Tyler Meldrum

A Xenon-Based Molecular Sensor Assembled on an MS2 Viral Capsid Scaffold

In MRI, anatomical structures are most often differentiated by variations in their bulk magnetic properties. Alternatively, exogenous contrast agents can be attached to chemical moieties that confer affinity to molecular targets; the distribution of such contrast agents can be imaged by magnetic resonance. Xenon-based molecular sensors are molecular imaging agents that rely on the reversible exchange of hyperpolarized xenon between the bulk and a specifically targeted host-guest complex. We have incorporated approximately 125 xenon sensor molecules in the interior of an MS2 viral capsid, conferring multivalency and other properties of the viral capsid to the sensor molecule. The resulting signal amplification facilitates the detection of sensor at 0.7 pM, the lowest to date for any molecular imaging agent used in magnetic resonance. This amplification promises the detection of chemical targets at much lower concentrations than would be possible without the capsid scaffold.

Xenon-based molecular sensors in lipid suspensions

There have been many proposals to use xenon-based molecular sensors in biological settings. Fundamental to understanding the properties of these sensors in vivo is characterizing their behavior in lipid environments. We report the investigation of xenon-based molecular sensors in suspensions of lipid vesicles with a size comparable to cells. We detail spectroscopic properties of sensors associated with lipid vesicles as well as those in equilibrium in the surrounding solution. We characterize the dependence of the spectral parameters on temperature, relevant for studies at physiological temperatures. We also demonstrate the ability to perform selective saturation transfer (Hyper-CEST) between sensor, both lipid bound and unbound, and the bulk solution. Lastly, we demonstrate the applicability of saturation transfer in the heterogeneous medium as an imaging modality.

Band-selective chemical exchange saturation transfer imaging with hyperpolarized xenon-based molecular sensors

Molecular imaging based on saturation transfer in exchanging systems is a tool for amplified and chemically specific magnetic resonance imaging. Xenon-based molecular sensors are a promising category of molecular imaging agents in which chemical exchange of dissolved xenon between its bulk and agent-bound phases has been use to achieve sub-picomolar detection sensitivity. Control over the saturation transfer dynamics, particularly when multiple exchanging resonances are present in the spectra, requires saturation fields of limited bandwidth and is generally accomplished by continuous wave irradiation. We demonstrate instead how band-selective saturation sequences based on multiple pulse inversion elements can yield saturation bandwidth tuneable over a wide range, while depositing less RF power in the sample. We show how these sequences can be used in imaging experiments that require spatial-spectral and multispectral saturation. The results should be applicable to all CEST experiments and, in particular, will provide the spectroscopic control required for applications of arrays of xenon chemical sensors in microfluidic chemical analysis devices.

Characterization of aging and solvent treatments of painted surfaces using single‐sided NMR

Typical experiments conducted with single‐sided NMR are incapable of unique chemical identification and, thus, often rely on comparative measurements in scientific study. However, cultural heritage objects have unique natures and histories, making a genuine ‘control’ sample a rarity and complicating many scientific investigations. In this paper, we present some comparative results enabled by such a rare, control sample. Two paintings, The Dinner and The Dance from the 1616 set Pipenpoyse Wedding, were made by the same artist with indistinguishable materials and techniques. However, despite their shared history, The Dinner has undergone varnishing and subsequent varnish removal multiple times, whereas The Dance has not. NMR measurements on these two paintings show the effect of organic‐solvent‐based treatments on the stiffness of the paintings as measured by T2,eff, supporting visual and tactile observations that The Dinner is stiffer throughout its thickness than The Dance, probably due to ingress of natural resins and organic solvents into the paint and ground layers. In addition to a comparative analysis of these two paintings, initial experiments to compare solvent penetration with different varnish removal methods are described. Model canvas painting samples were treated with solvent in two ways—with free solvent on a swab and with cellulose gel thickened solvent in a tissue. Both treatment methods cause a measurable change in T2,eff; however, the thickened‐solvent method affects a narrower region of the model than does the free solvent. Copyright

Hyperpolarized Xenon-Based Molecular Sensors for Label-Free Detection of analytes

Nuclear magnetic resonance (NMR) can reveal the chemical constituents of a complex mixture without resorting to chemical modification, separation, or other perturbation. Recently, we and others have developed magnetic resonance agents that report on the presence of dilute analytes by proportionately altering the response of a more abundant or easily detected species, a form of amplification. One example of such a sensing medium is xenon gas, which is chemically inert and can be optically hyperpolarized, a process that enhances its NMR signal by up to 5 orders of magnitude. Here, we use a combinatorial synthetic approach to produce xenon magnetic resonance sensors that respond to small molecule analytes. The sensor responds to the ligand by producing a small chemical shift change in the Xe NMR spectrum. We demonstrate this technique for the dye, Rhodamine 6G, for which we have an independent optical assay to verify binding. We thus demonstrate that specific binding of a small molecule can produce a xenon chemical shift change, suggesting a general approach to the production of xenon sensors targeted to small molecule analytes for in vitro assays or molecular imaging in vivo.

Nondestructive investigation of the internal structure of fresco paintings

New methods to measure the internal structure of wall paintings include single-sided nuclear magnetic resonance (NMR) and terahertz time-domain imaging (THz). We report the measurement of eight fresco models prepared with traditional fresco-making techniques in which we observe the structure of the wall paintings and verify the measurement techniques. Experimental results show that the two techniques are complementary; we expect these techniques to help in identification and analysis of historic wall paintings.

Xenon Biosensors for Multi-Purpose Molecular Imaging

Hyperpolarized xenon is an exquisite NMR probe for sensing molecular environments of the noble gas in solution. By trapping it in molecular cages like cryptophane-A, 129Xe can report information about molecular-specific binding events or resolve multiple signals simultaneously from different micro-environments in a lipid emulsion-a macroscopically-homogeneous phase that mimics properties of biological relevance. The Hyper-CEST detection scheme can be used in this context to pair significant signal enhancement with high specificity of xenon NMR resonances. Hyper-CEST can reduce the measurement time by a factor of up to 16 million and is currently able to detect biosensor concentrations as low as 1.4 nM. When combined with highly frequency-selective pulses, it also allows for demonstration of multiplexing potential using a single cage type as contrast agent for different environments in NMR imaging. This molecular imaging approach enables a switchable contrast that includes also temperature-sensitive imaging with molecular sensors that can be functionalized with various targeting molecules to bind, e.g., specifically to receptors of cancer cells.