Gadolinium-based Ferrite Nanoparticles Synthesis

Gadolinium-based Ferrite Nanoparticles SynthesisSAMRAT MAZUMDARAbstractCancer is by far one of the most(prenominal) challenging affections for centuries. In the US, it accounts for over a million deaths annually and is expected to rise in the coming future. Therefore, there is vital need to develop novel strategies, which toilette help in combating the disease at any level. Metallic nanoparticles present an interesting view, which can function as both therapeutic and diagnostic agents due to their unique properties. The main theme of the proposed work is development of gadolinium based magnetic nanoparticles, followed by their surface functionalization which may improve imaging and targeting outcomes. Doped Gadolinium nanoparticles will be ready by co-precipitation method for optimum magnetic properties. The synthesized particles will be subjected to functionalization with suitable group for specific target in nature for cancer cells. Eventually,in-vitrostudies will be carried out to validate the hyperthermy effect on cancer cells.1. IntroductionOverviewAlthough, it is difficult to define cancer, but in simple terms, it is a group of cerebrate diseases which is characterized by uncontrolled cell proliferation and spread, mostly due to loss of control in the cell cycle (Prez-Herrero and Fernndez-Medarde, 2015). The most commonly detected cancers argon lung cancer, teat cancer and skin cancer, etc. A variety of factors contributes to the disease progression, such as genetic changes, infections and exposure to carcinogens. In general, cancer is detected/diagnosed by assorted techniques like, blood tests, X-ray imaging, Computed Tomography (CT) scanning and Endoscopy etc. Conventional discourse strategies include surgery, chemotherapy and radiation therapy. However, they possess numerous limitations especially dose-related side effects and toxicity (Brigger et al., 2002). Currently, researchers atomic number 18 looking towards newer approaches which a re selective, non-invasive, non-toxic and effective. These efforts are led to the development of experimental cancer therapies. These not only improves the curing rate but in like manner, act as a supplement to the conventional therapies. However, it is still early to state that these alternatives can completely replace the existing treatment strategies and its authority in clinical settings, are yet to be determined.Alternative approaches include Gene therapy (Vile et al., 2000), Photodynamic Therapy (PDT) (Dougherty et al., 1998), hyperthermy (Urano, 1999) ,Targeted Nano-medicines (Xu et al., 2015). Recently, a tremendous amount of research is being carried out in the content of hyperthermia due to encouraging results and its potential for significantly lowered toxicity. hyperthermyHyperthermia is a very ancient technique which is now regaining popularity in the field of oncology (Seegenschmiedt and Vernon, 1995). It involves the use of change energy to elevate the temperatur e inside a neoplasm tissue and subsequently kill the cancer cells. The desired temperature run for for hyperthermia is 42-44C which is, greater than the physiological temperature (Wust et al., 2002).There is a variety of factors governing the effectiveness of hyperthermia which includes thermal variables, device characteristics, frequency, current and tumour morphology (Valdagni et al., 1988). At temperatures down the stairs 41C, blood flow increases while tissue oxygenation increases higher up 41C providing a dual effect against tumour. Once temperatures are increased above 42.5C-43C, the exposure time can be halved for every 1C rise to declare oneself a similar heating plant efficiency however, excessive heating should be avoided. The heating device used for hyperthermia should be versatile, comfortable as well capable of exhibiting uniform heating patterns. The applied frequencies may range from 5-500 KHz (Lacroix et al., 2008) while a current of about 100-800A skill be suf ficient for heating. Studies suggest that en wide-rangingd tumour with poor vasculature might be more susceptible to heat treatment (Kim et al., 1982).Hyperthermia has a radiosensitizing effect which can be advantageous in combination with radiotherapy since most radioresistant cells are heat sensitive.Classification of HyperthermiaDirect heating/Extracellular method Heat is applied by means of external sources such as thermostatic pee bath, infrared sauna and ultrasound. This approach is limited