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Development of virus-like particles for diagnostic and prophylactic biomedical applications - PubMed

Review

. 2015 Sep-Oct;7(5):722-35.

doi: 10.1002/wnan.1336. Epub 2015 Feb 13.

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Review

Development of virus-like particles for diagnostic and prophylactic biomedical applications

Benjamin Schwarz et al. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015 Sep-Oct.

Abstract

As ordered nanoscale architectures, viruses and virus-like particles (VLPs) remain unsurpassed by synthetic strategies to produce uniform and symmetric nanoparticles. Maintaining or mimicking the symmetry of pathogenic viruses, VLPs offer a ready platform for facilitating recognition, uptake, and processing by the immune system. An emerging understanding of how viruses interact with the immune system offers a means of precisely designing nanoparticles for biomedical use, both with respect to the structure of the particle as well as their ability to stimulate the immune system. Here we discuss recent advances by our group toward two parallel and complementary applications of VLPs, derived primarily from plants, bacteriophage, and nonviral sources, in biomedicine: diagnostic imaging and rational vaccine design. First we discuss advances in increasing VLP payloads of gadolinium magnetic resonance imaging (MRI) contrast agent as well as controlling the characteristics of individual gadolinium containing molecules to increase efficacy. In order to better understand the in vivo potential of VLP constructs, we then discuss the interface of protein-cages and the immune system beginning with the nonspecific innate immune system stimulation and continuing into the use of nonpathogenic VLPs as scaffolds for specific antigen presentation and control of the immune response.

© 2015 Wiley Periodicals, Inc.

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Figures

FIGURE 1
FIGURE 1

The symmetry of VLPs reflects a single change over the entire particle. The VLP from bacteriophage P22 is shown with a serine to cysteine point mutation at amino acid position 39, displayed as a red sphere. This single mutation provides a new site at each of the 420 coat proteins that make up the capsid. (Reprinted with permission from Ref . Copyright 2012 Nature Publishing Group)

FIGURE 2
FIGURE 2

There are several targets for optimizing the relaxivity of a T1 contrast agent. DTPA-Gd is shown with a single water molecule in the binding position. Factors that affect relaxivity are the number of water molecules that can bind to the Gd ion (q), the exchange lifetime of the water molecule or molecules bound to the Gd (τM), and the rotational correlation time of the Gd complex (τR). The parameters q and τM are difficult to change for a given Gd-chelator complex leaving τR particle loading as optimization targets. (Reprinted with permission from Ref . Copyright 2009 American Chemical Society)

FIGURE 3
FIGURE 3

The interior space of the P22 VLP can be utilized by introducing a scaffold via atom-transfer radical polymerization. The radical initiator 2-bromoisobutyryl aminoeythl maleimide (1) was coupled to an internal cysteine of the P22 coat protein. Polymerization of the capsid interior with 2-aminoethyl methacrylate (AEMA) introduced as many as 9000 amine sites within the intra-capsid space. These sites could then be functionalized with Gd-DPTA-NCS resulting in high particle loading. (Reprinted with permission from Ref . Copyright 2012 Nature Publishing Group)

FIGURE 4
FIGURE 4

iBALT readily forms in the murine lung after i.n. administration of sHSP. (a) iBALT structures,indicated by arrows, emerge adjacent to airways and blood vessels after five administrations of sHSP compared to a PBS control (b). Stained fluorescence microscopy reveals that, compared to a control (c), iBALT structures contain (d) CD4+ T-cells, B220+ B cells, and (e) CD21+ follicular DC. (Reprinted with permission from Ref . Copyright 2009 Public Library of Science (PLoS))

FIGURE 5
FIGURE 5

Biomimetic display of influenza hemagglutinin (HA) on HpFn leads to improved protection compared to a traditional trivalent vaccine (TIV) in the presence of adjuvant (Ribi). (a) A transmission electron micrograph showing 1999 (NC) HA genetically fused to HpFn and displayed as the native trimer at the threefold axis of the VLP (HA-np). (b) HA-np provides greater protection than TIV when administered to ferrets challenged with 106.5 EID50 dose of 2007 Bris. Viral titers are reported as 50% tissue culture infectious dose (TCID50). (Reprinted with permission from Ref . Copyright 2013 Nature Publishing Group)

FIGURE 6
FIGURE 6

Biomimetic encapsulation of influenza nucleoprotein can elicit CD8+ mediated immunity. (a) Nucleoprotein (NP) was encapsulated in the P22 VLP (left) via genetic fusion to the scaffolding protein (SP) mimicking the natural position of the NP in Influenza an artist’s rendering of which is shown (right). (b) Mice vaccinated with NP163-P22 (the first third of the NP gene encapsulated in P22) showed improved survival after subsequent challenge with PR8 and X31 compared to the empty P22 or a PBS control. Protection could be negated by the addition of the CD8+ T-cell depleting IgG (TIB210). (c) The initial weight loss of all the immunized mice suggests that even the NP163-P22 mice initially are infected and that the mechanism of protection is not humoral. (Reprinted with permission from Ref . Copyright 2013 American Chemical Society)

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