Iron Oxide Nanoparticles in Magnetic Resonance Imaging - Literature review Example

Iron Oxide nanoparticles in Magnetic Reasonance Imaging of Pancreatic Cancer Diagnosis and Treatment Introduction 1. Challenges in Imaging in Pancreatic cancer 1.2. Objectives 2. Background 2.1. MRI 2.2. MRI Contrast Agents 2.2.1 Gadolinium-based Contrast Agents 2.2.2 Iron Oxide Nanoparticles 3. Nanotechnology 4. Contrast Agents in Pancreatic Cancer 4.1. Gadolinium-based Contrast Agents in Pancreatic Cancer 4.2. IO nanoparticles contrast enhancement 4.2.1. Iron Oxide nanoparticples (IONPs) in MRI 4.2.2. IO nanoparticles for Tumor imaging 5. Other uses of Iron Oxide nanoparticles 5.1. Selected drug delivery of the Tumor-targeted IO nanoparticles 5.2. Use of enhanced IO nanoparticles in pancreatic cancer diagnosis and treatment 6. Conclusion Iron Oxide Nanoparticles Contrast Enhanced Magnetic Resonance in Pancreatic cancer diagnosis and treatment 1. Introduction 1.1. Challenges in Imaging in Pancreatic Cancer Pancreatic cancer is perceived as most aggressive of all cancers. Patients diagnosed with the disease have a 5-year relative survival rate. The situation is grave considering the percentage at which the patients survive which ranges between 2 and 10% (Miura et al, 2006). The survival rate of the pancreatic cancer patients would increase if the disease were diagnosed earlier. The most effective way of doing away with the pancreatic cancer is surgery. However, the effectiveness of the surgery is entirely dependent on the stage that the cancer is diagnosed. Earlier diagnosis increases the survival rates of the patients while rate diagnosis, which is mostly the case, increases he mortality rate. The first stage of the pancreatic cancer diagnosis is tumor detection. The tumor is not easily detectable and hence the increased mortality rate of the disease. The detection of the tumor is therefore an important stage in the efforts of treating and curing pancreatic cancer. MRI (Magnetic Resonance Imaging) is a process that enables the early confirmation of the pancreatic tumor thereby increasing the curability of the disease. Contrast agents are used in the MRI process. The commonly used contrast images are Gadolinium based Contrast agents and Iron Oxide nanoparticle enhanced contrast agents. The contrast agents allow for the formation of distinct images subsequently allowing for better determination of Carcinoma cells. The research paper looks into the role that Iron Oxide Nanoparticles enhance the magnetic Resonance in the quest for pancreatic cancer diagnosis and treatment. The paper is broken down to the different MRI and its contrast agents, Nanotechnology, Iron Oxide nanoparticles, and their importance in the diagnosis and treatment of pancreatic cancer and finally the effectiveness and dependability of the Nanoparticles in the curability of pancreatic cancer. The paper has clearly cut objectives, which should be addressed comprehensively throughout the paper. 1.2. Objectives Describe the mechanism in which Pancreatic Carcinoma develops. Relate the disease development with the accuracy and sensitivity of image detection. Compare the two main types of contrast agents used in MRI detection today along with their pros and cons. Show how contrast agents impact on improving image quality in MRI and how that improvement is achieved. Introduce the potential use of Nanoparticles as a multi-purpose tool. Combining the ideas together, from the research done on nanoparticles as Drug delivery vehicle to the practicality of using those same agents to detect and prevent aggressive forms of pancreatic cancer. 2. Background 2.1 Magnetic Resonance Imaging (MRI) According to Zhou and Lu (2012), Magnetic Resonance Imaging is a powerful medical modality that displays the anatomical structures of the body. MRI is quite important in detecting and characterizing the diseased tissues in the body as well as solid tumors. MRI produces a three-dimension, high resolution and contrast images of the tissues or tumor and does not release ionization radiation in the process. MRI uses a variety of contrast agents in relation to the tissue or body part involved in the process. Over the years, since its inception three years ago, the MRI technology has improved tremendously. General improvement in quality of the MR images that include spatial resolution, contrast-to-noise and signal-to-noise ratios have improved over the three decades. A combination of stronger magnets and adoption of safer and effective MRI contrast agents (CA) has improved the quality of images and the contrast between affected tissues and normal tissues. 