Viruses and Their Uses in Nanomedicine

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application of virus like particles in Nanomedicine

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Viruses and Their Uses in Nanomedicine:

Viruses and Their Uses in Nanomedicine Behnaz Ghaemi PhD student of Nanomedicine School of Advanced Technologies in Medicine Tehran University of Medical Sciences March 2016

VIRUSES: Components:

VIRUSES: Components 1) a nucleic acid genome (DNA or RNA: DS or SS) 2 ) a proteinaceous capsid or coat protein that covers the genome . In addition, many animal viruses contain : 3 ) a lipid envelope 4) targeting proteins that allow specificity of the virus for infecting particular cells Together this is called the nucleocapsid .

Virus Life Cycle:

V irus Life Cycle ‘‘Obligate Intracellular Pathogens’’ A typical virus life cycle comprises the following events: T he interaction and binding of a virus with its host cell ‘‘receptor’’ (usually a protein or glycan ) E ntry into the cell Un-coating , release of virus nucleic acid, transcription and translation of the viral proteins, replication of nucleic acid, assembly into new virus particles E gress to infect other cells De Clercq , Erik. "Strategies in the design of antiviral drugs." Nature Reviews Drug Discovery 1.1 (2002): 13-25 .

VIRUSES: Transitioning from PATHOGENS to NANOMATERIALS:

VIRUSES: Transitioning from PATHOGENS to NANOMATERIALS Virus capsids or virus-like particles (VLPs ) benefits: Regular Structures H omogeneity of Particle Size P otential for T argeted delivery with Manipulation of the Coat P roteins S tability of the P articles A ccessibility of the particle interior E ase of P roduction D ynamic Structural Properties . Roy, Polly, Mark Boyce, and Robert Noad . "Prospects for improved bluetongue vaccines." Nature Reviews Microbiology 7.2 (2009): 120-128.

THE USE OF VIRUSES IN NANOTECHNOLOGY APPLICATIONS:

THE USE OF VIRUSES IN NANOTECHNOLOGY APPLICATIONS Structure and Chemistry Using Virus Building Blocks: protein cages are in the nanometer range: exhibiting well-defined geometry and remarkable uniformity atomic structures of many viruses have been resolved , allowing researchers to identify or modify amino acids in the viral capsid for bioconjugation it is feasible to chemically conjugate molecules to those amino acids both on the interior and exterior: ease of genetic manipulation As virus capsids are relatively rigid, it has also become feasible to display molecules in a precise spatial distribution at a nanoscale level Bioconjugation to virus-based nanoparticles has been performed using commercially available homo- or hetero-bifunctional linkers using the lysines and/or cysteines of the viral capsid This level of control is not possible with inorganic or lipid materials .

THE USE OF VIRUSES IN NANOTECHNOLOGY APPLICATIONS:

THE USE OF VIRUSES IN NANOTECHNOLOGY APPLICATIONS Chemical bioconjugation of viral nanoparticles. Bioconjugation methods for (A) lysines in virus capsid reacting with NHS-ester derivatized molecules or (B) thiols of cysteines in virus capsid reacting with maleamide-derivatized molecules. Molecule to be conjugated is shown as a filled circle. C: Accessible residues (indicated in black) commonly utilized for bioconjugation to CPMV particles (space filling model shown in grey tone) ( i ) naturally occurring exposed lysine residues, and (ii) or (iii) are genetically modified CPMV with exposed cysteines either on the large subunit or small subunit, respectively. Singh, Pratik, Maria J. Gonzalez, and Marianne Manchester. "Viruses and their uses in nanotechnology."  Drug development research  67.1 (2006): 23-41.

