Magnetic Resonance Contrast Agents from Viral Capsid Shells:  A Comparison of Exterior and Interior Cargo Strategies

Abstract

Two high-relaxivity nanoscale magnetic resonance contrast agents have been built using bacteriophage MS2 as a biomolecular scaffold. Protein capsid shells were functionalized on either the exterior or interior surface to display multiple copies of an aldehyde functional group. Subsequently, approximately 90 heteropodal bis(hydroxypyridonate)terephthalamide ligands were attached to these sites through oxime condensation reactions. Upon complexation with Gd3+, contrast agents with ionic relaxivities of up to 41.6 mM-1 s-1 (30 MHz, 25 degrees C) and total molecular relaxivities of up to 3900 mM-1 s-1 (30 MHz, 25 degrees C) were produced. Capsids sequestering the Gd-chelates on the interior surface (attached through tyrosine residues) not only provided higher relaxivities than their exterior functionalized counterparts (which relied on lysine modification) but also exhibited improved water solubility and capsid stability. The attachment functional cargo to the interior surface is envisioned to minimize its influences on biodistribution, yielding significant advantages for tissue targeting by additional groups attached to the capsid exterior.

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

“…[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). The diameter of this nanosized assembly is 27.4 nm, and its surfaces can be modified through lysine, cysteine or through tyrosine molecules (one per monomer on the interior surface).…”

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

“…The internal conjugates also have greater solubility than the external conjugates, and hence present the advantage of attaching solubilizing and targeting groups to the exterior. 25 The τ R value for Gd-TREN-bis-HOPO-TAM-CO 2 H has been reported as 94 ps at 298 K ( Table 2). 30 The local reorientation correlation times (τ Rl ) can be compared to the τ R value for the small molecule complex and is 3 to 4 times slower for the conjugates (310 ps for the external and 440 ps for the internal conjugates).…”

The True Story and Advantages of RNA Phage Capsids as Nanotools

“…The RNA phage VLP-based applications that have been developed as imaging technologies are compiled in table 4. The first studies on the generation of nanoparticles for magnetic resonance imaging applications and the first comparisons of interior versus exterior cargo strategies appeared in the mid 2000s [271,272]. Following these reports, MS2 VLPs were loaded with positron emission tomography radiolabels [273].…”