In the 1967 film The Graduate, a party guest gave Dustin Hoffman’s young character the one-word tip: ‘plastics’. The implication was that the future lay in plastics and that he would do well to take note.
Today, the one-word tip might well be ‘nanotechnology’. It is easy to see why. Some projections have the commercial nanotechnology market reaching $1t by 2051.
The US Government’s National Nanotechnology Initiative was established in 2000 and will spend over $1bn in this fiscal year. Certainly, interest and scientific activity in nanotechnology is undergoing unprecedented growth. Patent applications related to nanotechnology have increased significantly, and a number of new companies have been formed around one nanotechnology application or another.
Most of the patent applications related to nanotechnology originate in the US, but Japan, Korea and certain European countries are also contributing to the nanotechnology boom.
Recognising this rapidly growing field, the US National Institutes of Health’s Roadmap Nanomedicine Initiatives, released in 2003, indicated that that “this cutting-edge area of research will begin yielding medical benefit as early as ten years from now”. This now looks to have been a rather conservative projection, with several new nanomedicines in clinical trials and a few already on the market. One analyst report projects that, by 2014, 16% of goods in healthcare and life sciences by revenue will incorporate nanotechnology.
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While nanotechnology has a variety of applications, and nanomedicine has broad relevance to diseases, the focus of this article will be limited to the use of nanotechnology against cancer.
Cancer is one area where the potential applications of nanotechnology are most visible, and ‘nano-oncology’ has been added to the lexicon of ‘nano-terms’. In 2005 the US National Cancer Institute (NCI) announced its commitment to spend over $140m over five years for its Alliance for Nanotechnology in Cancer programme.
This programme aims to accelerate the application of nanotechnologies in research and clinical care and comprises eight centres of cancer nanotechnology excellence, 12 platform programmes, and four interdisciplinary training programmes across the USA
Researchers in academia, government and industry are exploring nanotechnology for both cancer imaging and cancer therapy. Most of these applications are based on the ability of nanoparticles carrying a payload (the therapeutic molecule or imaging agent) to home in on cancer cells with some degree of selectivity.
Some nanotechnology cancer products are reformulations of previously approved drugs. Abraxane (Abraxis BioScience, Inc), which was approved by the FDA in 2005 for metastatic breast cancer, is a nanoparticulate form of the drug paclitaxel with improved efficacy and safety characteristics.
For cancer therapies based on nanotechnology, selective targeting of cancer cells provides an improvement in the therapeutic index – a term that refers to the ability to kill cancer cells while minimising collateral damage to normal cells and tissues. In short, the goal is more efficacy and fewer side-effects.
In the case of imaging applications, the selectivity of nanoparticles to go to cancer cells and not normal cells provides the signal-to-noise ratio upon which cancer imaging depends. Imaging technologies are used in cancer management for the non-invasive detection of tumours, for staging the disease and for monitoring therapeutic interventions.
A variety of imaging modalities are used in oncology including ultrasound, magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT) and various optical imaging techniques. A detailed description of these imaging modalities is beyond the scope of this article. Suffice to say that several of these modalities use molecules that either emit a signal (such as the emission of light or radioactivity by a radioisotope) or that serve as a contrast agent (as in MRI or CT).
ADDITIONAL ANTI-CANCER WEAPONS
Traditionally, cancer therapy has consisted of surgery, chemotherapy, radiotherapy or some combination of these modalities. More recently, other molecules with therapeutic potential have been added to the arsenal in the form of ‘biological therapeutics’.
Generally speaking, this term refers to more macromolecular entities, such as monoclonal antibodies and nucleic acid-based therapies, including gene therapy aimed at a gain-of-function encoded by the introduced gene, antisense therapy for ablation of specific gene expression, and therapeutics based on short interfering RNAs (siRNAs) that can also be used to ablate expression of specific genes.
To date, the theoretical potential of these macromolecular therapeutics has exceeded their actual impact on cancer patients. It is generally believed that delivery of these molecules via nanotechnology holds the best prospect of a realisation of their therapeutic potential.
Nanotechnology-based delivery is not limited to macromolecules. Nanoparticles are also being used to deliver small-molecule therapeutics, including already approved pharmaceuticals (such as paclitaxel and doxorubicin).
The more promising nanoparticles used for delivery to cancer cells (also termed nanovectors) are tripartite in their design, consisting of the payload surrounded by or conjugated to the constituent material of the nanoparticle, which is decorated with a tumour-targeting moiety.
The tumour-targeting moiety can be an antibody recognising a cancer cell surface molecule or a ligand for a receptor over-expressed on tumour cells (for instance, the folate receptor, transferring receptor or the receptors for growth factors). To illustrate, consider liposomes as one class of nanoparticle with a nucleic acid payload for gene therapy.
THERMAL ABLATION THERAPY
One very promising application of tumour-targeting nanoparticles in cancer treatment is thermal ablation therapy. Both nanoshells and carbon nanotubes are being tested in thermal ablation therapy applications. Both types of nanoparticles absorb near-infrared light and emit heat.
The principle of this approach is relatively simple. In this application, the tumour-targeting nanoshells or carbon nanotubes would be injected intravenously and home in on tumour cells based on the tumour-targeting moiety affixed to them. Near-infrared light can pass through several centimetres of normal tissue without harm. However, when the light interacts with the nanoshells or nanotubes in the vicinity of the tumour, heat capable of killing cells is produced.
The net effect is that only tumour cells that are in proximity to the nanoparticles are killed. Although thermal ablation has been used previously, the lasers used before to produce the heat did not discriminate between cancerous and normal tissue. Nanotechnology thus provides a means of producing deadly heat in the tumour but not in the normal surrounding tissue.
In cancer imaging, much attention has been directed at the use of a class of nanoparticles termed quantum dots, a class of nanocrystals. Quantum dots are composed of inorganic molecules (such as a cadmium selenide core and a zinc sulphide shell) and, depending upon chemical composition and size, these particles of less than 10nm emit powerful narrow-band fluorescence between 450nm and 850nm in wavelength.
Like other nanoparticles, quantum dots can be conjugated to antibodies, ligands or other targeting moieties to mediate specific interactions with cancer cells. The intense fluorescence of the quantum dots is being exploited in applications for optical imaging of tumours.
Nanotechnology is an emerging field. Its potential in medicine in general, and in applications aimed at cancer specifically, is just beginning to be realised. Few nanotechnology applications have made it into general medical use, but many are in the R&D pipeline. Scrutiny for efficacy and safety will be required, and more research is certainly needed to exploit the potential of nanotechnology.
However, one fact is already clear: this field, involving very small stuff, looms large in terms of its impact on patient care in the 21st century.