In recent weeks we have been seeing an increasing reference to the application of quantum dots in medical devices articles which left me to wonder; what on earth is a quantum dot???
A quantum dot is a very tiny (1 – 20 nanometers in size) semiconductor particle, that due to its very size takes on different properties than its larger counterpart. The characteristics alter regarding its optical and electronic properties, and by further altering their surface to volume ratio, these characteristics can be altered on a defined spectrum.
It is this unique behaviour, in response to quantum confinement, that makes them of interest and what gives them their name.
When these semiconductors are given energy, or “excited” this causes the electron within to move and creates a hole where the electron would normally be found, also known as an electron-hole-pair. As the electron loses this energy it moves back into the original position. This return of energy, as lost by the electron, shows as a photon of light. Manipulation of the energy given and then subsequently lost results in photons of varying wavelengths and frequencies – which is visually displayed as different colours of light. So simply put, larger Quantum dots emit photons with a longer wavelength which shows as an orange or red light and smaller ones emit photons with shorter wavelengths and display a blue or green colour – allowing for a complete spectrum of colours according to the manipulation exerted.
The discovery of the properties of Quantum Dots dates back to 1930, but it was not until the 1960’s that research began to focus on the light emissions and possible applications for this unique behaviour. Today the use of QD’s is present in a wide range of industries, including lighting, high specification LCD televisions, renewable energy and medical diagnostics.
The Application In Medical Diagnostics
Research into the application of QD’s into biotech was not immediately explored due to the toxicity of the cells. The materials most commonly used are zinc sulphide, lead sulphide, cadmium selenide and indium phosphide. The heavy metal content of these materials and the fear of them leaking into the body, alongside the inability to mix them with biologically compatible solutions, meant that investigation of their application in the arena of medicine was initially not considered. However, a way forward was discovered in 1998 when a water-soluble coating was perfected for the Quantum Dot. This opened up the scope for further research and between 2000 and 2010 almost 100,000 manuscripts were published about the further use for QD’s, 10% of these focused on biotech applications. It is possible to encompass a QD in a coating that mimics organic receptors and then binds to these disease biomarkers. The emitted light allows visibility of this in vivo.
So where can this be applied and what are the benefits over current methods?
QD’s can be used to replace current organic dyes used for in vivo diagnostics. These dyes, which bind to antibodies that are produced as an immune response to the presence of antigens, are by definition organic, which means that they will break down and deteriorate over time. They also have a narrow spectrum for emissions which means that the interpretation of results has a wider range of subjective errors and they also spread very quickly through human tissue. In the example of a surgical tumour removal the dye is injected into the affected area and a photograph of the area is captured for the surgeon to work from. Due to the bleed of the dye a wider margin of error is applied meaning that more healthy tissue than is necessary could also be removed to ensure that the tumour is extracted in its entirety.
When compared to QD’s it seems that current dyes are found wanting. The fluorescent yield for the QD is brighter, it has a narrower colour spectrum which means that colours vary on a greater scale and are more distinguishable from each other – this is largely as the QD can absorb more energy in comparison to organic dyes. QD’s are inorganic so although they suffer a little bit from photobleaching, they do not break down in the way that the dyes do and you can use one type of excitation source to produce results from multiple QD’s, whereas particular dyes will only be triggered by one type of energy. QD’s also move more slowly through healthy tissue and with the use of infra-red light the photon emitted is visible through this, resulting is less unaffected tissue and muscle mass having to be removed, as the boundaries of the tumour are more clearly located.
Quantum dots can be utilised by two different methods direct (active) or indirect (passive). In the direct process, the QD’s are manufactured as detection molecules and when added to the sample will bind to the target antigens, any that do not bind are washed away and then the biomarker mass/cells can be seen by the emitted light. As QD’s respond according to their own individual properties, rather than the energy source, it is possible to create a massively multiplexed assay that will highlight lots of different biomarkers in just one test. This is called Multiplexed Optical Coding.
The indirect method, rather than emitting the energy lost as light, it is transferred from the QD to other nearby fluorescent molecules and the process is repeated until the energy lost is emitted as light from the secondary molecules rather than the QD. This is known as Forster Resonance Energy Transfer (FRET).
It seems already clear that the application of QD’s into the sector of medical diagnostics offers many benefits over existing in vivo imaging options. Due to the ability of the QD’s to bind to antigens/biomarkers it also makes them ideal for targeted drug delivery, with the drug being held between the inorganic core and the polymer coating. This is ideal in scenarios where the dose is damaging to healthy cells – such as chemotherapy treatments.
They have also been shown to have antibacterial properties, as their presence disrupts the antioxidative system within cells – which can be used in a dose dependent method to be effective against bacteria.
As with any new technology, the application of QD’s is not without its problems. As mentioned the toxicity risk has been removed using a water-soluble coating, but there are still concerns with the application of this method – particularly for in vivo uses. The ability of the kidneys to remove QD’s from the body is an area for research as they are larger when compared with the dyes (6 – 60nm v’s 0.5nm) Also, manufacturing QD’s in high volumes, without variability is difficult as is labelling them. Clearly a method to do so is vital, in order to identify what antibodies, it is marked with, but as of yet there is no standard method to do so.
Regarding their drug delivery capabilities, there are also areas where the solution is not always ideal. Larger QD’s have problems penetrating solid tissues and in some cases the smaller QD’s have been cleared from the body by the kidneys, before the dose can take effect. However, research continues into changing the status quo to increase the positives and eradicate the negatives.
Many companies are looking at QD’s and the utilisation of nanotechnology in medical diagnostics. With well know diagnostics companies such as Thermofisher Scientific (https://bit.ly/2SvtaLy) and large manufacturers such as Samsung (https://bit.ly/2GGkxXk) looking into the application of Quantum Dots, across a variety of industries, in addition to an increasing number of nanotechnology firms across the UK (Nanoco Group) it is clear to see that the research into them and their unique properties will continue.