Wednesday, May 14, 2008

Role Of Nanotechnology In Developing Antiviral Agents


Nanoviricides (NanoViricides Inc) are polymeric micelles, which act as nanomedicines to destroy viruses. As defined by Nanoviricides Inc, "a nanoviricide is a polymeric single chemical chain with covalently attached ligands that specify the virus target. The antiviral spectrum of the drug is determined by the specificity of the set of ligands attached to the chain, in addition to other functionally important aspects inherent in the chemistries".

Nanoviricide is designed to seek a specific virus type, attach to the virus particle, engulf or coat the virus particle, thereby neutralizing the virus’s infectivity, destabilize and possibly dismantle the virus particle, and optionally it may also be made capable of attacking the viral genome thereby destroying the virus completely. Active pharmaceutical ingredients are optional and can be hidden in the core of the nanoviricide missile.

Role of micelles in nanopharmaceuticals

Micelles, biocompatible and flexible nanoparticles varying in size from about 20 to 200 nm in which poorly soluble drugs can be encapsulated, represent a possible solution to the delivery problems associated with such compounds and could be exploited to target the drugs to particular sites in the body, potentially alleviating toxicity problems. Cell membranes are one example of a micelle, a strong bilayer covering that is made of two sheets of lipid-based amphiphiles, molecules that have a hydrophilic, end and a hydropho bic end. Like two pieces of cellophane tape being brought together, the hydrophobic sides of the amphiphilic sheets stick to one another, forming the bilayered micelle. Polymeric micelles, sometimes referred to as "soft nanoparticles" in contrast to metal nanoparticles, can be synthesized and take any of the three basic shapes: globules, cylinders and sack-like vesicles. Traditionally, various metal nanoparticles have been attached to micelles to facilitate intracellular drug delivery, e.g. in cancer. Several academic institutions and companies are working on micelles for drug delivery.

pH-sensitive drug delivery systems can be engineered to release their contents or change their physicochemical properties in response to variations in the acidity of the surroundings. One example of this is the preparation and characterization of novel polymeric micelles (PM) composed of amphiphilic pH-responsive poly(Nisopropylacrylamide) (PNIPAM) or poly(alkyl(meth)acrylate) derivatives (Dufresne et al 2004). Maelor Pharmaceuticals (Newbridge, UK) is using micelle nanotechnology to entrap drugs inside polymer nanoparticles for delivery of effective concentrations of otherwise insoluble drugs to tissues. Micelles have also been used as non-viral vectors for delivery of DNA in gene therapy.

PreserveX™ Polymeric Micelles (QBI Life Sciences), with average diameter of 21
nanometers, are useful in working with difficult to handle proteins, such as the membrane proteins. These proteins reside on, near or embedded in cellular membranes and represent 70% of all known drug targets. In the presence of native cell membrane fractions, these micelles self-assemble and embed pieces of cellular membranes in the complex creating multiple particles each providing an environment similar to that of the native membrane. Solubilization of membrane proteins and associated lipids from membrane fractions result in stabilized micelle/protein/lipid complexes. Another QBI product, PreserveX™-QML-B Polymeric Micelles, contains a biotin label enabling the placement of the micelle/protein/lipid complex onto a solid support such as a protein microarray. Once immobilized with use of streptavidin, ligand binding or enzymatic activity can be determined, or the presence of the protein can be confirmed.

Some physicochemical characteristics common to polymeric micelles

Characteristics that distinguish polymeric micelles from other pharmaceuticals and
biologicals are:

§ They are conformationally flexible polymers, i.e. well defined non-particulate
materials. The material product can be defined operationally (i.e. in terms of
processes used to make it), and further can be characterized in terms of average result values of chemistries (e.g. average MW, and MWD, average number of ligands per chain, etc.).

§ As a polymer, it is not possible to manufacture a single molecular weight (MW)
species. However, it is generally possible to operationally define a molecular weight distribution of a production batch. The actual MW distribution can be characterized, but the result values are strongly dependent on the technique of measurement

§ Single molecular chains with heterogeneous molecular sizes.

§ Only polymer chemistries enable substantial attachment of ligand for blocking open sites.

Some limitations in physical characterization of polymeric micelles are:

§ Amphiphilic materials with self-assembly limit the use of many standard procedures in molecular weight distribution experiment.

§ They are mostly soluble in organic, aqueous as well as intermediate solvents leading to fractionation issues.

§ As non-particulate materials they are difficult to characterize by optical microscopy or by SEM, TEM, and AFM.

Structure and function of nanoviricides

NanoViricides are polymeric micelles, which bind to multiple virus-surface-receptors as antiviral agents. They are different from any of the other micellar nanotechnologies as there are no metal particles attached and the micelles can penetrate the virus and bind to multiple sites for effective destruction of the virus.

