Targeting drugs at the Nanoscale
Richard Moore looks at some further innovative nanoscale drug delivery vehicles In the first part of this article, printed in the previous issue of NANO, several challenges for drug delivery were outlined and a number of novel nanotechnology-based drug delivery systems were described. In the second part of this two-part article, Richard Moore looks at some further innovative nanoscale drug delivery vehicles and examines some of the challenges in bringing these technologies to the market.
Nanoscale drug delivery systems
Niosomes are one of a family of nanostructures that have a surface-acting action. They contain both water-soluble and insoluble parts and can assemble into closed bilayer nanostructures. They are useful in that they appear to be strongly taken up by the liver and spleen, which makes them useful for targeting drugs to diseases affecting those organs. Niosomal-based antigens are also strong stimulators of the immune response and therefore useful as adjuvants in vaccines.
Micelles are nanosized aggregates of surfactant (surface-acting) molecules dispersed in a liquid colloid. There are two common types:
- those where a hydrophilic (water-soluble) group is in contact with the surrounding aqueous solvent with the hydrophobic (water-insoluble) groups aggregated at the centre of the micelle… normal phase or “oil in water” micelle
- those where the hydrophobic groups are at the surface and the hydrophilic groups towards the centre... inverse phase or “water in oil” micelle
These are usually spherical in shape but other structures are possible including cylinders, ellipsoids and bilayers appearing similar to a liposome but without a central cavity. Their size and shape and geometry are primarily determined by the molecular geometry of the surfactant molecules, surfactant concentration, temperature, pH and ionic strength. The micelle acts as an emulsifier that allows a compound, normally insoluble in the solvent, to dissolve through incorporation in the micelle core, while the outer layers of the micelle cause the aggregate to become soluble in solution.
Stabilised micelles of around 15-30 nm are being used as delivery systems for individual drug molecules and can improve biodistribution and pharmacokinetic properties, and reduce toxicity of drugs with a narrow therapeutic index, e.g. paclitaxel. Active targeting is possible and micelles can take advantage of the leaky vasculature of tumours, e.g. for the delivery of doxorubicin or other therapeutic agents, and inflammation sites.
Drug release takes place by means of polymer degradation and the specificity of delivery (e.g. cell-specific targeting) can be influenced by the synthetic structure of the micelle, e.g. micelles containing attached sugar-group ligands can be used to target glyco-receptors in cellular plasma membranes. Micelle-based drug delivery systems are sometimes combined with non-invasive approaches such as the use of targeted ultrasound to trigger drug release at the target site.
Drug delivery systems based on fullerenes, carbon nanotubes, carbon nanohorns and similar structures
Fullerenes are carbon isoforms arranged in spherical cage-like structures of size range 0.7-1.5nm. The first to be discovered, also known as a “buckyball” consists of 60 carbon atoms. Carbon nanotubes are related single- or multi-walled elongated cylindrical structures based on a C60 structure. Both can be modified to carry small drug molecules. Other related structures are also possible, and are being evaluated as potential drug delivery systems such as carbon nanohorns which have a structure similar to carbon nanotubes, except that they are closed at one end forming a cone-shaped cap, or “horn”. Van der Waals forces cause them to self-assemble into spherical, flower-like assemblies of less than 100nm with the horn ends sticking out in all directions.
One attractive feature of carbon nanotubes, as a delivery system, is their large aspect ratio as compared with other delivery systems. They also possess high stability, which may prolong circulation time and bioavailability, and may overcome the aqueous insolubility problems associated with some drugs. With attachment of suitable ligands they may be targeted to specific cells and locations within the body to deliver small organic drug molecules, various peptides, proteins, and nucleic acids. Therapeutic and diagnostic agents can also be encapsulated, covalently attached, or adsorbed on the surface of carbon nanotubes.
Chitosan and lecithin nanoparticles
Chitosan and lecithin are two natural materials. Chitosan is derived from the shells of shrimps and other crustaceans. It has been used medically for some time as a haemostatic agent, is hypoallergenic and has anti-bacterial properties. Lecithin is a phospholipid, principally comprising phosphatidylcholine, usually extracted from egg yolk or soy beans, and widely used as a food additive.
Nanoparticles of diameter approximately 300 nm can be produced by self-assembly of chitosan and lecithin in ethanol and are currently being evaluated for the delivery of drugs via the nasal mucosa.
