Technology has revolutionised medicine in the past century. We now have imaging methodologies like X-rays, Computed Tomography (CT) scans and Magnetic Resonance Imaging (MRI) allowing us a look inside the body without cutting it open. Nanotechnology seems poised to write the next chapter of this revolution, with various applications in biomedical imaging, diagnosis and effective treatment of diseases. In yet another advancement in this direction, an interdisciplinary team of scientists from Materials Engineering Department and Department of Microbiology and Cell Biology at the Indian Institute of Science (IISc), Bangalore, have synthesised iron nanoparticles without any oxide cover that could be used to enhance the sensitivity of MRI by producing images with better contrast. They have also demonstrated the potential application of this research in the targeted delivery of medicines and other biological molecules to specific organs in the body.
MRI works on the principle of Nuclear Magnetic Resonance (NMR) and does not use harmful ionising radiation like X-rays. Instead, it takes advantage of the magnetic properties of hydrogen atoms present abundantly in our body as a constituent of water and fat. The nuclei of hydrogen atoms behave like little bar magnets. During MRI, a very strong magnetic field is applied which aligns the spins of hydrogen nuclei. A short duration radio frequency (RF) pulse is subsequently applied which disrupts the spin alignment and tips the direction of some spins in the opposite direction. Once the RF pulse ceases, nuclear spins relax back to the original aligned position.
The energy loss during relaxation generates signals that are captured by the detectors and are processed into images. The relaxation processes are governed by microscopic energy interactions between molecules and small fluctuations in the magnetic field surrounding the water molecules. Hence, relaxation time of nuclei and consequently, brightness levels of the tissues in the MR image vary with their type, composition and location, allowing different regions to be distinguished.
The sensitivity of MRI can be improved by increasing the contrast between different types of tissues. For this purpose, magnetic contrast agents - magnetic metal ions or nanoparticles - are administered either orally or by injection into the blood stream, depending on the body part to be imaged. Since the contrast agents are themselves magnetic, they produce disturbances in the magnetic field around them, thus altering relaxation rates of the nuclei in their proximity. Several contrast agents based on gadolinium and iron oxide nanoparticles are used clinically.
However, the researchers believe that pure iron nanoparticles are a better candidate as magnetic contrast agents. “The strength of the magnetic field generated in the nanoparticles due to application of an external magnetic field (also called magnetic saturation), of iron oxide is 3 times lower compared to pure iron. Use of pure iron nanoparticles would provide a better contrast at lower quantities. This is a major advantage since increased levels of such nanoparticles are toxic to the body”, explains Prof. K. Chattopadhyay, head of the Non-equilibrium processing and Nano materials group at IISc and one of the lead authors of the publication.
Yet, studies on using pure iron nanoparticles as MRI contrast agents are sparse presumably because of the difficulty in preparing these nanoparticles. Iron tends to oxidise fast and researchers end up with particles consisting of an iron core and an iron oxide shell by the end of the nanoparticle fabrication process. Dr. Tiwary, Sharan Kishore, Sanjay Kashyapand and the group head Prof. K. Chattopadhyay made headway in preparing pure iron nanoparticles in bulk, thanks to the in-house developed cryomill named KC0. The cryomill repeatedly goes on grinding metallic iron to eventually form particles of size in the nanometer range. Since the milling is done at liquid nitrogen temperature (-123oC), oxygen does not react with iron, thus keeping the particles free of iron oxide impurity. Nanoparticles of around 8-10 nm size were prepared using the cryomill for the present study.
Prof. Chattopadhyay’s group collaborated with the research groups of Prof. Dipshikha Chakravortty (Department of Microbiology and Cell Biology, Centre for Biosystems Science and Engineering) and Prof. Ashok M. Raichur (Materials Engineering department) for further study on the viability of using pure iron nanoparticles for biomedical imaging. Toxicity is the major concern faced in using nanoparticles inside the body. Most nanoparticles are administered after covering the surface with a biocompatible organic molecule in a process called biocapping. The researchers of this study used dextran, a polysaccharide to biocap the iron nanoparticles. They also observed the effects of these nanoparticles on red blood cells and two different cell lines, confirming that there is no significant toxicity at concentrations less than 50 µg/ml.
The interdisciplinary team of researchers used mice to study the functioning of iron nanoparticles in a living body. Since the biocapping molecule used was a dye, fluorescence imaging helped them track the movement of the nanoparticles within the mice. On application of an external magnetic field using a bar magnet near the abdomen, the nanoparticles accumulated there, suggesting that they can be easily guided using an external field. This demonstrates their use as potential targeted delivery systems– which can carry medicines to target organs or act as selective contrast agents for specific tissues in an MRI image.
This research is undoubtedly an addition to the worldwide efforts on MRI contrast agents and targeted delivery systems. “Going forward, we need to understand how it gets suspended in the body, how it will affect the liver, the amount of time it can remain suspended in the body during imaging, etc.”, remark lead authors Dr. Tiwary and Rajeev about the future of the study.