Nano-enabled drug discovery set to dominate

A new report has singled out various nanotechnologies, which are set to make a significant impact in drug research and development. Nanotechnology has been singled out as a tool, which could make the difference in an industry, which faces growing regulatory and pricing pressures. In addition there is the threat of antibiotic resistance seen in some disease-causing microorganisms and solid cancerous tumours.

According to the report, drawn up by NanoMarkets’​ and entitled "The Impact of Nanotechnology in Drug Discovery: Global Developments, Market Analysis and Future Prospects," nanotechnology is the natural progression in the drug discovery process as molecules of 100 nm down to the atomic level (approximately 0.2 nm) hold the most interest.

The report targets Atomic Force Microscopy (AFM) as a prominent nanotechnology. Currently, microscopic techniques have been unable to see how components of a cell react in biological processes such as their response to a specific chemical or compound.

New imaging techniques envisioned involve attaching antibodies specific to individual proteins to the tip of an atomic force microscopes’ probe. When an antibody reacts with the targeted protein, it creates a variance in the microscope’s reading compared to a reading with a bare tip, showing the protein’s presence.

The technique could prove particularly significant for drug discovery and will lead to a detailed understanding of the chemical dynamics involved in how cells react to stimuli, previously unachievable.

However, the widespread use of this technology, particularly in bioanalytical applications has been hindered by the limited throughput and the experimental burden of complicated and expensive instrumentation. Nanomarkets predict the development of highly parallel micrometer and submicrometer cantilever arrays, might increase the throughput of AFM-based force spectroscopy.

Microscopy has become the focus of nanotechnology primarily because images of biological samples will ultimately be a significant contributor to drug discovery.

Near-field Scanning Optical Microscope (NSOM) allows the study of optical properties of the sample surface with a resolution better than the wavelength of the light. By scanning the optical probe at very small distances from the sample (a few nanometers) “evanescent waves” from the surface are detected by the probe. The use of evanescent waves allows bypassing of the wavelength limitation of traditional optical techniques (the traditional limit of resolution being half the wavelength in use).

Nanomarkets also outlines an obstacle to such deployment. Manufacturing the probes reliably along with the requirement for a very small hole through which the light passes being problematic.

NanoMarkets believes there will be important improvements for imaging systems (and thus for drug discovery) as this learning process proceeds. The research reports on these improvements going on to identify Surface Plasmon Resonance (SPR) as a subject of interesting development.

SPR is a phenomenon that occurs when light is reflected off thin metal films and a small amount interacts with electrons in the film, reducing the light intensity. The refractive index of the materials sandwiching the film dictates the angle at which the light reduction (essentially a shadow) occurs.

Using an SPR-based approach, the interaction of biomolecules can be detected in real time, offering applications largely for observing biological systems in action on a very small scale, but also with potential for biosensors.

Applications using SPR are currently available from companies such as Applied Biosystems, which has introduced systems for identifying and characterising potential antibody, diagnostic and therapeutic candidates. Its 8500 Affinity Chip Analyser uses surface plasmon resonance to measure the binding of biomolecules in real time.

Current technologies used for proteomic studies are based on a variety of separation techniques followed by identification of the separated proteins and proteolytic peptides using mass spectroscopy (MS).

One technique focused upon is the high-resolution two-dimensional (2D) gel electrophoresis, which is capable of resolving 2500+ protein spots from samples. The in-gel protein spots are identified using sensitive MS and sequence database searching.

The in-gel protein spots are then identified using sensitive MS and sequence database searching. An alternative approach to 2D gel electrophoresis is chromatographic separation of peptides with electrospray ionisation (ESI)-MS or tandem MS (MS/MS) detection.

Whilst two-dimensional (2D) gel electrophoresis can be time-consuming and labour intensive, but its value to proteomics research will ensure that revenue in the world 2D gel markets will continue to grow.

Nanomarkets reported that one piece of nanotechnology certain to become prominent in the near future was nanolithography. This is the art and science of writing and printing at the nanoscopic level. This direct-write technique offers high-resolution patterning capabilities for a number of molecular and biomolecular “inks” on a variety of substrates, such as metals, semiconductors, and monolayer functionalised surfaces.

There are indications this process is starting to receive a warm reception. US company NanoInk, which has pioneered the dip pen nanolithography process which can provde nanoscale printing, is working with the manufacturer of a blockbuster drug to trial the encoding of unit doses of the product for brand protection.

