Cytokines are a group of small proteins or glycoproteins that regulate key intracellular communication within the body. While most of these small proteins are generated by the cells of the immune system, they can still play a role in many additional non-immune processes including cell differentiation and migration.
Cytokines have a diverse structure, and so far, over 200 different species have been identified. The cytokine superfamily consists of interferons, lymphokines, interleukins, and growth factors. The cytokines have many different modes of action such as:
- Surface-bound effectors of cell-cell interactions
- Substrates of specific surface receptors that trigger complex transduction pathways to regulate gene expression
- Soluble mediators that regulate transcription directly
Macrophage releasing cytokines. Credit: sciencepics/Shutterstock.com
Clinical applications of cytokines
As cytokines play an important role in a number of pathways across a wide range of biological systems, they have become a subject of intense research to gain a better insight into the signaling mechanisms behind key biochemical processes and thus, develop new therapeutic approaches.
Notable advances have been made by specific targeting of cytokines for the treatment of various diseases. In the treatment of inflammatory disorders, such as rheumatoid arthritis1 and Crohn's disease2, anti-tumor necrosis factor therapies have proved to be very successful. Cancer therapy3,4 was redefined through the use of drugs that prevent growth factors, such as fibroblast growth factor (FGF) and epidermal growth factor (EGF), from influencing the tumor cells.
There is a huge potential for cytokine-targeted therapies, as they mediate such wide-ranging cellular regulation. The clinical use of cytokines has also been investigated in many other disease areas such as chronic renal failure, bone marrow failure, ophthalmology, and acquired immunodeficiency syndrome.
New approach to cytokine-targeted chemotherapy
However, while the cytokines appear to be promising therapeutic targets for a number of disorders, because of their broad-ranging effects, the very same effects can also limit the clinical use of cytokine-targeted therapies.
Cytokines have many complex biological functions that overlap frequently, and hence, a given cytokine may cause changes in several systems. As a result, a trade-off between beneficial effects and detrimental effects is usually required when cytokines are used as therapy for disease states. However, in some cases, the side effects reach unacceptable levels before optimal therapeutic benefits can be realized. This presents problems during cancer treatment.
Antibody-cytokine fusions have been used for cytokine therapies in order to localize cytokine activity to the preferred area, and as a result, the systemic dose-limiting side effects are reduced. When tumors are the target, side effects present issues even though the treatment potential showed improvement in many areas. Additionally, cytokines short half-lives (due to being typically unstable) mean that they can become inactive prior to reaching the target site.
Recently, research was conducted on a new application of magnetic nanoparticles. The study showed that cytokine-targeted therapy could be limited to highly localized areas that require intervention, thus preventing the risk of systemic side effects. In this manner, a cytokine that encourages the growth of malignant tumors may be prevented from influencing the tumor cells without affecting many other pathways in which it is involved.
With diameters of just 1 to 100 nm, magnetic nanoparticles possess unique magnetic properties such as high magnetic susceptibility and superparamagnetism. When exposed to a magnetic field, these particles display a unique response that has made them useful in various environmental, industrial, and medical applications7.
Magnetic nanoparticles are non-immunogenic8,9 and non-toxic, and hence, are an attractive choice for medical applications. Moreover, due to their submicron size, they can travel freely in the human circulatory system and can cluster within the tissues. Magnetic nanoparticles are already being used as contrast agents for magnetic resonance imaging10 as well as targeted drug delivery11.
When a magnetic field is applied, magnetic nanoparticles generate heat, which can be used to activate a drug conjugated to the magnetic nanoparticles, or to kill target cells. However, a magnetic field has to be applied to achieve the desired therapeutic effect, and hence, it should be localized to a target area.
The nanoparticle and the specific application dictate the frequency and strength of the required magnetic field. With more and more use of magnetic nanoparticles, a unique system has been developed to provide the required magnetic field for their activation. The magneThermTM (nanoTherics Ltd, UK) produces homogeneous, monochromatic alternating magnetic fields across various field strengths and frequencies to facilitate easy selection based on requirements.
The thermal effects of magnetic nanoparticles can be measured by using the magneThermTM, thus making the system suitable for conducting calorimetric studies. The same system can be used for both in vivo and in vitro applications, thanks to its wide sample aperture.
Studies are being conducted on magnetic nanoparticles being agents for hyperthermia treatment and biotherapeutics12. Two such examples are described below.