2.2. MRI Contrast agents (CA) Contrast agents are important in the MRI process. Contrast agents are used to differentiate between the diseased tissues to normal parts of the body that are non-affected. A Magnetic Resonance image taken in the presence of a contrast agent shows a different contrast for the deceased tissue to the normal tissues. The contrast agents are biocompatible magnetic materials. The contrast of deceased tissues is achieved when agents alter the longitudinal (T1) and the Transverse (T2) relaxation rates of the available water protons in the tissue. The contrast agents are classified according to their magnetic properties, and their relaxation mechanisms in as either TI or T2. Good contrast agents must have a high relaxivity rate, tumor specific as well as have a low toxicity. This qualities increase the contrast efficiency in prediction diagnosing of the disease. Ever since the realization that the tumors have a different relaxation time to the normal tissues, MRI has been an important process in both the prediction and early diagnosis of cancerous tumors. Over the years, there has been an increased use of paramagnetic contrast agents to enhance image quality and thereby facilitating more accurate cancer detection and diagnosis. Early detection and diagnosis of cancer further makes it easy t evaluate the cancer stage and administering of efficient therapy. 2.2.1 Gadolinium-based Contrast Agents Gadolinium-based Contrast Agents (GBCAs) have been used for assessing tumors, inflammatory conditions and many other infectious conditions (Adiseshiah et al, 2013). GBCAs are made from Gadolinium metal (Gd) which is a scarce metal belonging to the lanthanide elements. Gadolinium has seven unpaired electrons that make it possible for slow electronic relaxation rate when used in MRI. Gadolinium based contrast agents produce a high T1 signal as they considerably shorten the T1 relaxation time for the surrounding water protons. Figure 1: Process of attaining a higher signal using GBCA in MRI (Source 2). In the above figure 1, the signal levels increases due to increasing relaxivity. The T1 relaxation time is short due to the increased T1 signal. The higher the T1 signal the higher the relaxivity r2 and hence a sharper image. The gadolinium in the GBCAs is in cheleated form and therefore does not increase toxicity by modifying the biodestribution. The USA Food and Beverage Administration (FDA) have categorized the GBCA into three regarding their biodestribution. The three categories include the extra cellular fluid agents, combined extra-cellular and liver agents and blood pool agents. The most commonly used are the extracellular agents used in the extracellular space. These agents do not cross to the blood vessels and therefore prevents toxicity and exit the body system through the kidneys in one and a half hours. 3. Nanotechnology Iron Oxide nanoparticles are made in a quite advanced technology referred to as nanotechnology. According to McCarrol et al (2010), nanotechnology is the manipulation of organic and inorganic substances to form much smaller scales called nanometers. Patil, Mehta & Guvva define Nanotechnology as the ‘research and development of materials, devices, and systems exhibiting physical, chemical, and biological properties that are different from those found on a larger scale.’ The products of Nanotechnology are much smaller than the viruses and molecules. However, the efficiency of the nanometers is greater than any person can imagine. The nanometers have a mighty effect on the different spheres of life. The smaller scales resulting from nanotechnology exhibit huge difference in functions as compared to the existing molecularorganic and non-organic matter. William Atkinson, the author of Nanoskom writes that the Nanotechnology seems inconceivably small but serves to exhibit huge differences in its functions. Atkinson compares nanotechnology to blizzards blowing across a city. The snowflakes have non-detectable weight even though they can stop all the activities in the city. Similarly nanotechnology produce small-scale nanoscales that contribute tremendously to the all the aspects of human life. Nanotechnology draws the researchers from many disciplines including, medicine, physics, and chemistry engineering and other subdisciplenes. It is aimed at providing so much desired solution for the problems presented in these disciplines. Nanomedicine is the technology in medicine facilitating the diagnostic, treatment, and disease prevention. The technology also helps in relieving