Nanodiamonds are an area of active research in drug delivery due to their very large surface area and tendency to cluster. Nanodiamonds 2nm in diameter can aggregate into clusters of 50 - 100nm. Drugs may be loaded onto the surface of individual nanodiamonds, but are inactive while the nanodiamonds are aggregated. Once the aggregates reach their target, the clusters break apart and release the drug cargo. Potentially, due to the very large surface area, nanodiamonds can carry up to five times the payload of other systems. Furthermore, the nanodiamonds are highly stable, soluble in water and compatible with a wide range of drug chemistries.
Nanosponges are complex structures, normally built up from long linear molecules that are folded by crosslinking into a more or less spherical structure, about the size of a protein. Typical nanosponges have been constructed from cyclodextrins crosslinked with organic carbonates. By choice of added materials, it is possible to control pore size, porosity and surface charge density which, in turn, makes nanosponges an interesting prospect for the attachment and delivery of many different types of drugs, both hydrophilic and lipophilic. In addition “molecular transporters” such as synthetic dendritic molecules can be attached to the nanosponges which are capable of passing through cell membranes while dragging the sponge, and its drug payload, along with them.
Implantable, drug-carrying nanofilms
A relatively new drug delivery idea is the development of implantable, drug-carrying nanofilms. The films, of thickness around 150nm are made from alternating layers of two materials: a negatively charged pigment and a positively charged drug molecule or positively charged molecule enclosing a drug. Following implantation, it is capable of delivering precise drug doses to specific targets in the body in response to the application of a remotely-administered electrical field that may be turned on or off. Different drugs could be carried on the film, and released independently, which could be useful in chemotherapy or other applications requiring a combination of drugs. The films may also be used to coat implants and substrates of different shapes and sizes and are capable of being mass-produced.
Researchers have recently developed "smart" bio-nanotubes of tubulin coated with a lipid, with open or closed ends, that could be developed for drug or gene delivery applications. The “smart” description refers to the possibility of encapsulating a drug or genetic material, and using the electrical charges of different cellular structures to “open” the nanotube at the desired site within the body.
A number of research groups are actively trying to combine a variety of functions into so-called multifunctional nanoparticles. These, for example, could include a metallic or semi-metallic core that responds to external energy field or which contains a delivered agent; a metallic or biodegradable shell according to application; targeting biomolecules for delivery to specific cellular or disease sites; an image contrast agent for tracking of movement and accumulation of the particles round the body; a payload of drugs and a polyethylene glycol (PEG) coating to counter detection of the particles by the immune system. Such multifunctional particles could also be tailored in size for delivery to different desired sites, tissues or cells.
Any new technology brings some degree of risk with it, and to bring a product to market based on that technology entails identifying all possible hazards, characterizing and quantifying the associated risks, including probabilities and severities, given current scientific knowledge, reducing risks to an acceptable level, balancing any remaining risk against benefit to the patient, and communicating effectively and appropriately on the nature of such remaining or “residual” risks.
While there is some accumulated knowledge on the toxicology of some nanomaterials that have already found use as drug delivery vehicles, e.g. liposomes and colloidal gold which have been in medical use for many years together with active research on nanomaterials such as carbon nanotubes, for others there remains little toxicological data so far.
In parallel with research on finding new nanoscale drug-delivery vehicles and systems, concomitant research is therefore essential on characterizing the properties of, and risks, including potential toxicity, associated with these novel materials.
To this end, in 2006, the European Medicines Evaluation Agency (EMEA) published a Reflection Paper on nanotechnology-based medicinal products for human use which includes the following statements:
Although the existing toxicological and ecotoxicological methods are appropriate to assess many of the hazards associated with the products and processes involving nanoparticles, they may not be sufficient to address all the hazards. Existing methodologies will need to be adapted and new methods will need to be devised.
Before marketing, toxicology and ecotoxicology for a specific nanomedicinal product, as well as the methodologies used for the evaluation of toxicity, would be assessed in the context of the evaluation of the Marketing Authorisation Application, which foresees evaluation of benefits and risks to patients as well as an environmental risk assessment. A description of the pharmacovigilance system will be submitted and, where appropriate, a EU risk management plan will be required.
Richard Moore is Manager of Nanomedicine and Life Sciences at the Institute of Nanotechnology
Source: NANO Magazine - Issue 11 /...
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