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

Abstract

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.

Coupling Chlorin e6 to the surface of Nanoscale Gas Vesicles strongly enhances their intracellular delivery and photodynamic killing of cancer cells

“…They are composed of two dominant protein subunits termed gas vesicle protein A (GvpA) and gas vesicle protein C (GvpC) 6 . Due to the presence of their air-filled internal core, GVs can respond to ultrasound waves and produce hyperpolarized magnetic resonance contrast for imaging 7,8 . Moreover, as a genetically encoded nanostructure new ligands can be introduced into the surface gvpC protein through genetic recombinant approaches 9 .…”

Molecular Sensing with Host Systems for Hyperpolarized 129Xe

“…Cryptophanes with their tailored cavity sizes have thus been used in many sensor designs as starting material for coupling with binding motifs for different biological targets [ 15 , 127 , 128 , 129 , 130 , 131 ]. Further development of the HyperCEST approach, however, showed that there are other hosts with better Xe exchange dynamics [ 123 , 124 , 132 , 133 ].…”

Acoustically Detonated Biomolecules for Genetically Encodable Inertial Cavitation

“…In nature, photosynthetic bacteria and archaea produce intracellular GVs as a means to achieve cellular buoyancy 18 . Recently it was discovered that GVs' gas-filled interiors allow them to serve as contrast agents for high-frequency diagnostic ultrasound and MRI 13,14,16,[19][20][21][22] . In addition, it was shown that engineered multi-gene clusters encoding GVs can be heterologously expressed in Escherichia coli and Salmonella typhimurium, two frequently used bacterial chasses for the development of cellbased diagnostic and therapeutic agents 15 .…”