pain and preservation and improvement of human life. The technology employs small nanoscales structured materials through genetic engineering, biotechnology using complex machines and nanorobots. The technology is seen to be an interdisciplinary act as it incorporates physics, chemistry, biology, engineering, and medicine to produce highly efficient nanoscales. In medicine, the technology has led to development of the Iron Oxide nanoparticles contrast Enhanced Magnetic Resonance. The Iron Oxide nanoparticles contrast work both as a better option for the Magnetic Resonance imaging (MRI) of the pancreatic cancer diagnosis. The technology is more advanced and thereby efficient than the commonly used Gadolinium contrast. However, the Iron Oxide particles have not been adopted fully because of the ethical discussions based on the implications of using such complex technology on the patients (McCarrol et al, 2010). 4. Contrast Agents in Pancreatic Cancer 4.1. Gadolinium based Contrast agents and pancreatic cancer While MRI is an efficient process in prediction and diagnosis of the disease, pancreatic cancer poses a problem to imaging. The problem is because of the ill-definitive nature of the cancerous tumor. In order to diagnose the tumor, there is need for optimizing the contrast for the tumor from that of the pancreatic parenchyma to enhance the ability to identify the disease (Tamm et al, 2010). 4.2. Iron Oxide Nanoparticles Contrast enhancement Iron oxide nanoparticles (IO) that are magnetic in nature are important in important for the biomedical applications. IO nanoparticles are used for cell labeling, magnetic Resonance Imaging and drug delivery (guided by the images from MRI). IO nanoparticles increase their uniformity and their magnetic properties when they are synthesized using pyrolysis of organometallic iron. The process leaves hydrophobic residue on the IO nanoparticles’ surface making them insoluble and unfit for biomedical applications (Gupta & Gupta, 2005). To make the nanoparticles biocompatible, increased efforts are carried out to fabricate them with biomedically functional coatings. The coating may also include synthetic polymers and natural products such as proteins. The transfer process of the IO hydrophobic nanoparticles to aqueous state aims at exchange the IO’s surface surfactants with the amphiphilic molecules for example PEG phospholipids, polyethylene glycol (PEG), polyethylinimine (PEI) and poly acrylic acid (PAA). The exchange method requires heating or sonicating to facilitate reactions between the IO nanoparticles and the coating materials. The process is conducted in a dipolar solvent (excluding protein coatings) such as the Dimethyl Sulphoxide (DMSO). The IO nanoparticles can be mixed with the IO proteins complex (aqueous) directly although it results to formation of large clusters, as the two materials are incompatible. Co-precipitation or post synthesis encapsulating of ferric or ferrous salts (inside protein cages) can also be used to form biomemic magnetic nanoparticles. The two processes of coating the IO nanoparticles may lead to formation of less powerful magnetic nanoparticles thereby developing a need to provide a more efficient method of protein coating the IO nanoparticles (Huang et al, 2014). Coating the IO nanoparticles with Casein enhances the ability of the IO nanoparticles in their biomedical activities. Other than being the main constituent of Bovine milk (80%), Casein contains phosphoproteins that are closely related. It specifically contains four types of phosphoprotein namely, αS1-, αS2-, β-, and κ-CN. The phosphoproteins have a molecular weight of 19-25 kDa and with an isoelectric point of 4.2-5.8. Casein binds small molecules and ions into micelles. The diameter of such micelles ranges from the 50-100 nm and deliver phosphates, calcium and other biomolecules thereby serving as a nanovehicle. The proline-rich phosphoproteins have an open structure and are hydrophobic and hydrophilic domains, which in turn allow casein to conform easily into the solution leading to the formation of Casein micelles. A Hair-like layer of k-casein molecules protrudes their hydrophilic C-terminal into the aqueous environment to stabilize the casein micelle. Casein structure is PH-responsive and changes in conformation and functionality while heated to 60-70 degrees Celsius. This property adds to its biodegradable and biocompatible nature. Numerous studies have been previously conducted on the Casein-based drug delivery systems anchored on the unique structural and physiochemical properties of casein. Figure 2: Shows the difference between a normal imaged tumor and an imaged tumor from an enhanced IO nanoparticle. (Source 19). 