Biodistribution and Clearance of A Filamentous Plant Virus in Healthy and Tumor-Bearing Mice

Abstract

Aim-Nanoparticles based on plant viruses are emerging biomaterials for medical applications such as drug delivery and imaging. Their regular structures can undergo genetic and chemical modifications to carry large payloads of cargos, as well as targeting ligands. Of several such platforms under development, only few have been characterized in vivo. We recently introduced the filamentous plant virus, potato virus X (PVX), as a new platform. PVX presents with a unique nanoarchitecture and is difficult to synthesize chemically.Methods-Here, we present a detailed analysis of PVX biodistribution and clearance in healthy mice and mouse tumor xenograft models using a combination of ex vivo whole-organ imaging, quantitative fluorescence assays and immunofluorescence microscopy.Results & conclusion-While up to 30% of the PVX signal was from the colon, mammary and brain tumor tissues, remaining particles were cleared by the reticuloendothelial system organs (the spleen and liver), followed by slower processing and clearance through the kidneys and bile.Keywords anisotropic nanoparticle; biodistribution; immunogenicity; mononuclear phagocyte system; nanoparticle shape; polyethylene glycol; tumor homing; viral nanoparticle Plant viruses and bacteriophages have been recognized as potentially useful biomaterials for a range of nanomedical applications, including tissue-specific imaging, drug delivery and vaccine development [1]. Viruses are versatile because they are symmetrical, monodisperse protein structures that form icosahedrons, tubes or filaments, which encapsulate nucleic acids and deliver them efficiently to cells. They have evolved robust structures that withstand the adverse conditions present during infection, but remain responsive to subtle physiological parameters, such as pH and temperature, allowing them to disassemble and reassemble for self-propagation. These attributes can be exploited to develop virus-based nanoparticles (VNPs) that are amenable to chemical and genetic modification, allowing the incorporation of drugs, contrast and imaging probes, as well as targeting ligands conjugated to either the external or internal particle surface, or packaged inside through the use of induced disassembly and reassembly strategies [2]. The ease of production by molecular farming in plants makes VNP technology highly scalable. Shukla et al. Page 2 Nanomedicine (Lond). Author manuscript; available in PMC 2014 September 19. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe application and development of plant VNPs is still a relatively young discipline.Although various platforms have been tested and developed in the test tube (e.g., various modification strategies have been devised), only few examples have been characterized in vivo; principally, the icosahedrons cowpea chlorotic mottle virus (CCMV) and cowpea mosaic virus (CPMV) [3,4]. Both plant VNPs demonstrated rapid blood pool clearance and were detected in a wide variety of tissues throughout the body; CPMV accumulated primari...

Biodistribution, pharmacokinetics, and blood compatibility of native and PEGylated tobacco mosaic virus nano-rods and -spheres in mice

“…Researchers have reported in vivo fate of spherical VNPs cowpea mosaic virus (CPMV) [51, 52], cowpea chlorotic mottle virus (CCMV) [53], bacteriophages Qβ [54], and MS2 [46] and filamentous potato virus X (PVX) [9]. For each system studied, RES clearance and deposition of VNPs in liver and spleen was observed, as indicated by sequestration by blood monocytes, dendritic cells and tissue macrophages.…”

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

“…62 Earlier studies have also highlighted the affinity of PVX to B-cell-rich regions in secondary lymphoid organs. 28 On the basis of these observations, we predicted induction of an antibody-mediated immune response upon repeat administration. Our results illustrate that initially anti-PVX IgM antibodies primarily dictate the clearance of PVX particles.…”

“…22–26 The shape and flexibility of PVX makes it a highly efficient platform for enhanced tumor homing and penetration based on the enhanced permeability and retention (EPR) effect and therefore has tremendous potential as a nanoplatform for delivering therapeutics and imaging contrast agents to solid tumors. 27,28 Studies pertaining to the biological fate of PVX, however, have so far been limited to single intravenous administration and fail to address particle fate upon repeat exposures.…”

Virus‐SiO2 and Virus‐SiO2‐Au Hybrid Particles with Tunable Morphology

“…Rod‐shaped particles can have a larger surface area than globular particles without losing one of the dimensions in the lower nanometer range because of the one dimensional increase in size making the rigid rods such as TMV more attractive than the globular particles such as CPMV. Additionally, both are stable under extreme pH, temperature or co‐solvent conditions, but the particles with greater flexibility such as Potato Virus X (PVX) makes them interesting as potential biomarkers or scaffolds for biocatalysts, albeit at the expense of stability as determined by comparative differential scanning calorimetry (DSC) studies . It is important to extrapolate procedures towards different types of viral structures due to the difference in size, mechanical properties, and chemical addressability.…”