Viral MRI contrast agents: coordination of Gd by native virions and attachment of Gd complexes by azide–alkyne cycloaddition

Prasuhn, Duane E.; Yeh, Robert M.; Obenaus, André; Manchester, Marianne; Finn, M. G.

doi:10.1039/b615084e

Cited by 195 publications

(214 citation statements)

References 36 publications

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“…These conjugates exhibited similar relaxivities (11-15 mM -1 s -1 per complex at 64 MHz). 20 These examples demonstrate that viral capsids offer significant potential for building nanometer scale contrast agents with very high overall relaxivities. They also indicate that a balance must be struck between the high relaxivity of weakly bound Gd 3+ and the need for strong chelators that reduce toxicity at the expense of available water exchange sites.…”

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confidence: 96%

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents¹

et al. 2008

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High relaxivity macromolecular contrast agents based on the conjugation of gadolinium chelates to the interior and exterior surfaces of MS2 viral capsids are assessed. The proton nuclear magnetic relaxation dispersion (NMRD) profiles of the conjugates show up to a five-fold increase in relaxivity, leading to a peak relaxivity (per Gd 3+ ion) of 41.6 mM -1 s -1 at 30 MHz for the internally modified capsids. Modification of the exterior was achieved through conjugation to flexible lysines, while internal modification was accomplished by conjugation to relatively rigid tyrosines. Higher relaxivities were obtained for the internally modified capsids, showing that (i) there is facile diffusion of water to the interior of capsids and (ii) the rigidity of the linker attaching the complex to the macromolecule is important for obtaining high relaxivity enhancements. The viral capsid conjugated gadolinium hydroxypyridonate complexes appear to possess two inner-sphere water molecules (q = 2) and the NMRD fittings highlight the differences in the local motion for the internal (τ Rl = 440 ps) and external (τ Rl = 310 ps) conjugates. These results indicate that there are significant advantages of using the internal surface of the capsids for contrast agent attachment, leaving the exterior surface available for the installation of tissue targeting groups. MANUSCRIPT TEXTMagnetic resonance imaging (MRI) is a routinely used noninvasive diagnostic technique, providing detailed images without the use of ionizing radiation. Although the resolution of MRI is excellent, its dynamic range is relatively narrow because of the limited variation in relaxation rates exhibited by water protons in vivo. When these differences are insufficient to distinguish between adjacent tissues, contrast enhancement is often achieved through the administration of synthetic agents that increase the water proton relaxation rates in accessible locations. Gadolinium complexes are the most often used for this purpose, with more than 10 million MRI studies being performed through their use each year. [2][3][4] The current commercially available Gd(III)-based contrast agents use poly(aminocarboxylate) chelates, and typically gram quantities of Gd must be injected to reach concentrations sufficient for usable contrast enhancement. However, this strategy is more difficult to apply to the specific imaging of biomarkers present in low (μM -nM) concentrations. To distinguish these sites from the background signal, targetable contrast agents will undoubtedly require significantly improved contrast enhancement efficiencies. 3,5 2 MRI contrast agents are commonly evaluated on the basis of relaxivity (r 1p ), which describes their ability to increase the longitudinal relaxation rate of nearby water molecule protons per millimolar concentration of agent applied. 6 Strategies for enhancing the relaxivity of contrast agents include increasing the number of bound water molecules (q), optimizing the water-residence time (τ M ) and increasing the rotational correlati...

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confidence: 96%

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents¹

et al. 2008

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“…[92] Virus capsids have recently been explored as potential scaffolds for attachment of Gd-chelates. [73,77,81,93] Covalent attachment of TREN-bis-HOPO-TAM-based chelates onto bacteriophage MS2 capsids (90 chelates per capsid) has led to one of the highest relaxivities yet reported for these systems (Figure 12). [94] The capsid shell consists of 180 copies of the coat protein (relative molecular mass (M r ) 13,700) assembled into an icosahedral arrangement ( Figure 12).…”

Section: Attachment To Dendrimers and Virus Capsidsmentioning

confidence: 99%

“…The attachment of current commercially available contrast agents such as [Gd (DOTA)] 2-and [Gd(DTPA)] 2-to macromolecular constructs has been extensively studied, and in several cases, enhancements have been observed upon slowing of molecular rotation. [71][72][73][74][75][76][77][78][79] These contrast agents, however, are somewhat restricted because they do not have the optimal water-exchange rates that would lead to large enhancements in relaxivity. The major advantage of these aminocarboxylate-based contrast agents is their high watersolubility.…”

