Implementation of P22 Viral Capsids As Intravascular Magnetic Resonance T₁ Contrast Conjugates via Site-Selective Attachment of Gd(III)-Chelating Agents

Abstract

P22 viral capsids and ferritin protein cages are utilized as templating macromolecules to conjugate Gd(III)-chelating agent complexes, and we systematically investigates the effects of the macromolecules' size and the conjugation positions of Gd(III)-chelating agents on the magnetic resonance (MR) relaxivities and the resulting image contrasts. The relaxivity values of the Gd(III)-chelating agent-conjugated P22 viral capsids (outer diameter: 64 nm) are dramatically increased as compared to both free Gd(III)-chelating agents and Gd(III)-chelating agent-conjugated ferritins (outer diameter: 12 nm), suggesting that the large sized P22 viral capsids exhibit a much slower tumbling rate, which results in a faster T1 relaxation rate. Gd(III)-chelating agents are attached to either the interior or exterior surface of P22 viral capsids and the conjugation positions of Gd(III)-chelating agents, however, do not have a significant effect on the relaxivity values of the macromolecular conjugates. The contrast enhancement of Gd(III)-chelating agent-conjugated P22 viral capsids is confirmed by in vitro phantom imaging at a short repetition times (TR) and the potential usage of Gd(III)-chelating agent-conjugated P22 viral capsids for in vivo MR imaging is validated by visualizing a mouse's intravascular system, including the carotid, mammary arteries, the jugular vein, and the superficial vessels of the head at an isotropic resolution of 250 μm.

High Relaxivity Gd(III)–DNA Gold Nanostars: Investigation of Shape Effects on Proton Relaxation

“…Similarly high values of r 1 are observed for Gd(III) conjugated to viral capsids, non-covalently bound to human serum albumin (MS-325), or entrapped in apoferritin. 15,48,49 …”

“…Many recent examples of nanoconjugate CAs appear to support this hypothesis, though in many cases we find that it is not described explicitly. 15,19,48,49 …”

“…In particular, for CAs that bear extended hydrophilic polymer or protein surfaces, the chemical environment surrounding the lanthanide center is believed to slow water diffusion in the second-sphere of the Gd(III) complexes. 15,19,37,48,49 The result of this hydrogen-bonding-rich environment is that each metal center has incrementally longer contact with second-sphere water molecules. In extensive work to study the effects of second-sphere relaxivity ( r 1 SS ), chelates of Gd(III) were synthesized using pendant phosphate groups.…”

Use of the confined spaces of apo-ferritin and virus capsids as nanoreactors for catalytic reactions

“…For example, the icosahedral cowpea chlorotic mottle virus (CCMV) viruses which have a 28-nm outer diameter and an 18-nm interior diameter were used to prepare highly monodisperse Prussian blue nanoparticles with an average diameter of 18 AE 1.7 nm [43]. Similarly, P22 capsids are functionalized with Gd(III) chelates for studying magnetic resonance (MR) relaxivities [44].…”

Ultrafast 3D spin-echo acquisition improves Gadolinium-enhanced MRI signal contrast enhancement

“…The sensitivity of gradient-echo readouts to susceptibility weighting is especially problematic for volumetric contrast-enhanced (CE) MRI with positive contrast agent, where non-negligible T 2 * effect of contrast agent tends to compromise the positive signal contrast and limits the range of MR acquisition parameters and injection doses for CE-MRI applications131415. As a result, there are a large number of investigations on the development of novel positive contrast agent, focused in increasing the in vivo r 1 / r 2 * ratio to minimize susceptibility-induced decays, while maximizing positive signal enhancements16171819. However, only limited number of positive contrast agents is being clinically approved.…”