Silica-coated Gd(DOTA)-loaded protein nanoparticles enable magnetic resonance imaging of macrophages

Abstract

The molecular imaging of in vivo targets allows non-invasive disease diagnosis. Nanoparticles offer a promising platform for molecular imaging because they can deliver large payloads of imaging reagents to the site of disease. Magnetic resonance imaging (MRI) is often preferred for clinical diagnosis because it uses non-ionizing radiation and offers both high spatial resolution and excellent penetration. We have explored the use of plant viruses as the basis of for MRI contrast reagents, specifically Tobacco mosaic virus (TMV), which can assemble to form either stiff rods or spheres. We loaded TMV particles with paramagnetic Gd ions, increasing the ionic relaxivity compared to free Gd ions. The loaded TMV particles were then coated with silica maintaining high relaxivities. Interestingly, we found that when Gd(DOTA) was loaded into the interior channel of TMV and the exterior was coated with silica, the T1 relaxivities increased by three-fold from 10.9 mM−1 s−1 to 29.7 mM−1s−1 at 60 MHz compared to uncoated Gd-loaded TMV. To test the performance of the contrast agents in a biological setting, we focused on interactions with macrophages because the active or passive targeting of immune cells is a popular strategy to investigate the cellular components involved in disease progression associated with inflammation. In vitro assays and phantom MRI experiments indicate efficient targeting and imaging of macrophages, enhanced contrast-to-noise ratio was observed by shape-engineering (SNP > TMV) and silica-coating (Si-TMV/SNP > TMV/SNP). Because plant viruses are in the food chain, antibodies may be prevalent in the population. Therefore we investigated whether the silica-coating could prevent antibody recognition; indeed our data indicate that mineralization can be used as a stealth coating option to reduce clearance. Therefore, we conclude that the silica-coated protein-based contrast agent may provide an interesting candidate material for further investigation for in vivo delineation of disease through macrophage imaging.

Template‐Directed Synthesis of Porous and Protective Core–Shell Bionanoparticles

“…[9] Although these strategies afford regulation of size,t he as-obtained MOF particles are typically several hundred nanometers in size. [14] TMV is also attractive because it can be isolated in gram quantities from ak ilogram of tobacco leaves.E ach coat protein possesses solvent-accessible amino acid residues-tyrosine on the exterior and glutamates on the interior-and these anionic residues have been shown to be available for chemical conjugation. [11] We selected the tobacco mosaic virus (TMV), at ubular viral particle that contains 2130 identical coat proteins self-assembled around as ingle strand of RNA.…”

“…[11] We selected the tobacco mosaic virus (TMV), at ubular viral particle that contains 2130 identical coat proteins self-assembled around as ingle strand of RNA. [14] TMV is also attractive because it can be isolated in gram quantities from ak ilogram of tobacco leaves.E ach coat protein possesses solvent-accessible amino acid residues-tyrosine on the exterior and glutamates on the interior-and these anionic residues have been shown to be available for chemical conjugation. [14] TMV is also attractive because it can be isolated in gram quantities from ak ilogram of tobacco leaves.E ach coat protein possesses solvent-accessible amino acid residues-tyrosine on the exterior and glutamates on the interior-and these anionic residues have been shown to be available for chemical conjugation.…”

Serum albumin ‘camouflage’ of plant virus based nanoparticles prevents their antibody recognition and enhances pharmacokinetics

“…Tissue-targeted delivery of these payloads decreases dose-limiting systemic side effects, and increases therapeutic efficacy and/or site-specific accumulation of contrast enhancement agents [1–5]. Various NP-based formulations carrying chemotherapeutic agents [6,7], photothermal therapeutics [6,8], or magnetic resonance imaging (MRI) contrast agents [7,9–12] are currently in the development pipeline. A few formulations have been approved for clinical applications; these include superparamagnetic iron oxide (SPIO) NPs, which are used in MRI prognosis [13] as well as liposomal doxorubicin [7] and micellar or albumin-bound paclitaxel [7].…”

Multiple Administrations of Viral Nanoparticles Alter in Vivo Behavior—Insights from Intravital Microscopy

“…Chemical ligation strategies to stealth and camouflage nanoparticles have been developed to overcome this; for example, we recently demonstrated that VNPs escape antibody recognition through coating with PEG, 19 silica, 20 or serum proteins. 21 Nevertheless, the effects of carrier-specific interactions after repeat administration of plant-based VNPs have not yet been studied.…”