and A.D.S. This work was supported by research grants from the National Institutes of Health (DK-095416) and the Cancer Prevention and Research Institute of Texas (RP180178). Ghosh S.K., Kim P., Zhang X.A., Yun S.H., Moore A., Lippard S.J., Medarova Z. Imaging Insulin Secretion from Mouse Pancreas by MRI Is Improved by Use of a Zinc-Responsive MRI Sensor with Lower Affinity for Zn(2+) Ions. Functional analysis of islet cells in vitro, in situ, and in vivo. Incidence, Admission Rates, and Economic Burden of Adult Emergency Visits for Chronic Pancreatitis: Data From the National Emergency Department Sample, 2006 to 2012. Kinetic stability and water exchange of its Gd3+ complex. Many other conditions have been linked to Zn2+ homeostasis. Finally, manganese-zinc ferrite nanoparticles [70,71] and manganese-porphyrin bimodal agents [72] are among other types of sensors that are also being explored. Gadolinium deposition and the potential for toxicological sequelaeA literature review of issues surrounding gadolinium-based contrast agents. Ghafoor S., Burger I.A., Vargas A.H. Multimodality Imaging of Prostate Cancer. A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, metal ion-responsive MRI agents, zinc secretion, macrocyclic chemistry, gadolinium-based contrast media. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Khalighinejad P., Parrott D., Jordan V.C., Chirayil S., Preihs C., Xi Y., Rofsky N., Sherry A.D. MRI detection of glucose-stimulated zinc secretion in the enlarged dog prostate as a potential method for differentiating prostate cancer from benign prostatic hyperplasia. The r1 of this modified agent was 4.2 mM1 s1 in aqueous buffer alone, 8.4 mM1 s1 in the presence of HSA, and 5.9 mM1 s1 in the presence of Zn2+. Botta M. Second Coordination Sphere Water Molecules and Relaxivity of Gadolinium(III) Complexes: Implications for MRI Contrast Agents. Doboszewska U., Myniec K., Wla A., Poleszak E., Nowak G., Wla P. Zinc signaling and epilepsy. Effects of Electron Spin Relaxation. government site. Zinc as an anti-tumor agent in prostate cancer and in other cancers. Costello J.R., Kalb B., Martin D.R. Choi B.Y., Jung J.W., Suh S.W. During the early stages of chronic pancreatitis, when acute pancreatitis is transitioning into the chronic phase, the body can maintain normal glucose homeostasis, as the remaining pancreatic islets compensate for those destroyed [106]. MRI has a lower sensitivity compared to optical probes but provides the opportunity to image at least extracellular Zn2+ levels nearly anywhere in deep tissues. GdDOTA-diBPEN was the first zinc-responsive MR contrast agent applied in mice in vivo [52]. All authors have read and agreed to the published version of the manuscript. Although the origin of these enhanced image regions is still under investigation, they appear to be consistent with the location of individual islets or clumps of islets near highly vascularized regions of pancreatic tissue. A close link between Zn2+ homeostasis and malignant proliferation of the prostatic tissue has been discovered [94,95,96]. A cocktail of (165)Er(iii) and Gd(iii) complexes for quantitative detection of zinc using SPECT and MRI. If you do not get a response rather its due after hours or our team is out of the office then please send us an email at our provided customer service email and we will respond to you as quickly as possible. Relaxation Processes in a System of Two Spins. To test this hypothesis, two other derivatives were prepared where either an acetate or an amide side-chain had extra CH2 groups inserted. One important reason for this limitation is the inadequate available techniques for tracking Zn2+ in biological systems [24]. In yet another approach, Yu et al. FOIA Two mono-side-chain derivatives, one with a nM binding affinity for Zn2+ (GdL1) (Figure 2k) and one with a M binding affinity for Zn2+ (GdL2), were compared for detection of glucose-stimulated zinc-secretion (GSZS) from the mouse pancreas in vivo [48]. Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Assessment of Manganese-Zinc Ferrite Nanoparticles as a Novel Magnetic Resonance Imaging Contrast Agent for the Detection of 4T1 Breast Cancer Cells. Yu J., Martins A.F., Preihs C., Clavijo Jordan V., Chirayil S., Zhao P., Wu Y., Nasr K., Kiefer G.E., Sherry A.D. Amplifying the sensitivity of zinc(II) responsive MRI contrast agents by altering water exchange rates. Harnessing chemical exchange: (19)F magnetic resonance OFF/ON zinc sensing with a Tm(iii) complex. Upon intravenous injection of GdL1 with glucose to a fasted rat, glucose stimulates the pancreatic -cells to secrete insulin and the co-stored zinc ions. Zn2+-related metabolism has been linked to the development of many disorders including diabetes [12], prostate cancer [13], benign prostatic hyperplasia (BPH) [14], Alzheimers disease [15], multiple sclerosis [16], epilepsy [17], leukemia [18], other cancers [19], and more recently, COVID-19 [20,21]. This observation suggests that there may be a signal downstream of glycolysis that initiates secretion of Zn2+ from prostate epithelial cells [89]. de Almeida Brasiel P.G. http://creativecommons.org/licenses/by/4.0/, https://www.ncbi.nlm.nih.gov/books/NBK482487/. Chemical structures of some of the zinc-responsive gadolinium-based MR contrast agents. Although complexes of other paramagnetic ions, including Mn2+, Mn3+, Fe3+, and Cu2+, have been proposed as MRI contrast agents, they each impact water proton relaxation and hence image contrast through somewhat different mechanisms. This remarkable 3-fold increase in r1, however, did not fully translate into a 3-fold increase in sensitivity for detection of Zn2+ release from the mouse pancreas in vivo [45,52,54]. Li D., Zhou W., Yuan R., Xiang Y. Non-Specific Zn. The dashed black circles show the hotspots that are thought to be the fast-acting islets known as first responder islets. However, the two bimodal probes introduced by Hanaoka et al. It is very well known that Zn2+ is a crucial factor in the crystallization and storage of insulin [78,79], showing a broader impact of zinc on both types of diabetes [12]. (Time after ordering). Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. In the presence of both HSA and Zn2+, however, the relaxivity increased to 15.3 mM1 s1, so even though the 3-pyrazolyl groups have a lower affinity for Zn2+, this chemical difference seemed to improve the binding interaction between the agent and HSA [45]. Gd3+-based contrast agents have a strong influence on T1 relaxation times and are consequently the most commonly used agents in both the clinical and research environments. Given that GdDOTA-diBPEN is a bis-amide bis-acetate complex, it was anticipated that the rate of water exchange in this complex might be slower than optimal for reaching the highest r1 possible [53]. Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Malikidogo et al. Interestingly, pyruvate has been shown to stimulate Zn2+ secretion from the rat prostate, much like glucose. All products are final sale. Yin P., Choi H.M.T., Calvert C.R., Pierce N.A. about navigating our updated article layout. Aime S., Crich S.G., Gianolio E., Giovenzana G.B., Tei L., Terreno E. High sensitivity lanthanide(III) based probes for MR-medical imaging. Isaac et al. Here, free Zn2+ refers to ions weakly associated with anions and proteins in plasma, perhaps better defined as Zn2+ that is readily available for binding with small-molecule chelating ligands such as EDTA [22]. A few bimodal MRI and fluorescence Zn2+-sensitive probes have also been reported. In the interstitial tissue, GdL1 binds to zinc and albumin, forming a ternary complex that results in a slower rotational correlation time, a decrease in T1, and signal enhancement in T1-weighted MR images. Received 2020 Sep 1; Accepted 2020 Sep 22. Stasiuk G.J., Minuzzi F., Sae-Heng M., Rivas C., Juretschke H.P., Piemonti L., Allegrini P.R., Laurent D., Duckworth A.R., Beeby A., et al. In overly simplified terms, when the molecular weight of the Gd3+ complex is relatively low, the complex rotates rather quickly and randomly in solution, so the impact of the seven unpaired electrons tends to average out such that the magnetic moment feels smaller to the exchanging water protons. Mishra A., Logothetis N.K., Parker D. Critical in vitro evaluation of responsive MRI contrast agents for calcium and zinc. The biochemical basis of zinc physiology. MR contrast agents that respond to the presence of Zn2+ in vivo offer the possibility of imaging changes in Zn2+ levels in real-time with the superior spatial resolution offered by MRI. Those images showed that the lateral lobe of the mouse prostate uniquely accumulates higher amounts of Zn2+, 1.06 0.08 mM, while the Zn2+ concentration was lower, averaging 0.370 0.001 mM in regions of malignant neoplasia. In those experiments, fasted mice were given a low dose of GdDOTA-diBPEN glucose to stimulate insulin secretion from the pancreas. Another novel approach was the use of [emailprotected]@DNA nanoprobes to detect the toehold-mediated strand displacement reaction (TSDR), by utilizing magnetic guidance