Gadolinium-Loaded Viral Capsids as Magnetic Resonance Imaging Contrast Agents

Usselman, Robert J.; Qazi, Shefah; Aggarwal, Priyanka; Eaton, Gareth R.; Russek, Stephen E.; Douglas, Trevor

doi:10.1007/s00723-014-0639-y

Cited by 20 publications

(24 citation statements)

References 26 publications

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“…Macromolecule (such as protein)-based contrast agents are known to yield significantly higher r 1 relaxivity due to decreased local motion and increased correlation time 28 29 30 ; however in vivo applicable positive contrast agents, which maintain considerably enhanced r 1 relaxivity (>10 mM −1 s −1 ) with an acceptable r 1 / r 2 ratio (0.5 ~ 1) at high magnetic field (7 T), are a rarity 8 31 32 33 34 .…”

mentioning

confidence: 99%

“…The structural robustness and functional plasticity of AaLS make it an attractive candidate for a versatile bio- and nanotechnological platform 37 38 39 40 41 42 43 44 . Its hollow spherical architectures have been used as templates for the encapsulation of functional proteins 37 43 44 45 46 and the biomimetic synthesis of iron oxides 44 , as well as delivery vehicles of therapeutic and/or diagnostic reagents 32 34 . AaLS has also been engineered into multifunctional building blocks for fabricating uniform layer-by-layer (LbL) assemblies using non-covalent interactions between surface-displayed hexahistidine and Ni-NTA of AaLS 39 .…”

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confidence: 99%

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Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI

Song

Kang

Jung

et al. 2015

Sci Rep

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With the applications of magnetic resonance imaging (MRI) at higher magnetic fields increasing, there is demand for MRI contrast agents with improved relaxivity at higher magnetic fields. Macromolecule-based contrast agents, such as protein-based ones, are known to yield significantly higher r1 relaxivity at low fields, but tend to lose this merit when used as T1 contrast agents (r1/r2 = 0.5 ~ 1), with their r1 decreasing and r2 increasing as magnetic field strength increases. Here, we developed and characterized an in vivo applicable magnetic resonance (MR) positive contrast agent by conjugating Gd(III)-chelating agent complexes to lumazine synthase isolated from Aquifex aeolicus (AaLS). The r1 relaxivity of Gd(III)-DOTA-AaLS-R108C was 16.49 mM−1s−1 and its r1/r2 ratio was 0.52 at the magnetic field strength of 7 T. The results of 3D MR angiography demonstrated the feasibility of vasculature imaging within 2 h of intravenous injection of the agent and a significant reduction in T1 values were observed in the tumor region 7 h post-injection in the SCC-7 flank tumor model. Our findings suggest that Gd(III)-DOTA-AaLS-R108C could serve as a potential theranostic nanoplatform at high magnetic field strength.

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confidence: 99%

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confidence: 99%

Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI

Song

Kang

Jung

et al. 2015

Sci Rep

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“…It is noted from Table 6 that the estimated relaxation times are approximately three orders of magnitude smaller than the simulated estimate of 0.1 ns performed by Rast et al [ 12 ]. A reason for the discrepancy is most likely due to the high solution concentration effects enhancing the dipole-dipole interactions and as a result significantly decreasing the electronic relaxation times [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

Thermal Excitation of Gadolinium-Based Contrast Agents Using Spin Resonance

2016

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Theoretical and experimental investigations into the thermal excitation of liquid paramagnetic contrast agents using the spin resonance relaxation mechanism are presented. The electronic spin-lattice relaxation time τ1e of gadolinium-based contrast agents, which is estimated at 0.1 ns, is ten orders of magnitude faster than the relaxation time of protons in water. The shorter relaxation time is found to significantly increase the rate of thermal energy deposition. To the authors’ knowledge this is the first study of gadolinium based contrast agents in a liquid state used as thermal agents. Analysis shows that when τ1e and other experimental parameters are optimally selected, a maximum theoretical heating rate of 29.4 °C.s−1 could be achieved which would suffice for clinical thermal ablation of neoplasms. The experimental results show a statistically significant thermal response for two out of the four contrast agents tested. The results are compared to the simulated estimates via analysis of a detailed model of the system. While these experimentally determined temperature rises are small and thus of no clinical utility, their presence supports the theoretical analysis and strongly suggests that the chemical structure of the selected compounds plays an important role in this mechanism of heat deposition. There exists an opportunity for the development of alternative gadolinium-based compounds with an order of magnitude longer τ1e in a diluted form to be used as an efficient hyperthermia agent for clinical use.

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“…Many viral systems have been engineered for biotechnology applications. For example, it has been demonstrated that CCMV and P22 can be modified to act as contrast agents for magnetic resonance imaging [44,45]. P22 has been further engineered to encapsulate a variety of exogenous proteins, including other viral proteins as a vaccine strategy [46][47][48][49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Removing the Polyanionic Cargo Requirement for Assembly of Alphavirus Core-Like Particles to Make an Empty Alphavirus Core

Button

Mukhopadhyay

2020

Viruses

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The assembly of alphavirus nucleocapsid cores requires electrostatic interactions between the positively charged N-terminus of the capsid protein (CP) and the encapsidated polyanionic cargo. This system differs from many other viruses that can self-assemble particles in the absence of cargo, or form “empty” particles. We hypothesized that the introduction of a mutant, anionic CP could replace the need for charged cargo during assembly. In this work, we produced a CP mutant, Minus 38 (M38), where all N-terminal charged residues are negatively-charged. When wild-type (WT) and M38 CPs were mixed, they assembled into core-like particles (CLPs). These “empty” particles were of similar size and morphology to WT CLPs assembled with DNA cargo, but did not contain nucleic acid. When DNA cargo was added to the assembly mixture, the amount of M38 CP that was assembled into CLPs decreased, but was not fully excluded from the CLPs, suggesting that M38 competes with DNA to interact with WT CPs. The composition of CLPs can be tuned by altering the order of addition of M38 CP, WT CP, and DNA cargo. The ability to produce alphavirus CLPs that contain a range of amounts of encapsidated cargo, including none, introduces a new platform for packaging cargo for delivery or imaging purposes.

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Gadolinium-Loaded Viral Capsids as Magnetic Resonance Imaging Contrast Agents

Cited by 20 publications

References 26 publications

Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI

Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI

Thermal Excitation of Gadolinium-Based Contrast Agents Using Spin Resonance

Removing the Polyanionic Cargo Requirement for Assembly of Alphavirus Core-Like Particles to Make an Empty Alphavirus Core

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