In vivo detection of cucurbit[6]uril, a hyperpolarized xenon contrast agent for a xenon magnetic resonance imaging biosensor

Hane, Francis; Li, Tao; Smylie, Peter; Pellizzari, Raiili M.; Plata, Jennifer A.; DeBoef, Brenton; Albert, Mitchell S.

doi:10.1038/srep41027

Cited by 58 publications

(87 citation statements)

References 39 publications

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“…Hyperpolarized 129 Xe-MRI is an active area of molecular imaging research, which is currently mainly performed in vitro with pure contrast agents or labeled cells 18 , 19 , while in vivo techniques are being developed 12 , 13 . This protocol describes the imaging of GVs using hyperpolarized 129 Xe MRI in vitro , as previously done with purified GVs, GV-expressing cells and GV-labeled cells 11 .…”

Section: Experimental Designmentioning

confidence: 99%

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Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI

et al. 2017

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Gas vesicles are a unique class of gas-filled protein nanostructures whose physical properties allow them to serve as highly sensitive imaging agents for ultrasound and magnetic resonance imaging (MRI), detectable at sub-nanomolar concentrations. Here we provide a protocol for isolating gas vesicles from native and heterologous host organisms, functionalizing these nanostructures with moieties for targeting and fluorescence, characterizing their biophysical properties and imaging them using ultrasound and magnetic resonance imaging. Gas vesicles can be isolated from natural cyanobacterial and haloarchaeal host organisms or from E. coli expressing a heterologous gas vesicle gene cluster, and purified using buoyancy-assisted techniques. They can then be modified by replacing surface-bound proteins with engineered, heterologously expressed variants, or through chemical conjugation, resulting in altered mechanical, surface and targeting properties. Pressurized absorbance spectroscopy is used to characterize their mechanical properties, while dynamic light scattering and transmission electron microscopy are used to determine nanoparticle size and morphology, respectively. Gas vesicles can then be imaged with ultrasound in vitro and in vivo using pulse sequences optimized for their detection versus background. They can also be imaged with hyperpolarized xenon MRI using chemical exchange saturation transfer between gas vesicle-bound and dissolved xenon – a technique currently implemented in vitro. Taking 3–8 days to prepare, these genetically encodable nanostructures enable multi-modal, noninvasive biological imaging with high sensitivity and potential for molecular targeting.

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Section: Experimental Designmentioning

confidence: 99%

“…In addition, the distinct chemical shifts of GVs in different microbial species enable multiplexed imaging. HyperCEST is currently performed in vitro , but is advancing toward in vivo use 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI

et al. 2017

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“…The self‐assembling micelle approach with a core of multiple hosts that are accessible for Xe but shielded from other interactions is very promising compared to the administration of individual, bare Xe hosts that have several shortcomings: examples such as cucurbit[6]uril (CB6) are problematic since they are accessible for competitive guests and are difficult to functionalize. Thus, they currently require unrealistic high (mM) concentrations for in vivo applications 26…”

Section: Hydrodynamic Diameter Of P‐cra‐a2 and P2a2 And Their Fluoresmentioning

confidence: 99%

Functionalized Lipopeptide Micelles as Highly Efficient NMR Depolarization Seed Points for Targeted Cell Labelling in Xenon MRI

et al. 2020

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Improving diagnostic imaging and therapy by targeted compound delivery to pathological areas and across biological barriers is of urgent need. A lipopeptide, P‐CrA‐A2, composed of a highly cationic peptide sequence (A2), an N‐terminally attached palmitoyl chain (P) and cryptophane molecule (CrA) for preferred uptake into blood–brain barrier (BBB) capillary endothelial cells, was generated. CrA allows reversible binding of Xe for NMR detection with hyperpolarized nuclei. The lipopeptide forms size‐optimized micelles with a diameter of about 11 nm at low micromolar concentration. Their high local CrA payload has a strong and switchable impact on the bulk magnetization through Hyper‐CEST detection. Covalent fixation of CrA does not impede micelle formation and does not hamper its host functionality but simplifies Xe access to hosts for inducing saturation transfer. Xe Hyper‐CEST magnetic resonance imaging (MRI) allows for distinguishing BBB endothelial cells from control aortic endothelial cells, and the small micelle volume with a sevenfold improved CrA‐loading density compared to liposomal carriers allows preferred cell labelling with a minimally invasive volume (≈16 000‐fold more efficient than 19F cell labelling). Thus, these nanoscopic particles combine selectivity for human brain capillary endothelial cells with great sensitivity of Xe Hyper‐CEST MRI and might be a potential MRI tool in brain diagnostics.

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“…Prominent examples for imaging applications are based on cryptophane-A (CrA) [10][11][12] or cucurbit [6,7]uril (CB6,7). [13][14][15] (Hyper-)CEST efficiency scales with the concentration of bound nuclei, [B] (Figure 1). …”

mentioning

confidence: 99%

Protein Nanostructures Produce Self-Adjusting Hyperpolarized Magnetic Resonance Imaging Contrast through Physical Gas Partitioning

Kunth

Witte

et al. 2018

ACS Nano

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Signal amplification strategies are critical for overcoming the intrinsically poor sensitivity of nuclear magnetic resonance (NMR) reporters in noninvasive molecular detection. A mechanism widely used for signal enhancement is chemical exchange saturation transfer (CEST) of nuclei between a dilute sensing pool and an abundant detection pool. However, the dependence of CEST amplification on the relative size of these spin pools confounds quantitative molecular detection with a larger detection pool typically making saturation transfer less efficient. Here we show that a recently discovered class of genetically encoded nanoscale reporters for 129 Xe magnetic resonance overcomes this fundamental limitation through an elastic binding capacity for NMR-active nuclei. This approach pairs high signal amplification from hyperpolarized spins with ideal, self-adjusting saturation transfer behavior as the overall spin ensemble changes in size. These reporters are based on gas vesicles, i.e., microbe-derived, gas-filled protein nanostructures. We show that the xenon fraction that partitions into gas vesicles follows the ideal gas law, allowing the signal transfer under hyperpolarized xenon chemical exchange saturation transfer (Hyper-CEST) imaging to scale linearly with the total xenon ensemble. This conceptually distinct elastic response allows the production of quantitative signal contrast that is robust to variability in the concentration of xenon, enabling virtually unlimited improvement in absolute contrast with increased xenon delivery, and establishing a unique principle of operation for contrast agent development in emerging biochemical and in vivo applications of hyperpolarized NMR and magnetic resonance imaging.

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In vivo detection of cucurbit[6]uril, a hyperpolarized xenon contrast agent for a xenon magnetic resonance imaging biosensor

Cited by 58 publications

References 39 publications

Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI

Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI

Functionalized Lipopeptide Micelles as Highly Efficient NMR Depolarization Seed Points for Targeted Cell Labelling in Xenon MRI

Protein Nanostructures Produce Self-Adjusting Hyperpolarized Magnetic Resonance Imaging Contrast through Physical Gas Partitioning

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