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The use of nanotechnology in disease diagnosis and molecular imaging

Continuing our science series theme of nanotechnology (PJ 2012;290:115), Hamde Nazar takes a look at the use of nanoparticles in diagnostics and molecular imaging

By Hamde Nazar

Continuing our science series theme of nanotechnology (PJ 2012;290:115), Hamde Nazar takes a look at the use of nanoparticles in diagnostics and molecular imaging

Recently there have been significant developments in the use of imaging techniques to identify and monitor diseased tissue in vivo. Physiological and pathological changes can be detected through the visualisation of tissue morphology and cell function.1 When diseases manifest, the biochemical activity of cells alters. For example, cancer cells are more active than normal cells and multiply at a much faster rate, dementia-affected brain cells consume less energy than normal brain cells and heart cells deprived of adequate blood flow during cardiovascular related conditions begin to die.

During disease progression anatomical changes that are subsequent to abnormal cellular activity can be seen on computerised tomography (CT) or magnetic resonance imaging (MRI) scans. Molecular imaging is able to detect cellular alterations occurring in the early stages of disease often well before structural changes can be seen on CT and MRI images.2 Molecular imaging is described as the visualisation, characterisation and measurement of biological processes at the molecular levels in humans and other living systems. It uses radiolabelled molecules (tracers) that produce signals by means of radioactive decay along with other molecules to image via means of sound (ultrasound), magnetism (MRI), or light (optical techniques of bioluminescence and fluorescence), as well as other emerging techniques. Modalities that fall within this technique include: molecular magnetic resonance imaging, magnetic resonance spectroscopy, optical bioluminescence, optical fluorescence, targeted ultrasound, single photon emission computed tomography, and positron emission tomography.3 These procedures allow early diagnosis, identification of the stage of disease, provide specific information on the pathological processes and can be used to monitor the efficacy of therapy.4

Most molecular imaging procedures involve an imaging device and an imaging agent (probe). Chemical processes involved in metabolism, oxygen use or blood flow have been visualised using various imaging agents.2 Advancements in molecular imaging require the development and application of sophisticated probes that are able to detect biological processes on the cellular and molecular level.4

These probes necessitate two key characteristics: a property that facilitates their accumulation at the site of interest and a property that allows them to be imaged.1 Nanoparticulate probes have demonstrated significant advantages over single molecule-based contrast agents.

The latest developments in nanoparticulate molecular imaging contrast agents incorporate the appropriate contrast-generating materials (eg, fluorescent, radioactive, paramagnetic, superparamagnetic or electron dense), targeting groups, a biocompatible coating and the possibility for other functionalities such as a therapeutic drug.4

These agents allow for brighter, tissue-specific imaging to help visualise and help diagnose disease at the earliest stages and, in some cases, even before disease manifestation. Additionally, due to their careful nanostructure design (tailored drug release characteristics, low immunogenicity, etc), there is the potential to improve treatment efficacy and reduce undesirable side effects. Most significantly there has been a combination of diagnostic imaging and drug delivery roles into unique singular nanoparticulate formulations that allow for real-time treatment tracking.5

Nanoparticles

The specificity of nanoparticles for select tissues in diagnostic imaging and drug-based therapies is critical to prevent non-specific cell binding in healthy tissue. Engineering of the formulations has aimed to reduce this effect via passive, active and magnetic targeting. Several nanoparticles have been used for diagnostics, most commonly gold nanoparticles, quantum dots (QDs) and magnetic nanoparticles.

Gold nanoparticles for diagnostics

Small sections of DNA can be attached to gold particles smaller than 13nm in diameter. These attach onto a sensor surface only in the presence of a complementary target. If a patterned sensor surface of multiple DNA strands is used, the technique can detect millions of different DNA sequences simultaneously. Gold nanoparticles are especially effective labels for sensors because of a variety of analytical techniques that can be used to detect them.