Dip-pen Nanolithography (DPN) has applications for researchers interested in fabricating and studying soft and hard matter on the nanoscale. DPN enables precise multiple patterns with near-perfect registration. It’s both a fabrication and imaging tool, as the patterned areas can be imaged with clean or ink-coated tips. NanoMarkets believes that together, all these attributes make DPN a valuable tool for studying fundamental issues on colloid chemistry, surface science, and nanobiotechnology.

There has been a significant push to develop alternative technologies that serve to alleviate the bottleneck that is occurring throughout high-throughput proteomic studies. Protein and DNA microarrays that allow the specific capture and analysis of a large number of proteins expressed in various cell types are currently the best the industry have to offer

Microarray technologies can be considered platforms for nanoscale bioanalysis, and these products have already proven their value in the marketplace. However, currently available microarray technologies suffer from certain limitations that prohibit the exploitation of the full range of drug discovery applications.

For example, microarrays, once exposed to the target protein, must be removed from solution and rinsed before they are scanned to see whether or not there have been any “hits.” Not only does this take time, but also the rinsing process can easily result in the degradation of the array itself.

These limitations are already being addressed at the nano level with “nanoarrays,” which are ultra-miniaturised versions of the traditional microarray that can measure interactions between individual molecules down to resolutions of as little as one nanometer.

Nanoarray’s are being touted as the next evolutionary step in the miniaturisation of bioaffinity tests for proteins, nucleic acids, and receptor-ligand pairs.

Nanomarkets noted that the final product held the promise of a true revolution in bio-imaging quality and sensitivity. The emergence of QuantumDot Fluorescence (Qdots) as a nanotechnogical application for diagnostics and medicine has taken the industry by storm. Quantum dots are semiconductor nanocrystals that fluoresce when excited by a light source, emitting bright colours that can identify and track properties and processes in various biological applications.

They have significant advantages over traditional fluorophores, particularly in terms of the brightness of the fluorescent signal they can generate, their range of colours and their stability.

QDots take advantage of the quantum confinement effect predicted by quantum mechanical theory to fluoresce extremely brightly when excited by a light source such as a laser. By varying the size of the crystals one can cause a rainbow of colors to fluoresce. In QDots stay lit for much longer periods of time than conventional dyes, often hours or days.

QDots enable the tagging of a variety of different biological components like proteins or different strands of DNA with specific colors. QDots are designed to bond with and illuminate individual biological targets of choice whether genes, nucleic acids, proteins, small molecules, cancer cells, or even entire blood vessels.

NanoMarkets noted that some of the world’s largest pharmaceutical and biotech companies, such as GlaxoSmithKline, Pfizer, and AstraZeneca, and leading biotech firm Genentech are applying QDots in high-content drug screening and have completed initial drug screens using QDots as the biological read-out. Genentech is applying QDots to the detection of breast cancer.

One such company is the QuantumDotCorporation, which were pioneering the use of this technology with its extensive Qdot conjugate range. The testament to this technological breakthrough, which was commercially launched in late 2002, led to recognition of quantum dot bioimaging as one of Science magazine’s top 10 scientific breakthroughs of 2003.

While in its infancy, Qdots could eventually be applied to early detection of disease in vivo due to its specific and high sensitivity. This could especially be applied to cancer where it is estimated that it would take 4-5 years to detect from the initial cancerous cell growth. The aim was to use the Qdot's qualities to reduce that figure to a year.

It was also envisaged that Qdots might have uses in the delivery of drugs to specific sites. By utilising dendrimer polymers with a size of less than 1nm, cancer drugs could be delivered to specific target sites where ordinarily the drug would not have access to if delivered on its own.

One particular application in which the FDA has given initial approval for is Advanced Magnetics’ Combidex technology.

Combidex (ferumoxtran-10) consists of iron oxide nanoparticles for use in conjunction with magnetic resonance imaging (MRI) to aid in the differentiation of cancerous from non-cancerous lymph nodes. Clinical studies have shown that Combidex accumulates in non-cancerous lymph node tissue, which enables doctors using magnetic resonance imaging to have improved diagnostic confidence in differentiating between normal and diseased lymph nodes.

As the drug industry strives to meet the increasingly difficult task of producing new drugs and especially new blockbuster drugs, it is increasingly seeking new drug discovery technologies that can improve R&D success rates and time to market. NanoMarkets therefore believes that these improvements are likely to lead to substantial new business revenues over the next few years.