4.2.1 Iron Oxide nanoparticles (IONPs) in MRI Gadolinium based contrasts have been used for a long time to in diagnosis of tumors and deceased cells. However, the Gadolinium based contracts, though clinically approved shows low contrast effect, and has a very short retention in Vito. According to Kim et al, the biocompatibility and toxicity of gadolinium is not known both before and after endocytosis and therefore their efficient is questionable. The emergence of the magnetic Io nanoparticles has therefore come to salvage the situation within the MRI contrasting acting as a solution. With Magnetic IO nanoparticles, the relaxation promoters and high magnetic promoters are manipulated by simply controlling the coating and core surface sizes. IO nanoparticles are biodegradable show lower toxicity and have a long blood retention time (Montet et al, 2006). IO nanoparticles ranging from 5-10 nm require surface coating using amphiphilic triblock polymers to increase their functionalism. The IO nanoparticles provide functional groups for coupling the tumor targeting biomolecules for example antibodies or peptides (Peng et al, 2008). Tremendous improvement of IO nanoparticles to increase the contrast in MRI has been made. However, there are challenges characterizing the process such as creation of a surface coating to stabilize the nanoparticles as well as allow bioconjugation of ‘probe’ ligands by providing functional groups for example coating the IO nanoparticles with Casein to produce CNIO nanoparticles. The higher the magnetism of nanoparticles, the higher their contrast in the MRI process. IO nanoparticles magnetism is determined by the size, crystal culture, morphology and uniformity (Yu et al, 2006). Controlling these aspects of the IO nanoparticles therefore increases the magnetism of the nanoparticles. Recent studies have utilized available commercial formulations for example Ferumoxtran to develop magnetic Imaging probe with the IO nanoparticles. Ferumoxtran controls the morphology and size of the IO nanopacticles albeit to some extent and thereby increases the magnetization of the particles, which is important in the imaging contrast (figure 1 shows the imaging contrast provided by the IO nanoparticles). Although difference sizes of IO nanoparticles offer different magnetizations, 5-150nm is the preferred size for the IO nanoparticles. These sizes exhibit great target specificity hence used to target specific cells during the MRI process (Thorek et al, 2006). Using IO nanoparticles to image pancreatic cancer cells is important in providing a spatial resolution providing dynamic information and clear contrast. This is because the noninvasive modalities of the superamagnetic IO nanoparticles are regulated. The SPIO reduces the T2, which in turn increases the sensitivity to the right amount required for the MRI process. This reduces the amount of IO nanoparticles taken into the pancreatic cancer cells. The reduction of the T2 signal therefore reduces the intake of IO nanoparticles into the cells thereby increasing the signal. The strength of the T2 signal depends on the amount of the IO taken in by the cells. Uptake of the right amount of IO nanoparticles increases the T2 signal making the MRI process effective for drug delivery or any other follow up activity (Zuo, 2014). 4.2.3. IO nanoparticles for Tumor imaging When using the IO nanoparticles for providing contrast in MRI, both targeted and nontargeted IO nanoparticles are used. However, in nontargeted-IO nanoparticles, the particles cannot reach enough concentration in the tumors site to produce strong tumor signals for imaging subsequently, the IO nanoparticles do not carry enough therapeutic agents to the tumors site (Ryner et al, 2007). Developing tumor targeted IO nanoparticles, which are highly sensitive, and have a capability of taking sufficient amounts of therapeutic agent to the tumor site (Through conjugation). Targeting cancerous tumor cells is an example of the efficient use of tumor-targeted IO particle. Cancer develops by forming alterations and deformities to human cells thereby supporting the growth and progression of tumors. Cellular receptors develop a different imaging for normal cells as opposed to those of the cancerous tumor and therefore making it easy for them to be targeted through image probes as shown below in figure 3. According to Zuo (2014), the therapeutic nature of the IO nanoparticles are is achieved by coupling up the iRGD peptide with