Quantum dots

Quantum dots are inorganic fluorophores offering significant advantages over traditionally used fluorescent markers. They have high sensitivity (brighter imaging signals), broad excitation spectra, stable fluorescence with simple excitation and do not require lasers. Their infrared colours enable whole blood assays and have a wide range of applications for molecular diagnostics and genotyping. Multiplexed diagnostics and integration of diagnostics with therapeutics is also a possibility, with the most important potential application for cancer diagnosis. Luminescent and stable QD bioconjugates enable visualisation of cancer cells in living animals. They can be combined with fluorescence microscopy to follow cells at high resolution in living animals. QDs have been coated with polyacrylate cap and covalently linked to antibodies for immunofluorescent labelling of breast cancer marker HER2.

Carbohydrate-encapsulated QDs with detectable luminescent properties are useful for imaging of cancer. QDs can be used in multicolour optical coding for biological assays. 

One research group linked QDs to a peptide for labelling tumour vasculatures in live mice. The silica nanoparticles coated with gold nanoshells demonstrated photothermal properties for cancer treatment, and iron magnetic particles were used to track progenitor cells in vivo using magnetic resonance imaging. Another group demonstrated simultaneous in vivo targeting and imaging of tumours in live animals using QDs tagged to antibodies.

Magnetic nanoparticles

Nanoparticles are used as labelling molecules for bioscreening. Superparamagnetism is a form of magnetism that appears in ferromagnetic or ferrimagnetic (types of permanent magnetism) nanoparticles. Superparamagnetic nanoparticles are useful for cell-tracking cells and for calcium sensing. A family of calcium indicators for MRI is formed by combining a powerful superparamagnetic iron oxide (SPIO) nanoparticle-based contrast medium with the versatile calcium-sensing protein calmodulin and its target.
Superparameganetic nanoparticles measuring 2–3nm have been used in conjunction with MRI to reveal small and otherwise undetectable lymph node metastases. Ultrasmall SPIO enhances MRI for imaging cerebral ischaemic lesions. A dextran-coated iron oxide nanoparticle enhances MRI visualisation of intracranial tumours for more than 24 hours.6

Application in cardiovascular conditions

A major focus of application of nanotechnology for cardiovascular research has been directed imaging and therapy of atherosclerosis, restenosis and other CV conditions. Contrast-generating nanomaterials for CV imaging include fluorescent, radioactive, paramagnetic, superparamagnetic, and electron-dense and light-scattering particles. CV imaging by MRI requires powerful magnetic fields and radiofrequency waves to generate images of internal structures. Energy changes in response to magnetic field are detected and the presence of contrast agents amplifies these changes.

Some tissues appear brighter or darker than others on an MRI scan, where darkness is directly proportional to the density of protons in that area. The relaxation times for protons can vary and two times are commonly measured: T1 and T2. When each of these are measured different intensities of images are recorded and each method has its own advantages and disadvantages. In T1 scans, fat, water and fluid are bright and so it is optimal for picking up tissue oedema. T2 scans allow visualisation of neural activity in the brain by detecting areas of increased blood flow. Off-resonance is a phenomenon that occurs during imaging to introduce artifacts and undesired blurring and imperfections. By understanding the cause behind these anomalies correction measures can be applied to perfect the image.

Three MRI techniques are T1, T2 and off-resonance. Off-resnonance depends on pulse sequences that excite and refocus off-resonance water, leading to positive contrast. Paramagnetic contrast agents, such as gadolinium chelates, enhance T1 contrast, resulting in bright contrast in MR images. Manganese nanoparticles represent another recently introduced example of T1 enhancing contrast agent. Superparamagnetic contrast agents, such as iron oxide nanoparticles, typically enhance T2 contrast and produce dark contrast. The choice of technique depends on the application and the weight of sensitivity, specificity and artefact minimisation, such as bright contrast originating from perivascular fat on atherosclerotic plaque images.

