By Dr. Laleh Safinia, Research Analyst, Drug Discovery Technologies
Email: laleh.safinia@frost.com

'I want to build a billion tiny factories, models of each other, which are manufacturing simultaneously...The principles of physics, as far as I can see, do not speak against the possibility of manoeuvring things atom by atom. It is not an attempt to violate any laws; it is something, in principle, that can be done; but in practice, it has not been done because we are too big'. Richard Feynman, Nobel Prize winner in physics

The term nanotechnology emerged in 1959, when the great physicist Richard Feynman suggested that it should be possible to build machines small enough to manufacture objects with atomic precision in his talk, 'There's Plenty of Room at the Bottom'. From 1970s onwards, Eric Drexler published many scientific journals, introducing the term 'nanotechnology' and ways to manufacture extremely high performance miniaturised machines.

Nanotechnology is a multidisciplinary science involving the creation and utilisation of materials, devices or systems on the nanometer scale. Nanotechnology plays a critical role in various biomedical applications, not only in drug delivery, but also in molecular imaging, biomarkers and biosensors. Target-specific drug therapy and methods for early diagnosis of pathologies are the priority research areas where nanotechnology would play a vital role.

There are two approaches to adopting nanotechnology; the 'top-down approach' and the 'bottom-up approach'. The top down approach aims at miniaturising current technologies in which materials are processed to fabricate microscopic objects. The bottom up approach builds structures on an atom-by-atom basis through bonding and intermolecular forces to assemble a nanostructure. There have been considerable amounts of R&D funds made available for the application of nanotechnology in a broad range of disciplines including pharmaceuticals, drug delivery, aerospace/defence and food (Figure 1).

Figure 1. Distribution of the R&D budget on the application of nanotechnology in different sectors.

Nanotechnology is already filtering through the pharmaceutical system, with the adoption of nanotools such as nanoarrays and lab-on-a chip (LOC) assays throughout the R&D process to aid high-throughput screening of drug candidates, identify new drug targets and biomarkers for preclinical and clinical studies, and to develop diagnostic and imaging agents (Figure 2).

Figure 2. Application of nanotechnology in the pharmaceutical industry.

Nanotechnology may enhance the drug discovery process through the miniaturisation of screening assays helping to reduce volume and the use of expensive reagents, increased automation and reduction in inter and intra assay variability, providing additional information on cellular and molecular interactions e.g. protein-protein interaction and helping identify and validate new chemical entities and drug targets. An area of drug discovery where microfluidic lab-on-a-chip has been applied is in genomics and proteomics, where conventional analysis devices are expensive and labour intensive and where fast and low-cost analysis techniques are in great demand. Microchip electrophoresis (MCE) of DNA samples is one of the leading applications of microfluidics in genomics. MCE has many advantages such as smaller dimensions, lower sample consumption, high-throughput ability and ease of automation. In addition, microfabrication systems have the potential to control and automate dozens of the sample processing steps that are used in proteomics and offer new possibilities that are not readily available in the macroscopic world. One of the applications of microfluidics in proteomics has been chip-based separation in conjunction with mass spectroscopy or laser-induced fluorescence as the detection method.

The first microfluidic chip was designed in 1991, and by 1994 the chip concept was patented. The first LOC device was launched by Agilent Technologies, Agilent 2100 Bioanalyzer, is a desktop microfluidics-based platform designed to analyse DNA, RNA, proteins and cells. Since then numerous companies have launched LOC technologies, integrating the chip into the labs, such as Affymetrix (product: GeneChip), BioTrove (product: Open ArrayTM RapidFire), Caliper Life Sciences (Product: LabChip 90 and 3000 drug discovery system) and many more. In July 2003, Caliper Technologies acquired Zymark Corp. This combination bridged the interface between micro- and macrofluidics. It combined Caliper's detection platform with Zymark's experience in nanoliter liquid handling to feed a microfluidics platform and interface existing mutiwell plate architecture. Today, Caliper Life Sciences is working with others-including Agilent Technologies, Bio-Rad, QIAGEN and Affymetrix to establish microfluidics products in a range of applications.

By eliminating variations in sample preparation, reaction conditions and detection methods, microfluidics has the potential to enable the efficient screening of more drugs in less time and drastically cut down the costs of drug development. Platforms for cell culture and single cell studies that chips can provide will be helpful in proteomics research, which in turn will accelerate target identification. Microcytometry and cell sorting and the generation and handling of small liquid volumes also find applications in structure-based drug discovery, protein crystallisation, and screening of compound libraries, which can aid in lead identification. Further, LOCs can be used for testing the efficacy of drugs, pharmacological profiling, and toxicity testing by studying the effect of drugs on living cells. Realising the potential of microfluidics tools for studying target selection, lead identification and optimisation and preclinical test and dosage development, both pharmaceutical and life science companies are gearing up to implement it in their drug discovery pursuit. However, despite the growth of microfluidics in the past few years, a number of challenges still need to be addressed, especially in the context of versatility and application in both academic and industrial pharmaceutical laboratories. Also more studies should be conducted to determine the reliability of microfluidic chips over thousands of samples and months of constant use. Thus, advances need to be made to further enhance the use of microfluidics in addressing the challenges of drug discovery and development studies.