the nanoparticles. This enables the proper penetration of the therapeutic drugs into the tissues. Since the drugs are targeted for the pancreatic tumor, they provide an exclusive therapy to the tumor inhibiting it growth and increasing the survival rate of the person. If the pancreatic tumor is detected earlier, then the cancerous cells can be completely suppressed and eliminated from the pancreas. Figure 3: Shows the process involved in imaging out a tumor through the MRI process. Shows the organic ligands used to coat the IO nanoparticles. B is shows initial imaging. Increased contrast of the IO nanoparticles gives Imaging C while Imaging D is the final contrast of the image obtained (source 23). Several laboratories have studied antibody-targeted IO nanoparticles and found them to both the antibodies and the magnetic properties (Serda et al, 2007). In the studies, magnetism-engineered (MEIO) nanoparticles were conjugated with the Herceptin (antibody), against the HER2/neu receptor, which is highly expressed in breast cancer. In vivo cancer targeting and imaging of HER2/neu with high sensitivity enables the Magnetic Resonance of mall tumors as small as 50mg. The process however, requires large amounts of antibodies. The large amounts of antibodies not only inhibit the conjugation on the surface of IO nanoparticles but also limit its penetration through the vasculature into the tumor cells. The antibodies also overrode the tumor specificity of the targeted IO nanoparticles. To prevent all the disadvantages of the process, the peptides or single chained antibodies having small molecular masses are used as target deities in the IO nanoparticles. To create a persistent MRI contrast, peptides are used to target receptors on the tumors surface through receptor-related endocytosis. This increases the uptake of the conjugated IO nanoparticles producing a clear contrast for the cell in the process. Peptides of such nature can therefore be used to produce tumor targeted IO nanoparticles, which is useful in the detection of cancerous tumors in the tissue. There are several challenges associated with IO nanoparticles in tumor detection. For example, optimal number of ligands to targeted tumor is investigated every time as increased IO nanoparticles do not guarantee tumor detection but can affect the R2 characteristics. The ratio of ligands depends entirely on the molecular mass of the receptors the number of receptors as well as the binding affinity of ligands to the specific receptors. Another challenge associated with the process is the fate of the targeted IO nanoparticles once they get into the cell. While some scholars insist that the cells are degraded into lysosomes when they enter the endosomes, other scholars show that the particles can escape the endosomes and enter into the cytoplasm or settle around the nucleus. Conclusively, the conjugation of ligands and surface coating affect the IO nanoparticles’ distribution into the cell. The other problem associated with use of nanoparticles in tumor detection is the different amounts of IO nanoparticles used in different studies ranging from 1mg to 250 mg. This makes it hard to come up with a general conclusion from the different studies. It is also difficult to quantify the amount of IO nanoparticles in vivo. The MRI process can be combined with other labeling technologies to come up with multimodal imaging and measuring the IO nanoparticles biodistribution. In terms of sensitivity and specificity of IO nanoparticles contrast in MRI, the spleen, liver cells (kupffer) and bone marrow usually takes up some of the particles. This reduces the specificity and sensitivity of the IO nanoparticles. A study performed by Lee et al showed that as much as there were IO nanoparticles in the tumor, its traces were also found in the liver spleen and muscle of the mice they were using for the research (Lee et al, 2007). Research on how to reduce the unspecified intake of IO nanoparticles showed that injection of the macrophalanges with MG-CoA reductase inhibitor Lovastanin (1μM) significantly reduces particles intake by 61%. The inhibitor inhibits the macrophalanges receptors from taking in the tumor-targeted IO nanoparticles thereby increasing their specificity and specificity (Rogers & Basu, 2005). The size of the IO nanoparticles also affects the distribution in the tumor. For example particles with 200nm and above diameter have a higher chance of absorption by the spleen as compared to those that range from 5-150nm. The smaller the diameter of the IO nanoparticles, the most evenly it is distributed tissues (tumors) and hence specificity (Gupta & Gupta, 2005). 