Recombinantly expressed gas vesicles as nanoscale contrast agents for ultrasound and hyperpolarized MRI

Farhadi, Arash; Ho, Gabrielle H.; Kunth, Martin; Ling, Bill; Lakshmanan, Anupama; Lu, George J.; Bourdeau, Raymond W.; Schröder, Leif; Shapiro, Mikhail G.

doi:10.1002/aic.16138

Cited by 41 publications

(46 citation statements)

References 34 publications

(63 reference statements)

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“…GVs comprise 2 nm-thick protein shells enclosing hollow, gas-filled compartments with dimensions on the order of 200 nm, varying in their exact size and shape based on which bacteria they come from. 25 GVs have previously been developed as contrast agents for ultrasound [22][23][24]26 and susceptibility-based 1 H-NMR/MRI. 24 They can be engineered at the genetic level to alter their surface and targeting properties, 21 and can be expressed heterologously as genetically encoded reporters.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…2C). The 9 genes originate from an eleven-gene B. megaterium gene cluster previously used to express gas vesicles in E. coli (13,18), with the exception of GvpR and GvpT, which were found to be unnecessary for gas vesicle formation ( Supplementary Fig. 2).…”

Section: Identifying Mammalian Acoustic Reporter Genesmentioning

confidence: 99%

Ultrasound imaging of gene expression in mammalian cells

Farhadi

Sawyer

et al. 2019

Science

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The study of cellular processes occurring inside intact organisms requires methods to visualize cellular functions such as gene expression in deep tissues. Ultrasound is a widely used biomedical technology enabling noninvasive imaging with high spatial and temporal resolution. However, no genetically encoded molecular reporters are available to connect ultrasound contrast to gene expression in mammalian cells. To address this limitation, we introduce mammalian acoustic reporter genes. Starting with a gene cluster derived from bacteria, we engineered a eukaryotic genetic program whose introduction into mammalian cells results in the expression of intracellular air-filled protein nanostructures called gas vesicles, which produce ultrasound contrast. Mammalian acoustic reporter genes allow cells to be visualized at volumetric densities below 0.5% and permit high-resolution imaging of gene expression in living animals.

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“…This limits the usefulness of contrast agents when imaging vascular structures, as the microbubbles are unable to pass through the endothelium [80]. Ultrasound and MRI are capable of visualizing deep tissues within animal models and for human applications, but have few molecular reporters compared to optical imaging [82][83][84].…”

Section: Gas Vesicles As Contrast Agentsmentioning

confidence: 99%

Microbial gas vesicles as nanotechnology tools: exploiting intracellular organelles for translational utility in biotechnology, medicine and the environment

Hill

Salmond

2020

Microbiology

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A range of bacteria and archaea produce gas vesicles as a means to facilitate flotation. These gas vesicles have been purified from a number of species and their applications in biotechnology and medicine are reviewed here. Halobacterium sp. NRC-1 gas vesicles have been engineered to display antigens from eukaryotic, bacterial and viral pathogens. The ability of these recombinant nanoparticles to generate an immune response has been quantified both in vitro and in vivo. These gas vesicles, along with those purified from Anabaena flos-aquae and Bacillus megaterium , have been developed as an acoustic reporter system. This system utilizes the ability of gas vesicles to retain gas within a stable, rigid structure to produce contrast upon exposure to ultrasound. The susceptibility of gas vesicles to collapse when exposed to excess pressure has also been proposed as a biocontrol mechanism to disperse cyanobacterial blooms, providing an environmental function for these structures.

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Recombinantly expressed gas vesicles as nanoscale contrast agents for ultrasound and hyperpolarized MRI

Cited by 41 publications

References 34 publications

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

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

Ultrasound imaging of gene expression in mammalian cells

Microbial gas vesicles as nanotechnology tools: exploiting intracellular organelles for translational utility in biotechnology, medicine and the environment

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