HistoMag: Nanomaterials in Medical Physics

Long ago when I used to be a medical student, my Anatomy teacher said that the breasts were an ornament to a lady and it gave motherhood to a woman. The words still reverberate in my ears. This aesthetic organ is frequently targeted by cancer. Put in other way, cancer of the breast is the second most common cancer worldwide (lung cancer tops the list) among both the sexes, and the most common type of cancer in women.

Diagnosing cancerous cells have been a nightmare for pathologists. We can not define a normal cell properly and differentiating them with cancerous cells can be pretty tough. Apart from their detection by radiological investigations which include X-rays, CT scan, MRI and other imaging modalities; we depend heavily on tissue biopsy samples collected from the patient's suspected specimen. We then stain the specimen using various dyes and examine them under the microscope.

For example, in the above picture, a section of breast tissue has been stained with immunoperoxidase. Such staining employs targeting and latching onto a tissue antigen of interest by using an external antibody (the immuno part), and then making these tissue antigens visible by the formation of a colored product by catalytic reactions brought about by peroxidase.

Now scientists have gone one step further. In some cancers of the breast there is an overexpression of a protein (antigen) called HER2/neu (Erb B2). This is a transmembrane protein, meaning that this molecule has an extracellular domain, a membrane spanning portion and an intracellular part. The peculiar nomenclature derives from the fact that this molecule is in fact a receptor for human epidermal growth factor and was found in rat neuroblastoma cell lines. Surprisingly, HER does not seem to have a physiological ligand, making the receptor look like a lady who does not have a mate! The protein when over-expressed, may form complexes among themselves, thereby transactivating its inherent tyrosine kinase activity. Unleashing the tyrosine kinase activity results in a cascade of activity that fosters tumorigenesis (picture on the left).

Scientists are now tagging magnetic nanoparticles with antibody to HER2/neu. Trastuzumab (herceptin), as the antibody is known, is a humanized monoclonal antibody (only one type/clone of molecule). Thus magnetic nanoparticles attaches to HER proteins (via trastuzumab); the density (intensity) of which can then be probed by applying the specimen to a magnetic field and extrapolating the the distortion these nanoparticles induce in them. Researchers at University College London (UCL) in the UK have developed HistoMag system which uses this technology. A drive coil (picture shown) produces a magnetic field which is made to vary with time, and a magnetometer using SQUID (superconducting quantum-interference device) as the pick up coil. The tissue section was sandwiched in the middle. Apart from detection of malignant cells it is also capable of predicting what population of women are likely to benefit from Herceptin (Trastuzumab) therapy. (In passing, it may be said that the same magnetometer device is being developed further so that it may, one day be able to pick-up your thoughts non invasively.) Many different approaches are cropping up which use nanotechnology, optical imaging and other modalities for the imaging of tissue sections. Quentin Pankhurst, professor of physics at UCL, the man behind HistoMag, has previously developed and commercialized SentiMag, a device which detects sentinel lymph nodes (lymph nodes first to enlarged in cancer).

In another development, researchers at the University of Debrecen, Debrecen, Hungary and Max Planck Institute for Biophysical Chemistry, Göttingen, Germany, have used paramagnetic microspheres coated with ligands (Herceptin) to attach to HER2. They then used confocal laser microscopy and digital image processing to 'see' the trans-activation (of ErbB2 (HER-2)). In confocal laser microscopy, a laser light is thrown into the sample through a special dichroic mirror, which allows light of one (long) wavelength to pass and that of other (short) wavelengths to reflect. When a laser of blue color (say) strikes the sample, which has been treated with a fluorescent dye, light of another wavelength say green is emitted. The dichromatic mirror now filters the blue light, while letting the green light pass, which is then amplified by photomultiplier tube and visualized. They found this to be an efficient tool in assessing Erb (HER2) activation, signal propagation and heterodimer formation.

In vivo neoplasms may be imaged by administering the patient a dose of these nanomagnets by mouth or by injection, and then imaging the patient. A modification of the device will be necessary.