Viral particles commonly utilized for nanotechnology:

Viral particles commonly utilized for nanotechnology Name Type Genetics Capsid Size Properties Cowpea Mosaic Virus (CPMV) Plant Ss RNA 30nm Stable in a wide range of: T emperature , pH, B uffers Facilitated attachment to Thiol Cowpea Chlorotic Mottle Virus (CCMV) Plant Ss RNA 28nm Alteration in pH: capsid find 60 pores of 2 nm Capsid could selfassemble in vitro as VLPs MS2 Bacteriophage Bacteriophage Ss RNA 27nm Capsid could selfassemble in vitro as VLPs Empty capsids contain 32 pores of 1.8 nm: easy access to the capsid interior for chemical modifications Stable at a wide range of pH (3-10) Facilitated attachment to Thiol TMV Plant Ss RNA 300-nm rod-shaped, helical capsid symmetry, grow in extreme thermal environments Singh, Pratik, Maria J. Gonzalez, and Marianne Manchester. "Viruses and their uses in nanotechnology."  Drug development research  67.1 (2006): 23-41.

Virus particle applications in nanotechnology:

Virus particle applications in nanotechnology The natural container-like properties of viruses A bility to specifically target individual cells 1- Gene delivery 2- Therapeutic delivery 3- Visualization of structures Depending on the shape and chemical character of the particles, they are suited to different types of applications Portsmouth, Daniel, Juraj Hlavaty , and Matthias Renner. "Suicide genes for cancer therapy." Molecular aspects of medicine 28.1 (2007): 4-41.

Virus particle applications in nanotechnology:

Virus particle applications in nanotechnology Using a virus as the base platform, a variety of tissue-specific ligands or other molecules may be attached or genetically displayed on the particle surface . These include insertion of residues as substrates for attachment ( lysines , cysteines , short peptides) to act as ligands. Further, the attachment of small molecules, polymers, fluorophores , QDs, oligonucleotides, and metals has been achieved. Whole proteins and antibodies retain their function and achieve multivalent display when arrayed on virus nanoparticles.

VLPs Modified by Bio-conjugation for Cell Specific Delivery:

VLPs Modified by Bio-conjugation for Cell Specific Delivery Internalization of molecules into cells: Receptor-mediated endocytosis Viral particles (described in Structure and Chemistry Using Virus Building Blocks) act as a versatile scaffold system for a controllable attachment with spatial precision. Therefore, bioconjugation of transferrins , folic acid, or other targeting molecules together with drugs or toxins or imaging agents to viral scaffolds for cell-specific delivery has emerged as an attractive strategy.

Characterization of the Natural Cellular Uptake Pathways of Virus-Based Nanoparticles:

Characterization of the Natural Cellular Uptake Pathways of Virus-Based Nanoparticles Each VLP has a characteristic pathway of entry and intracellular trafficking in their host cells; however, modifying the VLP surface can alter these mechanisms. Three mechanisms that have been reported on cell uptake Clathrin -coated endocytic vesicles Clathrin -independent caveolae system M acropinocytosis

TOXICITY AND IMMUNOGENICITY OF VIRUS NANOPARTICLES:

TOXICITY AND IMMUNOGENICITY OF VIRUS NANOPARTICLES Most of the viruses being developed for these applications are typically not human pathogens : VLPs, or bacteriophages used for nanotechnology applications do not replicate in humans, and hence are less likely to induce innate antiviral responses such as interferons and other cytokines that can lead to toxicity. adenovirus shows severe hepatotoxicity. Virus or its components were found to be eliminated by macrophages within 24 h Smith, Douglas M., Jakub K. Simon, and James R. Baker Jr. "Applications of nanotechnology for immunology." Nature Reviews Immunology 13.8 (2013): 592-605.

FUTURE DIRECTIONS:

FUTURE DIRECTIONS Further studies of the toxicity, immunogenicity, and bio-distribution of virus particles in vivo must be performed: safety and potential efficacy of the particles in a therapeutic situation Reliable methods of inactivation of the replicating viruses, or conversion to a VLP system, need to be considered, even when the viruses themselves are not human pathogens The public perception of viruses in general as dangerous pathogens, rather than as friendly therapeutic tools, is a potential problem!

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