in order to introduce the nanoprobes into the cells [64]. Careers. Herynek V., Turnovcova K., Galisova A., Kaman O., Marekova D., Koktan J., Vosmanska M., Kosinova L., Jendelova P. Manganese-Zinc Ferrites: Safe and Efficient Nanolabels for Cell Imaging and Tracking In Vivo. When Zn2+ was added to the solution containing the probe, both r1 and r2 increased. Orders can be canceled by clicking the 'Chat with us!' 25 Years of Contrast-Enhanced MRI: Developments, Current Challenges and Future Perspectives. Solomon I. In addition to NSF, other complications such as allergic reactions [74,75] and Gd deposition in the brain [76] have also been reported. Multifunctional Fe. The relaxivities changed due to an increase in water associated with the gadolinium oxide nanoparticle and an increase in its rotational tumbling time [62]. Mottet N., Bellmunt J., Bolla M., Briers E., Cumberbatch M.G., De Santis M., Fossati N., Gross T., Henry A.M., Joniau S., et al. In the late stages of the disease, islets are digested with the leaking pancreatic enzymes, leading to insulin-dependent diabetes [105]. Transrectal ultrasound (TRUS) has been the primary imaging modality used for prostate cancer, but it also has mediocre specificity and suboptimal sensitivity [98]. A modified version of Gd-daa3 containing one pyridine and one acetate arm was later introduced (Figure 2e). Lee T., Zhang X., Dhar S., Faas H., Lippard S.J., Jasanoff A. The prostate is an exocrine gland, producing a fluid rich in glucose, fructose, citric acid, zinc, and prostatic-specific antigen (PSA) [91]. Images of mice fed a high-fat (60%) diet over a 12-week period and subjected to this same imaging protocol showed a larger volume of contrast-enhanced pancreatic tissue, consistent with the expansion of pancreatic -cell mass during progression toward type 2 diabetes [52]. Diagnosis and Management of Chronic Pancreatitis: A Review. The new PMC design is here! and transmitted securely. This likely reflects the greater complexity of the molecular environment of these agents in vivo compared to simple aqueous solutions and presents a strong argument for testing all new agents in vivo. Srivastava K., Ferrauto G., Harris S.M., Longo D.L., Botta M., Aime S., Pierre V.C. When dissolved in serum, however, the basal r1 values both in the absence and presence of Zn2+ were higher, 5.8 mM1 s1 in the absence of added Zn2+ and 7.7 mM1 s1 after further addition of Zn2+ [31]. Like the first agent reported by Hanaoka et al. In that first high-impact publication, Moats et al. Such responsive agents, often referred to as smart agents, are typically composed of a paramagnetic metal ion with a ligand encapsulating it and one or more chelating units that selectively bind with the analyte of interest. While blocking GLUT-1,4 transporters did eliminate Zn2+ secretion as expected, inhibition of insulin receptors did not affect the process. Zn2+ with or without human serum albumin (HSA). Although zinc is considered a trace mineral, it plays critical roles in various types of cellular processes and intercellular signaling [8], and it can be anticipated that an imbalance in zinc homeostasis can lead to disruptions in multiple processes, presenting as pathologies such as autoimmunity [16] or malignancy [19]. With convenient and widely available methods for checking blood glucose levels, clinicians do not need a MR scan to diagnose diabetes, yet there are many unanswered questions about diabetes. Paramagnetic metal ion complexes, mostly based on gadolinium (Gd3+), have been used for over 30 years as magnetic resonance imaging (MRI) contrast agents. Although r1 can be further improved by optimizing the rate of water exchange in these Gd3+-based agents [54], it was interesting to find that a 10-fold increase in r1 as measured in vitro did not translate to a 10-fold improvement image enhancement in vivo. The .gov means its official. In 2015, a Zn2+-sensitive fluorescence agent was injected directly into the mouse prostate to demonstrate the changes that occur in total tissue Zn2+ content during the progression of prostate cancer in TRAMP (transgenic adenocarcinoma mouse prostate) mice [81]. The variables that contribute most to the relaxation efficiency (r1) of a Gd3+-based contrast agent include the hydration number (q), the mean residence lifetime of the inner-sphere water molecule (m), and the rotational correlation time (R) of the entire Gd3+-complex. Parrott D., Khalighinejad P., Clavio-Jordan V., Thapa B., Lo S.