Nanoliposomes as carriers for contrast agents such as iodine for MRI, and CT scans have shown to prevent rapid clearance of the contrast agent from the body efficiently, thereby improving the effectiveness of total blood pool and cardiac imaging in animal models. An improved liposomal formulation of iodine demonstrated a high blood pool iodine concentration that facilitated excellent contrast  between the myocardium and blood in the right and left ventricles, aorta, pulmonary trunk and inferior vena cava. There is significantly lower liver and spleen contrast, as is expected from the delayed clearance of the PEGylated liposomal iodine formulation via the reticulo-endothelial system. Normal iodine usually accumulates in areas such as the spleen and liver, which reduces brightness and contrast of image in the CV regions. This long residence time at stable, high opacity makes liposomal iodine a promising effective micro-CT agent for contrast enhancement within sub-millimeter vessels without significant renal clearance.7

The promise of nanomedicine in vascular disease is attributed to the similarity in scale within which biological interactions occur to the nanomaterials that are used. For example, QDs can be engineered on the single nanometer scale to tune their fluorescence emission profiles from the UV to the infrared spectrum, facilitating colour-coding of specific cell populations within atherosclerotic plaques. Polymeric nanospheres can be coated with bioactive ligands to permit their efficient entry into diseased cells for the site-specific delivery of antithrombotic agents.8

The future use of nanotechnology

The use of molecularly targeted radiolabelled nanoparticles offers many advantages over conventional molecular imaging probes. Primarily, hundreds, thousands, or even more imaging labels or a combination of labels for different imaging modalities can be attached to a single nanoparticle, which can lead to significant signal amplification. Also, multiple, potentially different, targeting ligands on the nanoparticle can provide enhanced receptor binding affinity or specificity. Efficacy of targeting is enhanced through the bypassing of biological barriers. Compared with nanoparticles labelled with other imaging tags, the two most significant advantages of radiolabeled nanoparticles are the extreme detection sensitivity and the capability for quantitative imaging, which is only true if the radioisotope remains attached to the nanoparticle.

Nanoparticles do not leach out of blood supply well due to the integrity of the blood vessels, so this limits their use or targeting to specific peripheral tissues that rely on the leaching of substances via extravasation into the extracellular fluid that surrounds the cells of that tissue. Therefore, in this case, the low extravasation is a disadvantage to image many tissues. However, it can be used to an advantage since it means nanoparticles will remain circulating in the blood supply, allowing imaging of vasculature related conditions that occur within vessels. Also, due to the fact that the vessels in tumours are leaky, it means that there should be increased extravasation leading to accumulation of the nanoparticles where they are actually needed for imaging and drug delivery purposes.

More recently developed nanoparticles with smaller sizes (preferably <10nm diameter) and longer half-lives (at least a few hours) may allow for extravasation from the leaky tumour vasculature to a certain extent. Since the major disadvantage of MRI is its inherent low sensitivity, which is exacerbated by almost exclusive vasculature targeting, future development of novel contrast agents with the capability of targeting tumour cells in addition to the vasculature might dramatically increase the MR signal and facilitate the biomedical applications of nanoparticle-based imaging agents.3

References

1 Minchin RF, Martin DJ. Minireview: nanoparticles for molecular imaging — an overview. Endocrinology 2010;15:474–81.
2 SNM, Centre for Molecular Imaging, Innovation and Translation. Fact sheet: what is molecular imaging 2010. Available at: http://www.snm.org/mi (accessed 11 January 2013).
3 Hong H, Zhang Y, Sun J et al. Molecular imaging and therapy of cancer with radiolabelled nanoparticles. Nanotechnology Today 2009;4:399–413.
4 Cormode DP, Skajaa T, Fayad ZA et al. Nanotechnology in medical imaging: probe design and applications. Arteriosclerosis, thrombosis and vascular biology 2009;29:992–1000.
5 Veiseh O, Gunn J, Zhang M. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Advanced Drug Delivery Reviews 2010;62:284–304.
6 Rajasundari K, Ilamurugu K. Nanotechnology and its applications in medical diagnosis. Journal of Basic Chemistry and Applied Chemistry 2010;1:26–32.
7 Godin B, Sakamoto JH, Serda RE et al. Emerging applications of nanomedicine for therapy and diagnosis of cardiovascular diseases. Trends in Pharmacological Science 2010;31:199–205.
8 Jayagopal A, Linton MF, Fazio S et al. Insights into atherosclerosis using nanotechnology. Current Atherosclerosis Reports 2010;12:209–15.

 

Citation: The Pharmaceutical JournalURI: 11119421

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Supplementary images

  • Coloured scanning electron micrograph of gold nanoparticles: gold nanoparticles are effective labels for sensors because of a variety of analytical techniques that can be used to detect them (david mccarthy/science photo library)

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