Mechanism of action of NanoViricides

For a virus to infect a cell, it needs to bind to more than one site. For example, binding of HIV only to CD4 on T cells is insufficient to cause sustained disease; it needs HIV binding to at least two and possibly three different sites on the T cell and that too, at multiple points. For an antiviral to be effective, it should match the strategy to bind to more than one site on the virus. Ideally it should block all of these to prevent virus from infecting the cell and multiplying. Most of the current antiviral drugs have a single mechanism of action and block a single receptor. Drug combinations from different categories are required to increase the number of receptors blocked. Still this is not fully effective.

In contrast to other approaches, a NanoViricide™ micelle can recognize and bind to more than one type of binding site on the virus. The NanoViricide™ system enables design of a drug that binds to more than one type of site - currently as many as three different sites, on the virus - for a highly effective attack. NanoViricides Inc terms this as "multi-specific targeting".

A NanoViricide™ drug goes much further than just blocking all of the binding sites of the virus. The base material of a NanoViricide™ is a specially designed polymeric micelle material. It has the ability to disassemble an HIV particle by itself. Thus, after coating the virus particle, the NanoViricide™ loosens the virus particle, and weakens it. Some virus particles will even fall apart (uncoat). This provides a further therapeutic benefit.

NanoViricides plans to enhance the viral disassembly capabilities of the NanoViricides™ by attaching specially designed "molecular chisels" to the NanoViricide™. Once the NanoViricide™ micelles coat the virus particle, the attached "molecular chisels" will go to work. They literally insert themselves into the virus coat at specific vulnerable points and pry apart the coat proteins so that the virus particle falls apart readily. The mechanism of action of NanoViricide is depicted schematically in Figure 4-1.

This description is a simplification. There is no fully adequate explanation of the observed efficacy because the mechanisms of action of nanomaterials as drugs and particularly, NanoViricides in vivo, are multiple and somewhat complex. Targets for this approach include influenzas, HIV, HCV, rabies and other viruses.

Figure 4-1: Schematic representation of NanoViricide attacking a virus particle

A: NanoViricide micelles attach to the virus at multiple points with nanovelcro
effect and start engulfing the virus.
B. Flexible micelle coats and engulfs the virus particle, dismantles and
neutralizes it, and fuses with viral lipid coat.
Reproduced by permission of NanoViricides Inc

Advantages of NanoViricides

NanoViricides have been compared to current approaches to viral diseases, which are seldom curative and some of the advantages include the following:

§ Specific targeting of the virus with no metabolic adverse effects on the host.

§ The biological efficacy of NanoViricides drugs may be several orders of magnitude
better than that of usual chemical drugs. This in itself may limit the potential for
mutant generation.

§ There are also other key aspects of the design of NanoViricides that are expected to lead to minimizing mutant generation.

§ Nanoviricides are safe because of their unique design and the fact that they are designed to be biodegradable within the body.

§ The new technology enables rapid drug development against an emerging virus, which would be important for global biosecurity against natural as well as man-made (bioterrorism) situations. It is possible to develop a research drug against a novel life-threatening viral disease within 3-6 weeks after the infection is found, i.e. as soon as an antibody from any animal source is available.

§ It is possible to make a single NanoViricide drug that responds to a large number of viral threats by using targeting ligands against the desired set of viruses in the construction of the drug. It is possible to “tune” the specificity and range (spectrum) of a NanoViricide drug within a virus type, subtype, or strain, by appropriate choices of the targeting ligand(s).

§ The safety of NanoViricide drugs is proven now as they specifically attack the virus and not the host.

§ A variety of formulations, release profiles and routes of administration are possible.

§ Low cost of drug development, manufacture, distribution.

NanoViricide drug candidates are currently in preclinical studies. Clinical trials are planned. Initially injectable products are considered to be most effective but alternative routes of administrations such as nasal sprays and bronchial aerosols can also be developed. Various Nanoviricide products will be described further along with relevant viral diseases.

Advantages of Nanoviricides over vaccines are:

§ Nanoviricides work where vaccines fail and are effective even when the immune
system is impaired such as in AIDS.

§ Nanoviricides work where effective vaccines are unavailable

§ Sufficient short term protection for an individual outbreak cluster-

§ Treatment can be started after infection

§ No need to vaccinate whole world population for control of a viral epidemic

Advantages of Nanoviricides over immunoglobulin therapies are:

§ Fully chemical, room-temperature stable NanoViricides can be made against many diseases

§ Nanoviricides based on antibody fragment conjugates do not require humanized
antibodies. Antibodies from virtually any source can be used for developing
NanoViricides, thus significantly reducing time and cost of development.

Immunoglobulin therapies require the patient's immune system (complement system) to function well, which is often not the case in advanced disease states. NanoViricides function completely independently of the human immune system while accomplishing the same goal of reduction in viremia.


NanoViricides Incorporated

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