-T., Suh E.H., Sherry A.D. Metabolic Pathway of Glucose Stimulated Zinc Secretion in the Healthy Prostate. The basic design of each agent was to trigger a change in r1 of Gd3+ upon binding of Zn2+ in its recognition site by either a change in hydration number (q), the mean residence lifetime of the inner-sphere water molecule (m), or the rotational correlation time (R) of the entire Gd3+ complex. Zinc imbalance is also either a cause or a consequence of Alzheimers disease. 8600 Rockville Pike Garg S.K., Singh D., Sarvepalli S., Bazerbachi F., Puthanveedu N.D., Obaitan I., Haffar S., Goyal H., Sanaka M.R. Choosing a selection results in a full page refresh. Knop R.H., Frank J.A., Dwyer A.J., Girton M.E., Naegele M., Schrader M., Cobb J., Gansow O., Maegerstadt M., Brechbiel M., et al. Kawahara M., Tanaka K.I., Kato-Negishi M. Zinc, Carnosine, and Neurodegenerative Diseases. reported a D-glucuronic acid-coated ultrasmall Gd2O3 nanoparticle for Zn2+ sensing. [(accessed on 22 September 2020)]; Hanaoka K., Kikuchi K., Urano Y., Nagano T. Selective sensing of zinc ions with a novel magnetic resonance imaging contrast agent. Hines C.D.G., Jordan V.C., Gantert L.T., Wang S., Conarello S., Preihs C., Chirayil S., Michael K., Sherry A.D., Evelhoch J.L. Somewhat later, Mishra et al. King J.C., Brown K.H., Gibson R.S., Krebs N.F., Lowe N.M., Siekmann J.H., Raiten D.J. The influence of paramagnetic complexes on water proton relaxation can be rather dramatic depending upon the concentration of the agent. These authors concluded that the first Zn2+ ion formed a strong tetrahedral complex with the four pyridine ligands from the two BPEN moieties and this restricted access of water to the inner-sphere of the Gd3+ ion. Although this type of agent was not shown to respond to changes on Zn2+ levels in the brain, it does represent a different type of MR-responsive Zn2+ sensor if it indeed accumulates only in Zn2+-rich regions of the brain. In 2009, Esqueda et al. These characteristics make DOTA the preferred choice for in vivo use. The crucial role of Zn2+ in crystallization and storage of insulin in -cells is well-established, and the extracellular concentration of Zn2+ around -cells is known to increase by about 10-fold during active secretion of insulin [78,79]. Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. used a thulium-based agent with a DO3A core, a pyridine chelate, and a perfluoro-tert-butyl tag which was only visible by 19F NMR in the presence of Zn2+. It was likely disappointing to find that the r1 of this agent decreased after addition of the first Zn2+ ion (see Table 1) and remained low after addition of a second equivalent of Zn2+. [41] reported a lanthanide-based DTPA-quinoline DPA conjugate, using Gd3+ for a dual-purpose MR and fluorescent probe (Figure 2c), and europium (Eu3+) for a luminescent sensor. Upon binding with Zn2+, both lanthanide probes showed ratiometric fluorescent changes with a Stokes shift from 410 to 500 nm. button within 24 hours after placing the order, stating you would like to cancel. Clinically available Gd3+-based contrast agents are referred to as extracellular agents because they distribute into all tissue extracellular space and have little tissue specificity. The different signal intensities seen as grayscale intensity differences in MR images reflect differences in water and fat content in various tissues and the relaxation characteristics of those water, fat, and other protons, specifically their T1 and T2 relaxation times [1]. [43] were first to report that Zn2+-sensitive agents such as these form ternary complexes between Zn2+ and HSA. Solvent water molecules in the presence of a Gd3+-based contrast agent can be described at a minimum as three types (Figure 1): (1) typically, a single inner-sphere water molecule that binds weakly with the Gd3+ ion and exchanges rather rapidly with all other nearby water molecules, (2) a number of second-sphere water molecules that interact weakly with the entire Gd3+-complex, and (3) the remaining outer-sphere or bulk water molecules [31]. Glazer D.I., Mayo-Smith W.W., Sainani N.I., Sadow C.A., Vangel M.G., Tempany C.M., Dunne R.M. Due to Covid-19 we do not due returns on any products. Even a small decrease in T1 and/or T2 can change the appearance of an image rather dramatically by brightening or darkening the water intensity in those tissues where the agent is present. Sobhani T., Shahbazi-Gahrouei D., Rostami M., Zahraei M., Farzadniya A. Vallee B.L., Falchuk K.H. Olchowy C., Cebulski K., asecki M., Chaber R., Olchowy A., Kawak K., Zaleska-Dorobisz U. 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