Friedländer, E., Arndt-Jovin, D.J., Nagy, P., Jovin, T.M., Szöllősi, J., Vereb, G. (2005). Signal transduction of erbB receptors in trastuzumab (Herceptin) sensitive and resistant cell lines: Local stimulation using magnetic microspheres as assessed by quantitative digital microscopy. Cytometry Part A, 67A(2), 161-171. DOI: 10.1002/cyto.a.20173
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Nano Does a Mega Tango: FETs To Change The Fate Of Diabetics

The role of electronics in medicine or physiology is a very important one. Ranging from CT scan, fMRI, PET scan or electron microscopes and a variety of other medical investigations, medical science depends on electronics and its allied disciplines.

A simple illustration is as follows. Everyone knows that the estimation of blood glucose is the cornerstone in the diagnosis and therapy of diabetes mellitus and other hyperglycemic illnesses such as hyperthyroidism, hyperpituitarism and others. Even hypoglycemic ailments (conditions where the blood glucose levels are less than normal) like hypothyroidism, hypopituitarism or hyperinsulinemia, hypoadrenocorticism need the estimation or quantitation (quantification) of blood glucose, in order to clinch their diagnosis.

Glucose may be estimated in the blood in a variety of methods. One of the easiest methods rely on the simple reaction of glucose with potassium per-manganate. Glucose is a reducing monosachharide; while potassium permanganate is a strong oxidizing agent, so much so that it produces frank fire when added to glycerine not to mention of its emanation of oxygen (O2) when heated. When KMnO4 (potassium permanganate) is added to glucose, it (KMnO4) is reduced to manganese ions (Mn++). The colour changes from purple pink to colorless. This can be seen by the naked eye, giving us an estimate of the amount of total glucose that is present.

Another approach that is adopted nowadays is the enzymatic oxidation of glucose and their quantitation thereof. Here enzyme glucose oxidase (GOD) is used to oxidize glucose to D-gluconic acid and hydrogen peroxide (H2O2). In the presence of H2O2, hydrogen peroxidase (POD) oxidizes phenol, which combines with 4-amino antipyrine to form a red dye (quinone imine). The intensity of the red dye is linearly proportional (upto 500 mg% i.e. 500 mg per dl) to the glucose concentration in the specimen. The intensity of the color that is formed is measured by using a colorimeter; a device that measures the transmittivity of light (through the liquid) by employing LDR (Light Dependent Resistor) or phototransistors or similar devices.

Recently, advances in nanotechnology and nanoscience as a whole, is offering a brand new hope of determining blood glucose within the patients blood itself. That is you don't need to prick the guy. They are using a device called ISFET (Ion Sensitive Field Effect Transistor). It is variant of FET devices (a picture of a MOSFET i.e metal oxide semiconductor FET, is shown on the left). In a ordinary bipolar transistor, we forward bias the emitter-base junction by applying a current and make the collector strongly reverse biased. Thus any input current in the base emitter circuit is amplified several times when the electrons 'rushes' towards the attracting collector. A FET also works in much the same way. The difference is that the flow of charge carriers are controlled by a electric field applied in the Gate (G) Source (S) junction. This electric field is generated by a voltage: VGS. Thus while bipolar junction transistors (BJT) are current controlled, the FET devices are voltage controlled.

Recently, a team of physicists led by Raj Mohanty from Boston University has made a nanoscale glucose sensor using ISFETs and nanowires consisting of silicon. The silicon nanowires were primed with glucose oxidase on their surfaces and these nanowires bridged the source and the drain electrode of the MOS device. The conductivity of the 'wire' would change depending upon the glucose concentration in blood as it is reacted upon by the enzyme present on its surface. A voltage drop will ensue between the source and the drain electrodes, which may be read and interpreted by a voltage comparator. The researchers claimed that these could be put in vivo with virtually no risk. Humans do have the habit of carrying silicon on their bodies and that hardly do them any harm! We may be able to noninvasively monitor the blood glucose of diabetic persons, may even be able to act upon it, by incorporating a feedback circuit that would actuate an insulin pump, in times of hyperglycemia.