Distance-dependent magnetic resonance tuning as a versatile MRI sensing platform for biological targets.

Nanoscale distance-dependent phenomena, such as Förster resonance energy transfer, are important interactions for use in sensing and imaging, but their versatility for bioimaging can be limited by undesirable photon interactions with the surrounding biological matrix, especially in in vivo systems. Here, we report a new type of magnetism-based nanoscale distance-dependent phenomenon that can quantitatively and reversibly sense and image intra-/intermolecular interactions of biologically important targets. We introduce distance-dependent magnetic resonance tuning (MRET), which occurs between a paramagnetic 'enhancer' and a superparamagnetic 'quencher', where the T1 magnetic resonance imaging (MRI) signal is tuned ON or OFF depending on the separation distance between the quencher and the enhancer. With MRET, we demonstrate the principle of an MRI-based ruler for nanometre-scale distance measurement and the successful detection of both molecular interactions (for example, cleavage, binding, folding and unfolding) and biological targets in in vitro and in vivo systems. MRET can serve as a novel sensing principle to augment the exploration of a wide range of biological systems.

(129)Xe NMR Relaxation-Based Macromolecular Sensing.

We report a (129)Xe NMR relaxation-based sensing approach that exploits changes in the bulk xenon relaxation rate induced by slowed tumbling of a cryptophane-based sensor upon target binding. The amplification afforded by detection of the bulk dissolved xenon allows sensitive detection of targets. The sensor comprises a xenon-binding cryptophane cage, a target interaction element, and a metal chelating agent. Xenon associated with the target-bound cryptophane cage is rapidly relaxed and then detected after exchange with the bulk. Here we show that large macromolecular targets increase the rotational correlation time of xenon, increasing its relaxation rate. Upon binding of a biotin-containing sensor to avidin at 1.5 µM concentration, the free xenon T2 is reduced by a factor of 4.

Nondisruptive Dissolution of Hyperpolarized (129)Xe into Viscous Aqueous and Organic Liquid Crystalline Environments.

Studies of hyperpolarized xenon-129 (hp-(129)Xe) in media such as liquid crystals and cell suspensions are in demand for applications ranging from biomedical imaging to materials engineering but have been hindered by the inability to bubble Xe through the desired media as a result of viscosity or perturbations caused by bubbles. Herein a device is reported that can be reliably used to dissolve hp-(129)Xe into viscous aqueous and organic samples without bubbling. This method is robust, requires small sample volumes (<60 µL), is compatible with existing NMR hardware, and is made from readily available materials. Experiments show that Xe can be introduced into viscous and aligned media without disrupting molecular order. We detected dissolved xenon in an aqueous liquid crystal that is disrupted by the shear forces of bubbling, and we observed liquid-crystal phase transitions in (MBBA). This tool allows an entirely new class of samples to be investigated by hyperpolarized-gas NMR spectroscopy.

Investigation of DOTA-Metal Chelation Effects on the Chemical Shift of (129) Xe.

Recent work has shown that xenon chemical shifts in cryptophane-cage sensors are affected when tethered chelators bind to metals. Here, we explore the xenon shifts in response to a wide range of metal ions binding to diastereomeric forms of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) linked to cryptophane-A. The shifts induced by the binding of Ca(2+) , Cu(2+) , Ce(3+) , Zn(2+) , Cd(2+) , Ni(2+) , Co(2+) , Cr(2+) , Fe(3+) , and Hg(2+) are distinct. In addition, the different responses of the diastereomers for the same metal ion indicate that shifts are affected by partial folding with a correlation between the expected coordination number of the metal in the DOTA complex and the chemical shift of (129) Xe. These sensors may be used to detect and quantify many important metal ions, and a better understanding of the basis for the induced shifts could enhance future designs.