by the presence of biological barriers which is amenable for insulation. Therefore, excess heat is required to achieve the same which can motivate side effects (burns, bleeding).Indirect heating/Intracellular method Provides a safer and effective means through the injection of nanoparticles followed by their internalization (Ningthoujam et al., 2012).Ex. magnetic hyperthermia. implement of HyperthermiaPrimarily, hyperthermia induce apoptosis, necrosis or autophagy through multiple pa thways to cells (Hurwitz and Stauffer, 2014). Reports suggest that it can deliver a higher amount of oxygen into the hypoxic tumour region through changes in blood perfusion. Generally, tumour cells express lower concentration of Heat Shock Proteins (HSP) in comparison to normal cells. Therefore, HSP-peptide complex levels can be increased significantly by the application of hyperthermia, further leading to anti-tumour immunity response (Kobayashi et al., 2014).Magnetic HyperthermiaIn order to prevent aggrieve to surrounding healthy tissues from the hyperthermia effect, nanoparticles should be confined to a defined area (tumour region). These are achieved through targeting of nanoparticles by functionalization and application of magnetic fields to condition regions (Baobre-Lpez et al., 2013). Metallic magnetic nanoparticles under the influence of oscillating magnetic field undergo a change in magnetic moment attributed to Neel and Brownian fluctuations. These fluctuations are resp onsible for heat generation through friction, which might be effective in damaging the cancer cells.Limitations of Magnetic HyperthermiaThere are technical problems which may act as a barrier towards effective treatment. The two main aspects include uniform heat distribution and desired target temperature (Brusentsova et al., 2005). Treatment might be a failure in case of insufficient thermal dose .There are no well-defined methods used to evaluate the temperature distribution in the target area but, Magnetic Resonance Imaging (MRI) can be used to generate a temperature profile corresponding to hyperthermia. MRI can also be helpful in tracking the release of drug from a formulation (Tashjian et al., 2008).MRI Contrast AgentsIn the Magnetic Resonance Imaging (MRI) system, most of the magnetic materials (iron based materials) act as T2 contrast agents which give rise to darkened image/negative contrast. Subsequently, this is mode is useful for tracking purpose. However, there are a fe w disadvantages which limit their usability in clinical settings. Firstly, the dark images accompanied by low signal intensity may often lead to misdiagnosis and secondly, the large magnetic susceptibility can produce MRI artifacts making it increasingly difficult to determine the exact state of the injury or damage. T1 contrast agents (Gadolinium, Manganese) provide a brighter signal, which can be easily observed in the MRI due to their paramagnetic nature which do not disrupt the magnetic homogeneousness (Gallo and Long, 2015). Through nanotechnology, it is also possible to simultaneously carry out imaging and drug delivery further, overcoming the limitations posed by the conventional system.2. Hypothesis/RationaleThe paramagnetic Gadolinium exhibits excellent MRI imaging capabilities which can be exploited for several purposes and possesses high magnetic moment. Due to its limited inter-atomic interactions, it is unable produce hyperthermia. We meditate that by modifying the pr operties of gadolinium, it may serve a dual purpose i.e. hyperthermia and imaging. Furthermore, these particles can be tagged with various targeting moieties or loaded with anti-cancer drugs to increase the effectiveness of the therapy.3. ObjectivesOn the basis of above background, the objectives are as follows.Synthesis and optimization of Gadolinium-based ferrite nanoparticles.Surface modification of prepared nanoparticles.Folate adjunction to the modified surface coating.Optimization of hyperthermiaCharacterization and in-vitro studies4. Plan of work4.1 Synthesis and Optimization of Gadolinium-based ferrite nanoparticlesGadolinium based ferrite nanoparticles will be synthesised using suitable mechanisms such as chemic co-precipitation method and optimized.4.2 Surface modification of prepared nanoparticlesSurface modification will be carried out by layer by layer (LBL) synthesis.4.3 Folate conjugation to the modified surface coatingSince most cancer cells overexpress folate rece ptor, folic acid will be conjugated to