequency field. A relationship is derived that provides the water exchange rate from the X-intercept of a plot of steady-state CEST intensity divided by reduction in signal caused by CEST irradiation versus 1/omega(1)(2), referred to here as an omega plot. Furthermore, it is shown that this relationship is independent of agent concentration. Exchange rates derived from omega plots using either high-resolution CEST NMR data or CEST data obtained by imaging agree favorably with exchange rates measured by the more commonly used Bloch fitting and line-width methods. Thus, this new method potentially allows access to a direct measure of exchange rates in vivo, where the agent concentration is typically unknown.

174 citations

Journal ArticleDOI
TL;DR: The properties of a novel Gd(3+)-based MRI zinc sensor are reported and it is shown to have a relatively strong binding affinity for Zn(2+) (K(D) = 33.6 nM), similar to the affinity of the Zn (2+) ion with HSA alone.
Abstract: The properties of a novel Gd3+-based MRI zinc sensor are reported. Unlike previously reported Gd3+-based MRI contrast agents, this agent (GdL) differs in that the agent alone binds only weakly with human serum albumin (HSA), while the 1:2 GdL:Zn2+ ternary complex binds strongly to HSA resulting in a substantial, 3-fold increase in water proton relaxivity. The GdL complex is shown to have a relatively strong binding affinity for Zn2+ (KD = 33.6 nM), similar to the affinity of the Zn2+ ion with HSA alone. The agent detects as little as 30 μM Zn2+ in the presence of HSA by MRI in vitro, a value slightly more than the total Zn2+ concentration in blood (∼20 μM). This combination of binding affinity constants and the high relaxivity of the agent when bound to HSA suggests that this new agent may be useful for detection of free Zn2+ ions in vivo without disrupting other important biological processes involving Zn2+.

141 citations

Journal ArticleDOI
TL;DR: It is demonstrated here that divalent zinc ions coreleased with insulin from β-cells in response to high glucose are readily detected by MRI using the Zn2+-responsive T1 agent, GdDOTA-diBPEN, which offers the exciting potential for deep-tissue monitoring of β-cell function in vivo during development of type 2 diabetes or after implantation of islets in type I diabetic patients.
Abstract: Elevation of postprandial glucose stimulates release of insulin from granules stored in pancreatic islet β-cells. We demonstrate here that divalent zinc ions coreleased with insulin from β-cells in response to high glucose are readily detected by MRI using the Zn2+-responsive T1 agent, GdDOTA-diBPEN. Image contrast was significantly enhanced in the mouse pancreas after injection of a bolus of glucose followed by a low dose of the Zn2+ sensor. Images of the pancreas were not enhanced by the agent in mice without addition of glucose to stimulate insulin release, nor were images enhanced in streptozotocin-treated mice with or without added glucose. These observations are consistent with MRI detection of Zn2+ released from β-cells only during glucose-stimulated insulin secretion. Images of mice fed a high-fat (60%) diet over a 12-wk period and subjected to this same imaging protocol showed a larger volume of contrast-enhanced pancreatic tissue, consistent with the expansion of pancreatic β-cell mass during fat accumulation and progression to type 2 diabetes. This MRI sensor offers the exciting potential for deep-tissue monitoring of β-cell function in vivo during development of type 2 diabetes or after implantation of islets in type I diabetic patients.

123 citations

Journal ArticleDOI
TL;DR: Results show that CEST contrast can be modulated by changes in electron density at a single ligating atom, and this forms the basis of creating imaging agents that respond to chemical oxidation and reduction.
Abstract: The chemical exchange saturation transfer (CEST) efficiency for a series Eu3+-based tetraamide complexes bearing p-substituents on a single coordinating pendant arm is highly sensitive to water exchange rates. The CEST effect increases in the order Me < MeO < F ∼CO2tBu < CN ≪ H. These results show that CEST contrast can be modulated by changes in electron density at a single ligating atom, and this forms the basis of creating imaging agents that respond to chemical oxidation and reduction.

