History of Nanotechnology
Richard Feynman is usually credited with first conceiving the idea of nanotechnology in the speech he made in 1959 to a meeting of the American Physical Society at Cal Tech: ‘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’.

From 1970s onwards, Eric Drexler published many scientific journals including his first book ‘Engines of Creation’ (1986), introducing the term ‘nanotechnology’ and ways to manufacture extremely high performance miniaturized machines. Today, the Institute of Nanotechnology in the U.K. expresses it as ‘science and technology where dimensions and tolerances in the range of 0.1 nanometer (nm) to 100 nm play a critical role’.

Nanotechnology is a multidisciplinary science involving the creation and utilization of materials, devices or systems on the nanometer scale. This term can be applied to many areas of research and development, from medicines to manufacturing to computing and even to textiles and cosmetics. 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.

Nanotechnology has attracted over $3 billion in funds from governments globally, which is being applied to a broad range of disciplines including pharmaceuticals, drug delivery, aerospace/defense and food (Figure 1).
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Nanotechnology Applications in the Pharmaceutical Industry
There are two approaches to adopting nanotechnology – the ‘top-down approach’ and the ‘bottom-up approach’. The top down approach aims at miniaturizing 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. 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).
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Screening Diagnostics
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 validating 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.

Imaging Drug Delivery Diagnostics
Another area where nanotechnology has made a significant impact is in the delivery of therapeutics agents through the application of nanoformulations or nano-enabled delivery systems. Advances in nanomaterials, nanostructures (e.g., quantum dots, dendrimers, nanotubes and fullerenes) and nanosystems are expected to drive the value of the global nanotechnology market to over a trillion dollars by 2015. Today, researchers are focussing on introducing specially designed nanoparticles, composed of tiny fluorescent ‘quantum dots’ that are ‘bound’ to targeting antibodies. These antibodies can bind in turn to diseased cells, after which the quantum dots fluoresce brightly. This fluorescence can then be picked up by new, specially developed, advanced imaging systems, enabling the accurate pinpointing of a disease even at a very early stage. Qdot nanocrystals from Invitrogen are an example of nanometer-scale fluorophores (Figure 3).
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In a recent study published in the Journal of the American Chemical Society, researchers at Georgia Institute of Technology are currently looking into magnetic nanoparticles, which are just 10 nanometres or less in diameter, having cobalt-spiked magnetite at their core. On the surface of the particle is a peptide, designed to attach to a marker that protrudes from most ovarian cancer cells. To test this technology, researchers first injected cancer cells and then magnetic nanoparticles into the abdominal cavities of mice. The cancer cells were tagged with a green fluorescent marker and the nanoparticles with a red one. When a magnet was brought near the mouse’s belly, a concentrated area of green and red glow appeared just under the skin, indicating that the nanoparticles has latched onto the cancer cells and dragged them towards the magnet. It is thought that this technology has the potential to diagnose and detect cancer cells in the future.

Imaging Diagnostics
Another growing sector within nanotechnology is the application of inexpensive and reliable nanotools to scientists and engineers in academia and industry. Using nanotools such as atomic force microscopy (AFM) (Figure 5), scanning electron microscopy (SEM), scanning near field optical microscopy (SNOM), transmission electron microscopy (TEM), surface enhanced raman scattering (SERS), surface plasmon resonance (SRP) and fluorescence resonance energy transfer (FRET) can be used for nanoscale detection and analysis of nanostructures.

The earliest commercial nanotechnology used for pharmaceutical applications was the atomic force microscope (AFM). Using a silicon-based needle of atomic sharpness, this approach was first used to image the topography of surfaces with atomic-scale precision. The ultra-fine tip scans the sample and creates a three-dimensional image of the surface. The AFM is fast becoming the principal technology that scientists and researchers use, allowing them to directly view single atoms or molecules and manipulate samples at the nanometer scale. While AFM is invaluable for imaging objects at the nanoscale in various areas (such as life science, materials science and polymer science), until recently, they have been used in techniques to better understand the chemical dynamics of how cells react to stimuli, which may prove particularly significant for drug discovery. Covalent biding of bio-ligands to AFM tips converts them into monomolecular biosensors by which cognate receptors can be localised on the sample surface and fine details of ligand-receptor interaction can be studied.

Concluding Remarks
The current drug discovery paradigm constantly needs to progress, increasing efficiency and reducing time to market. The post-genomic era has unveiled many potentially important targets. However, to exploit their value in full, the efficiency of screening and validation processes must be improved. Many governments are keen to apply nanotechnology across pharmaceuticals, drug delivery and healthcare monitoring in an effort to reduce R&D costs and enhance levels of productivity.

Regulatory authorities are supporting nanotechnologies that can improve the development of pharmaceutical and diagnostic agents, with many regulatory policies currently being reassessed to ensure innovation and safety when utilising nanotechnologies. In vitro diagnostic use of nanomaterials and nanoparticles does not pose any safety risks to people but there is a concern over the in vivo use of nanoparticles those < 50 nm in size, which can enter the cells and there are still many unanswered questions about their fate in the living body. The FDA/EMEA approval is essential for clinical applications of nanotechnology and substantial regulatory problems could be encountered in the approval of nanotechnology-based products.

The application of nanotechnology in life sciences, nanobiotechnology, is already having an impact on diagnostics and drug delivery, with nanoscale assays contributing significantly to cost-saving in screening campaigns. In addition, the advent of nanotechnology-based products such as nano-arrays and dendrimers (novel class of three-dimentional, nanoscale and core-shell structures) is anticipated to revolutionise the early detection of disease such as cancer improving the chances of cure. Also, nanotechnology enables not only the testing of relatively small volumes but the nanoscale particles, used as tags or labels increase the sensitivity, speed and flexibility of selected substance. The realisation that the nano-scale has certain properties needed to solve important medical challenges and cater to unmet medical needs is driving nano-medical research. Increasingly, research is focusing on the novel chemical and physical properties of nano-sized materials to develop new applications that improve human health.