nanoparticles through amine functionalization.4.4 Optimization of hyperthermiaThe work on will be optimized by monitoring the parameters affecting it.4.5 Characterization and in-vitro studies4.5.1 CharacterizationThe developed nanoparticle will be characterized by the following techniques.Particle size compend -Zetasizer.Chemical Composition determination-Fourier Transform Infrared Spectroscopy (FTIR),Structural and Crystalline analysis- X-ray Diffraction pattern.Surface Morphology-Scanning Electron Microscopy, Transmission Electron Microscopy.Magnetic Property Testing- Vibrating warning Magnetometry.4.5.2 In vitro studiesCytotoxicity studies MTT Assay will be performed to assess the cytotoxicity and biocompatibility of nanoparticles.In-vitro hyperthermia studies with cancer cell linesCellular uptake studies- Performed using Transmission electron microscopy and Electron distributive X-ray spectroscopy.Magnetic Resonance Imaging studies.5. Expected OutcomesThe developed nanoparticles might exhibitImproved magnetic hyperthermia in comparison to unmodified gadolinium particle.Target localization may be observed through Magnetic Resonance Imaging.6. Future ProspectsBased on in-vitro results in-vivo studies can be performed in animals. This treatment modality can be combined with Photodynamic Therapy and Chemotherapy for better results.7. ReferencesBaobre-Lpez, M., Teijeiro, A. Rivas, J. 2013. Magnetic Nanoparticle-Based Hyperthermia For Cancer Treatment. Reports Of Practical Oncology Radiotherapy, 18, 397-400.Brigger, I., Dubernet, C. Couvreur, P. 2002. Nanoparticles In Cancer Therapy And Diagnosis. Advanced Drug bringing Reviews, 54, 631-651.Brusentsova, T. N., Brusentsov, N. A., Kuznetsov, V. D. Nikiforov, V. N. 2005. Synthesis And Investigation Of Magnetic Properties Of Gd-Substituted MnZn Ferrite Nanoparticles As A Potential Low-T C Agent For Magnetic Fluid Hyperthermia. Journal Of Magnetism And Magnetic Materia ls, 293, 298-302.Dougherty, T. J., Gomer, C. J., Henderson, B. W., Jori, G., Kessel, D., Korbelik, M., Moan, J. Peng, Q. 1998. Photodynamic Therapy. Journal Of The National Cancer Institute, 90, 889-905.Gallo, J. Long, N. J. 2015. Nanoparticulate Mri Contrast Agents. The Chemistry Of Molecular Imaging, 199-224.Hurwitz, M. Stauffer, P. Hyperthermia, Radiation And Chemotherapy The Role Of Heat In Multidisciplinary Cancer Care. Seminars In Oncology, 2014. Elsevier, 714-729.Kim, J. H., Hahn, E. W. Ahmed, S. A. 1982. Combination Hyperthermia And Radiation Therapy For Malignant Melanoma. Cancer, 50, 478-482.Kobayashi, T., Kakimi, K., Nakayama, E. Jimbow, K. 2014. Antitumor Immunity By Magnetic Nanoparticle-Mediated Hyperthermia. Nanomedicine, 9, 1715-1726.Lacroix, L. M., Carrey, J. Respaud, M. 2008. A Frequency-Adjustable Electromagnet For Hyperthermia Measurements On Magnetic Nanoparticles. Rev Sci Instrum, 79, 093909.Ningthoujam, R., Vatsa, R., Kumar, A., Pandey, B., Banerjee, S. Tyagi, A. 2012. Functionalized Magnetic Nanoparticles Concepts, Synthesis And Application In Cancer Hyperthermia. Functionalized Materials, 229-260.Prez-Herrero, E. Fernndez-Medarde, A. 2015. Advanced Targeted Therapies In Cancer Drug Nanocarriers, The Future Of Chemotherapy. European Journal Of Pharmaceutics And Biopharmaceutics, 93, 52-79.Seegenschmiedt, M. Vernon, C. 1995. A Historical Perspective On Hyperthermia In Oncology. Thermoradiotherapy And Thermochemotherapy. Springer.Tashjian, J. A., Dewhirst, M. W., Needham, D. Viglianti, B. L. 2008. Rationale For And Measurement Of Liposomal Drug Delivery With Hyperthermia Using Non-Invasive Imaging Techniques. International Journal Of Hyperthermia, 24, 79-90.Urano, M. 1999. Invited Review For The Clinical Application Of Thermochemotherapy Given At Mild Temperatures. International Journal Of Hyperthermia, 15, 79-107.Valdagni, R., Liu, F.-F. Kapp, D. S. 1988. Important Prognostic Factors Influencing Outcome Of Combined Radiation A nd Hyperthermia. International Journal Of Radiation Oncology* Biology* Physics, 15, 959-972.Vile, R., Russell, S. Lemoine, N. 2000. Cancer Gene Therapy lowering Lessons And New Courses. Gene Therapy, 7, 2-8.Wust, P., Hildebrandt, B., Sreenivasa, G., Rau, B., Gellermann, J., Riess, H., Felix, R. Schlag, P. 2002. Hyperthermia In Combined Treatment Of Cancer. The Lancet Oncology, 3, 487-497.Xu, X., Ho, W., Zhang, X., Bertrand, N. Farokhzad, O. 2015. Cancer Nanomedicine From Targeted Delivery To Combination Therapy. Trends In Molecular Medicine, 21, 223-232.8. RequirementsChemicalsInstruments