78 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: In this review, state-of-the-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergy therapy.
Abstract: The complexity, diversity, and heterogeneity of tumors seriously undermine the therapeutic potential of treatment. Therefore, the current trend in clinical research has gradually shifted from a focus on monotherapy to combination therapy for enhanced treatment efficacy. More importantly, the cooperative enhancement interactions between several types of monotherapy contribute to the naissance of multimodal synergistic therapy, which results in remarkable superadditive (namely “1 + 1 > 2”) effects, stronger than any single therapy or their theoretical combination. In this review, state-of-the-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergistic therapy as well as the intensive exploration of the underlying synergistic mechanisms for explaining the significant improvements in synergistic therapeutic outcome. Furtherm...

1,220 citations

Journal ArticleDOI
TL;DR: Two classes of lanthanide probes are focused on that are subsets of the larger area of metalloimaging: luminescent and magnetic lanthanides.
Abstract: The chemistry of the less familiar elements is a fascinating topic especially for the inorganic minded. The lanthanides, or rare earths, comprise the 5d block of the periodic table and represent a huge array of applications from catalysis to lasers, and of course, imaging agents.1 Recent advances in luminescence and magnetic resonance microscopy have, in part, been stimulated by extraordinary success in the development of new lanthanide probes. The unique properties of the lanthanides provide for a deep tool chest for the chemist, biologist and the imaging scientist to exploit, and that exploitation is in full swing. In this review we focus on two classes of lanthanide probes that are subsets of the larger area of metalloimaging: luminescent and magnetic lanthanides. In Section 2 we discuss the general design and photophysical properties of lanthanides and how these parameters are tuned to develop bioresponsive probes for optical imaging. In Section 3 we provide a brief description of how MR images are acquired and the how MRI contrast agents are engineered to respond to biological events of interest. These guiding principles have driven research that has produced a truly diverse number of new agents that are target specific and bioresponsive (or bioactivatable). While other imaging modalities utilize lanthanide-based probes, these topics are beyond the scope of this review. We direct the reader to explore some excellent reviews in the important areas of radiometals and multimodal imaging.2–5

901 citations

Journal ArticleDOI
TL;DR: This review of molecular imaging of intact living subjects focuses specifically on small molecules, peptides, aptamers, engineered proteins, and nanoparticles and cites examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics.
Abstract: Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.

890 citations

Journal ArticleDOI
TL;DR: The focus of this review is on basic magnetic resonance principles underlying CEST and similarities to and differences with conventional magnetization transfer contrast.
Abstract: Chemical exchange saturation transfer (CEST) imaging is a relatively new magnetic resonance imaging contrast approach in which exogenous or endogenous compounds containing either exchangeable protons or exchangeable molecules are selectively saturated and after transfer of this saturation, detected indirectly through the water signal with enhanced sensitivity. The focus of this review is on basic magnetic resonance principles underlying CEST and similarities to and differences with conventional magnetization transfer contrast. In CEST magnetic resonance imaging, transfer of magnetization is studied in mobile compounds instead of semisolids. Similar to magnetization transfer contrast, CEST has contributions of both chemical exchange and dipolar cross-relaxation, but the latter can often be neglected if exchange is fast. Contrary to magnetization transfer contrast, CEST imaging requires sufficiently slow exchange on the magnetic resonance time scale to allow selective irradiation of the protons of interest. As a consequence, magnetic labeling is not limited to radio-frequency saturation but can be expanded with slower frequency-selective approaches such as inversion, gradient dephasing and frequency labeling. The basic theory, design criteria, and experimental issues for exchange transfer imaging are discussed. A new classification for CEST agents based on exchange type is proposed. The potential of this young field is discussed, especially with respect to in vivo application and translation to humans.

866 citations

Journal ArticleDOI
TL;DR: This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety and efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives.
Abstract: Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.

817 citations