Section: Increasing Rotational Correlation Times Through Macromoleculmentioning

confidence: 99%

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

et al. 2008

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“…Here we report the plasma clearance kinetics and biodistribution of CPMV following intravenous administration. CPMV particles were decorated with a gadolinium chelate, or, alternatively, Gd +3 and Tb +3 ions were complexed directly to the capsid by association to the nucleoprotein [45]. Clearance and biodistribution analyses of CPMV particles were performed by measuring the presence of the Gd and Tb metals in plasma and in tissue homogenates using inductively coupled plasma-optical emission spectrometry (ICP-OES).…”

Section: Introductionmentioning

confidence: 99%

“…6. Plasma pharmacokinetics and bio-distribution of CPMV-CPMV particles were either labeled with Gd +3 or Tb +3 ions by binding to nucleoprotein sites on the interior of the particle or by covalent attachment of a Gd(DOTA) derivative to the external surface of the capsid by the CuAAC reaction [45]. The former was accomplished by mixing a solution of 50 mM GdCl 3 or TbCl 3 in HEPES buffer containing 30 mM EDTA with a 5 mg/mL solution of CPMV in buffer.…”

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confidence: 99%

Bio-distribution, toxicity and pathology of cowpea mosaic virus nanoparticles in vivo

Singh

Prasuhn

Yeh

et al. 2007

Journal of Controlled Release

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Virus-based nanoparticles (VNPs) from a variety of sources are being developed for biomedical and nanotechnology applications that include tissue targeting and drug delivery. However, the fate of most of those particles in vivo has not been investigated. Cowpea mosaic virus (CPMV), a plant comovirus, has been found to be amenable to the attachment of a variety of molecules to its coat protein, as well as to modification of the coat protein sequence by genetic means. We report here the results of studies of the bio-distribution, toxicology, and pathology of CPMV in mice. Plasma clearance and tissue biodistribution were measured using CPMV particles derivatized with lanthanide metal complexes. CPMV particles were cleared rapidly from plasma, falling to undetectable levels within 20 minutes. By 30 minutes the majority of the injected VNPs were trapped in the liver and to a lesser extent the spleen with undetectable amounts in other tissues. At doses of 1 mg, 10 mg and 100 mg per kg body weight, no toxicity was noted and the mice appeared to be normal. Hematology was essentially normal, although with the highest dose examined, the mice were somewhat leukopenic with relative decreases in both neutrophils and lymphocytes. Histological examination of spleen showed cellular infiltration, which upon flow cytometry analyses revealed elevated B lymphocytes on the first day following virus administration that subsequently subsided. Microscopic evaluation of various other tissues revealed a lack of apparent tissue degeneration or necrosis. Overall, CPMV appears to be a safe and non-toxic platform for in vivo biomedical applications.

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Viral MRI contrast agents: coordination of Gd by native virions and attachment of Gd complexes by azide–alkyne cycloaddition

Abstract: Icosahedral virus particles decorated with a Gd(DOTA) analogue by Cu-mediated azide-alkyne cycloaddition (CuAAC) and/or with Gd(3+) ions by coordination to the viral nucleoprotein show increased T(1) relaxivity relative to free Gd(DOTA) complexes in solution.

Cited by 195 publications

References 36 publications

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents¹

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents¹

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

Bio-distribution, toxicity and pathology of cowpea mosaic virus nanoparticles in vivo

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Viral MRI contrast agents: coordination of Gd by native virions and attachment of Gd complexes by azide–alkyne cycloaddition

Abstract: Icosahedral virus particles decorated with a Gd(DOTA) analogue by Cu-mediated azide-alkyne cycloaddition (CuAAC) and/or with Gd(3+) ions by coordination to the viral nucleoprotein show increased T(1) relaxivity relative to free Gd(DOTA) complexes in solution.

Cited by 195 publications

References 36 publications

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents1

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents1

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

Bio-distribution, toxicity and pathology of cowpea mosaic virus nanoparticles in vivo

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High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents¹

High Relaxivity Gadolinium Hydroxypyridonate−Viral Capsid Conjugates: Nanosized MRI Contrast Agents¹