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WIREs Nanomed Nanobiotechnol
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Virus‐based nanomaterials as positron emission tomography and magnetic resonance contrast agents: from technology development to translational medicine

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Viruses have recently emerged as ideal protein scaffolds for a new class of contrast agents that can be used in medical imaging procedures such as positron emission tomography (PET) and magnetic resonance imaging (MRI). Whereas synthetic nanoparticles are difficult to produce as homogeneous formulations due to the inherently stochastic nature of the synthesis process, virus‐based nanoparticles are genetically encoded and are therefore produced as homogeneous and monodisperse preparations with a high degree of quality control. Because the virus capsids have a defined chemical structure that has evolved to carry cargoes of nucleic acids, they can be modified to carry precisely defined cargoes of contrast agents and can be decorated with spatially defined contrast reagents on the internal or external surfaces. Viral nanoparticles can also be genetically programed or conjugated with targeting ligands to deliver contrast agents to specific cells, and the natural biocompatibility of viruses means that they are cleared rapidly from the body. Nanoparticles based on bacteriophages and plant viruses are safe for use in humans and can be produced inexpensively in large quantities as self‐assembling recombinant proteins. Based on these considerations, a new generation of contrast agents has been developed using bacteriophages and plant viruses as scaffolds to carry positron‐emitting radioisotopes such as [18F] fluorodeoxyglucose for PET imaging and iron oxide or Gd3+ for MRI. Although challenges such as immunogenicity, loading efficiency, and regulatory compliance remain to be address, virus‐based nanoparticles represent a promising new enabling technology for a new generation of highly biocompatible and biodegradable targeted imaging reagents. WIREs Nanomed Nanobiotechnol 2015, 7:708–721. doi: 10.1002/wnan.1335 This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures
Viral nanoparticles provide structural diversity. (a) Icosahedral Cowpea mosaic virus (CPMV) capsid presents residues on both exterior (A) and interior surfaces (B) for chemical conjugation of contrast agents; (b) Genetic engineering enables expression of proteins of interest fused to the coat proteins; (c) shape transformability can be achieved through the top‐down approach using heat or (d) using the bottom‐up approach such as self‐assembly (scale 50 nm).
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Magnetic resonance imaging (MRI) of atherosclerotic plaques using targeted Tobacco mosaic virus. (a) Tobacco mosaic virus (TMV) structure and addressable amino acid residues on interior and exterior surfaces; (b) confocal images of aorta cryo‐sections highlights enhanced localization of VCAM‐targeted TMV (green) in atherosclerotic plaques (scale 250 µm); (c) pre‐ and post‐injection MRI scans of VCAM‐TMV (A) and Gd(DOTA) (B) in ApoE/ mice. (Reprinted with permission from Ref . Copyright American Chemical Society 2014)
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Combining positron emission tomography (PET) imaging with replicating viral vectors. (a) Herpes simplex virus‐1 (HSV‐1) vector infection, replication and transgene expression leading to in situ uptake and generation of PET contrast agent; (b) PET Imaging of melanoma micrometastases in regional lymph nodes with NV1023 HSV‐1 vector in vivo; (c) [18F]‐2′‐fluoro‐5‐ethyl‐1‐[β]‐d‐arabinofuranosyluracil (FEAU)–PET imaging with NV1066 allows detection of cancerous neural invasion in vivo.
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MicroPT‐CT imaging using bacteriophage MS2. (a) Radiotracer [64Cu] is placed at the interior through chelation by 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA), while polyethylene glycol (PEG) forms the outer protective coating; (b) positron emission tomography (PET)‐CT images of mice injected with free 64Cu (A) and 64Cu‐labeled DOTA‐MS2 (B) shows distinct accumulation sites suggesting; (c) comparative biodistribution of free 64Cu, 64Cu‐labeled DOTA‐MS2, and PEGylated 64Cu‐labeled DOTA‐MS2.
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