5. Other uses of IO nanoparticles 5.1. Selective drug delivery of the Tumor-targeted IO nanoparticles The increased level of sensitivity in the tumor-targeted IO nanoparticles has been used successfully to deliver drugs exclusively to the tumor (Hadjipanayis et al, 2010) According to the drug delivery can take place by conjugating specific antibodies to the tumor-targeted IO nanoparticles to selectively bind the related receptors, subsequently inhibiting the further growth of the tumor. Another drug delivery method involves loading the targeted IO nanoparticles with the drugs to the target tumor for treatment and therapy (as shown in figure 4). Finally, tumor therapy using hypothermia can be administered through the targeted IO nanoparticles (Jordan et al, 2006). The strategies used to incorporate the drugs into the IO nanoparticles include trapping drugs within the nanoparticles, depositing the drugs into the surface layer and linkage to the carrier particle. They are released into the tumor cell through vehicle rapture, endocytosis, diffusion, and dissolution. Drug distribution can be determined by the imaging distribution in the targeted site and complemented by radio- or dying of the drugs for clear contrast (Chen et al, 2007). Figure 3: shows the drug delivery process using targeted IO nanoparticles (Source 6) 5.2. Use of enhanced IO nanoparticles in pancreatic cancer diagnosis and treatment Surgery has for a long time been the most common method of treating pancreatic cancer for patients. However, the effective of the process is questionable as not many people who are treated for pancreatic cancer live for more than five years after surgery (Jemal et al 2010, Chari 2007). The gradual process of developing magnetic nanoparticles such as the Iron Oxide nanoparticles has influenced the way the cancer is handled in a revolutionary way (Gupta et al, 2007). The process involves Targeted (pancreatic cancer) tumor IO nanoparticles sent to the pancreas to detect the tumor (Kelly et al, 2007) .First the biomarkers of pancreatic cancer are identified to make it easier for the Magnetic resonance imaging (MRI). Efficient biomarkers of the pancreatic cancer tumors have been developed owing to numerous researches on nanotechnology and cancerous tumor. The tumor then follows the above outlined process of MRI. The IO nanoparticles used in the MRI are enhanced with Casein to provide efficiency and correct detection of the tumor. Once the tumor has been detected then the right mechanism of drug administration is chosen. The drug administration method can either be done by conjugating the IO nanoparticles with antibodies to deliver chemotherapy drugs (Chertok et al, 2008), binding the tumor cells to prevent further growth or hypothermia for tumor therapy (Jordan et al, 2007). 6. Conclusion Pancreatic cancer has for a long time been a killer disease to its patients. The survival rate of cancer patients is not guaranteed even after a successful surgery for the tumor removal. Nanotechnology however has given rise to nanomedicine, which has been a revolutionary invention. Nanotechnology has subsequently led to the production of nanoparticles, which are small yet efficient molecules not only in physics but also in biology chemistry and engineering. A combination of these sciences has further led to creation of the Iron Oxide nanoparticles. The Io nanoparticles have revolutionalized the pancreatic cancer treatment as well as many other numerous diseases. Magnetic resonance Imaging through enhanced IO nanoparticles contrast has enabled the diagnosis of pancreatic cancer tumor and subsequent treating of the disease. The enhanced IO nanoparticles provide a clear contrast to the pancreatic cancer tumor when used in MRI. Consequently, the IO nanoparticles have replaced the use of Gadolinium-based contrast agents that have been used previously in pancreatic cancer diagnosis. Gadolinium-based contrast agents are at times toxic to other body tissues and hence the need to replace them with IO nanoparticles. In addition, iron oxide nanoparticles are also used in the drug delivery to the pancreatic cancer tumor exclusively without affecting any other part of the body. With this new technology of pancreatic cancer treatment, patients are treated without toxic cancer drugs affecting their body systems and functionality and the patients are assured of a prolonged survival period. References Adiseshaiah, P., Dellinger, A., MacFarland, D., Stern, S., Dobrovolskaia, M., Ileva, L., and Kepley, C. (2013). ‘A Novel Gadolinium-Based Trimetasphere Metallofullerene for Application as a Magnetic Resonance Imaging Contrast Agent.’ Investigative radiology, vol. 48, issue 11, pp. 745-754. ‘Attaining a higher MRI image.’ (n.d) Retrieved on 15th March 2015 Chari, S. T. (2007, August). ‘Detecting early pancreatic cancer: problems and prospects.’ In Seminars in oncology  WB Saunders, Vol. 34, issue 4, pp. 284-294. Chen H, Gu Y, Hub Y, et al (2007). ‘Characterization of pH- and temperature-sensitive hydrogel nanoparticles for controlled drug release.’ PDA J Pharm Sci Technol. Vol. 61, pp. 303–13. Chertok, B., Moffat, B. A., David, A. E., Yu, F., Bergemann, C., Ross, B. D., and Yang, V. C. (2008). ‘Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors.’ Biomaterials, vol. 29, issue 4, pp. 487-496. ‘Drug delivery through target Iron Oxide Nanoparticles.’ (n.d.). Retrieved on 15th March 2015 Gupta, A. K., and Gupta, M. (2005). ‘Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications.’ Biomaterials, vol. 26, issue 18, pp. 3995-4021. Gupta, A. K., Naregalkar, R. R., Vaidya, V. D., and Gupta, M. (2007). ‘Recent advances on surface engineering of magnetic iron oxide nanoparticles and their biomedical applications.’ Hadjipanayis, C. G., Machaidze, R., Kaluzova, M., Wang, L., Schuette, A. J., Chen, H., and Mao, H. (2010). ‘EGFRvIII antibody–conjugated iron oxide nanoparticles for magnetic resonance imaging–guided convection-enhanced delivery and targeted therapy of glioblastoma.’ Cancer research, vol. 70, issue 15, pp. 6303-6312. Haroyan, H., and Ginat, D. T. (2015). ‘Gadolinium- Based Contrast Agents.’ InNeuroimaging Pharmacopoeia, pp. 105-110. Huang, J., Wang, L., Lin, R., Wang, A. Y., Yang, L., Kuang, M., and Mao, H. (2013). ‘Casein-coated iron oxide nanoparticles for high MRI contrast enhancement and efficient cell targeting.’ ACS applied materials & interfaces, vol. 5, issue 11, pp. 4632-4639. Huh YM, Jun YW, Song HT, et al (2005).  ‘In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals.’ J Am Chem Soc. Vol. 127, pp. 12387–91. Jemal, A., Siegel, R., Xu, J., and Ward, E. (2010). ‘Cancer statistics, 2010.’ CA: a cancer journal for clinician. Kelly, K. A., Bardeesy, N., Anbazhagan, R., Gurumurthy, S., Berger, J., Alencar, H., and Weissleder, R. (2008). ‘Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma.’ PLoS medicine, vol. 5, issue 4, e85. Kim D, Hong KS, and Song J. ‘The present status of cell tracking methods in animal models using magnetic resonance imaging technology.’ Mol Cells. Vol. 23, pp. 132–7.  Lee JH, Huh YM, Jun YW, et al. (2007b). ‘Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging.’ Nat Med. Vol.13, pp. 95–9.  Miura, F., Takada, T., Amano, H., Yoshida, M., Furui, S., and Takeshita, K. (2006). ‘Diagnosis of pancreatic cancer.’ HPB, vol. 8, issue 5, pp. 337-342. Montet X, Montet-Abou K, Reynolds F, et al. (2006). ‘Nanoparticle imaging of integrins on tumor cells.’ Neoplasia. Vol. 8, pp. 214–22.  ‘Pancreatic Cancer Tumor Imaging using Iron Oxide nanoparticles.’ (n.d.). Retrieved on 15th March 2015 Patil, M., Mehta, D. S., and Guvva, S. (2008). ‘Future impact of nanotechnology on medicine and dentistry.’ Journal of Indian Society of Periodontology, vol. 12, issue 2, pp. 34. Tamm, E. P., Balachandran, A., Bhosale, P. R., and Marcal, L. P. (2010). ‘MRI and MRCP for Diagnosis and Staging of Pancreatic Cancer.’ In Pancreatic Cancer. pp. 731-761. Thorek DL, Chen AK, Czupryna J, et al. (2006). ‘Superparamagnetic iron oxide nanoparticle probes for molecular imaging.’ Ann Biomed Eng. Vol. 34, pp. 23–38. ‘Tumor imaging using IO nanoparticles.’ (n.d.). Retrieved on 15th March 2015 Yu, M. K., Jeong, Y. Y., Park, J., Park, S., Kim, J. W., Min, J. J., and Jon, S. (2008). ‘Drug‐loaded superparamagnetic iron oxide nanoparticles for combined cancer imaging and therapy in vivo.’ Angewandte Chemie International Edition. Vol. 47, issue 29, pp. 5362-5365. Zeng, L., Ren, W., Zheng, J., Cui, P., and Wu, A. (2012). ‘Ultrasmall water-soluble metal-iron oxide nanoparticles as T 1-weighted contrast agents for magnetic resonance imaging.’ Physical Chemistry Chemical Physics, Vol 14, issue 8, pp. 2631-2636. Zhou, Z., and Lu, Z. R. (2013). ‘Gadolinium‐based contrast agents for magnetic resonance cancer imaging.’ Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, volume 5, issue 1, pp. 1-18. Zuo, H. D., Yao, W. W., Chen, T. W., Zhu, J., Zhang, J. J., Pu, Y., and Zhang, X. M. (2014). ‘The effect of superparamagnetic iron oxide with iRGD peptide on the labeling of pancreatic cancer cells in vitro: a preliminary study.’ BioMed research international. Read More