P22 Viral Capsids as Nanocomposite High-Relaxivity MRI Contrast Agents

Abstract

Attachment of multiple chelated Gd3+ ions to the interior of bacteriophage P22 viral capsids afford nanoscale MRI contrast agents with extremely high relaxivity values. Highly fenestrated ‘wiffleball’ morphology is unique to P22 and assures water exchange between the environment and interior cavity of the capsid. The cavity of P22 ‘wiffleball’ was functionalized with a branched oligomer comprising of multiple DTPA-Gd complexes resulting in an impressive payload of 1,900 Gd3+ ions inside each 64nm capsid. High relaxivities of r1 ionic = 21.7 mM−1 sec−1 and r1 particle = 41,300 mM−1 sec−1 at 298K, 0.65T (28MHz) are reported, with r1/r2 ratio of 0.80 and optimized rotational correlation time for this system. Specific design modifications are suggested for future improvements of viral capsid-based MRI contrast agents directed toward clinical translation.

Manganese(III) porphyrins complexed with P22 virus-like particles as T 1-enhanced contrast agents for magnetic resonance imaging

“…On the basis of the Solomon-Bloembergen-Morgan analytical model for understanding paramagnetic relaxivity [34-39], we expected that the r 1,ionic relaxivity would be enhanced after conjugation of MnPP to the macromolecular P22 capsid [27, 28, 40]. But contrary to expectations, we did not observe an enhancement.…”

“…The Solomon-Bloembergen-Morgan model predicts that the relaxivity is dominated by three important parameters: the number of metal-bound water molecules ( q ), the mean residence lifetime for metal-bound water (s M ), and the rotational correlation time (s R ). We, and others, have effectively used this model to predict and design new contrast agents that optimize these important parameters [17, 27, 41]. Both s R and s M of free MnPP (s R = 50-80 ps, s M = 10 ns) [42] are comparable to those of free gadolinium diethylene-triaminepentaacetic acid (s R = 70 ps, s M = 16 ns) [27].…”

“…P22 (S39C) procapsid, made up of 420 subunits, was produced by a heterologous expression system in E. coli. and purified by a previously described procedure [27]. The resulting virus pellet, after purification, was resuspended in 100 mM sodium phosphate, 50 mM NaCl, pH 7.0, and spun at 17,000 rpm for 20 min to remove particulates and lipid.…”

“…In those studies, organic polymers were synthesized in the confined environment of the interior cavity of P22 VLPs either by a series of azide-alkyne “click” reactions [27] or by atom-transfer radical polymerization [28], and were used as a scaffold to conjugate imaging molecules via a reactive functional group on the polymer. This resulted in a significant increase in loading capacity of the cargo by taking full advantage of the capsid volume.…”

Understanding the enormous diversity of bacteriophages: The tailed phages that infect the bacterial family Enterobacteriaceae

“…In addition, phage virions and related particles are being developed as nanocontainers for specific chemical cargoes that can be delivered to specific targets ( e.g. , Nam et al , 2006; Lee et al , 2009; Shen et al , 2010; Cardinale et al , 2012; Hyman, 2012; Culpepper et al , 2013; Farkas et al , 2013; Farr et al , 2013; Kale et al , 2013; Qazi et al , 2013). …”