Magnetic nanoparticles in targeted hyperthermia cancer treatment
Generally, epidermal growth factor (EGF) regulates normal cell growth, differentiation, and repair, but is over-expressed in a number of tumors. EGF receptors are abundantly present on the surface of the cells, and therefore, EGF can be employed to treat tumor cells. However, healthy cells also contain EGF, and hence, non-cancerous cells can also be damaged by the side effects caused by the attachment of cytotoxic agents.
EGFR (or ErB-1 or HER1 in humans): epidermal growth factor receptor: an extracellular protein ligand and its signaling pathway. Credit: ellepigrafica/Shutterstock.com
When magnetic nanoparticles get attached to the EGF, the destructive effects are focused only to the target malignant tissue. When subjected to a magnetic field, magnetic nanoparticles generate heat. Thus, when an alternating magnetic field is applied to the area where tumor is present, the heat causes damage only to this tumor-existing area. In this manner, the cancer cells can be destroyed with no noticeable increase in temperature of the medium containing the cells13. This study conclusion could pave the way for targeted destruction of metastatic cancers and small tumors through magnetic nanoparticle hyperthermia treatment.
Remote activation of cytokines using magnetic nanoparticles
The regulation of various key cellular functions, including apoptosis, cell differentiation, cell growth, and cellular homeostasis, depends on the cytokine transforming growth factor beta (TGFB). TGFB is present in high concentrations in bones and blood platelets, though it has an effect on all types of cells in the human body. TGFB is said to cause many diseases, including atherosclerosis, prostate cancer, and fibrosis. Hence, controlling the activity of this cytokine TGFB would provide a powerful tool in regenerative medicine. Yet this is difficult to achieve because TGFB exists mostly in a latent form and has to be activated prior to its binding to the surface receptors and the active form is not very stable.
Magnetic nanoparticles have been used in recent research studies to successfully activate the latent TGFB complex at the site in which active TGFB is needed14. Iron oxide magnetic nanoparticles were conjugated with the latent TGFB complex. When a radio frequency magnetic field was applied, the active TGFB was released in a controlled area. Thus, the regenerative effects of the TGFB could be utilized where they were required, without causing detrimental effects in the body.
- Chaabo K, Kirkham B. Rheumatoid Arthritis - Anti-TNF. Int Immunopharmacol 2015;27(2):180‑184.
- Berns M, Hommes DW. Anti-TNF-α therapies for the treatment of Crohn's disease: the past, present and future. Expert Opin Investig Drugs 2016;25(2):129‑143.
- Zhang H. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer. Drug Des Devel Ther. 2016 Nov 24;10:3867-3872.
- Ohhara Y, et al. Role of targeted therapy in metastatic colorectal cancer. World J Gastrointest Oncol. 2016 Sep 15;8(9):642-55.
- Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nature Reviews Drug Discovery 2016;15:385–403.
- LaConte L, et al. Magnetic nanoparticle probes. Materials Today, 2005;8(5): 32‑38.
- Mohammed L, et al. Magnetic nanoparticles for environmental and biomedical applications: A review. Particuology 2017;30:1–14.
- Neuberger T, et al. Superparamagnetic nanoparticles for biomedical applications: possibilities and limitations of a new drug delivery system. Journal of Magnetism and Magnetic Materials 2005;293(1):483‑496.
- Issa B, et al., Magnetic nanoparticles: surface effects and properties related to biomedicine applications. International Journal of Molecular Sciences 2013;14(11):21266‑21305.
- Nitin N, et al., Functionalization and peptide-based delivery of magnetic nanoparticles as an intracellular MRI contrast agent. Journal of Biological Inorganic Chemistry 2004; 9(6):706‑712.
- Shenoy, D.B. and M.M. Amiji, Poly (ethylene oxide)-modified poly ([-caprolactone) nanoparticles for targeted delivery of tamoxifen in breast cancer. International Journal of Pharmaceutics 2005;293(1):261‑270.
- Kai Yan, et al. Recent advances in multifunctional magnetic nanoparticles and applications to biomedical diagnosis and treatment. RSC Advances 2013;3:10598‑10618.
- Creixell M, et al. EGFR-Targeted Magnetic Nanoparticle Heaters Kill Cancer Cells without a Perceptible Temperature Rise. ACS Nano 2011;5(9): 7124–7129.
- Monsalve A, et al. Remotely Triggered Activation of TGF-β With Magnetic Nanoparticles. IEEE Magnetics Letters 2015;6:1‑4.
nanoTherics are based in Staffordshire, United Kingdom. Their mission is to become the leading supplier of IP protected products addressing the field of magnetic nanoparticle research and applications. In particular they aim to be the number one supplier of products for nanoparticle heating applications utilizing AC field and solenoid coil principles.
They also apply their significant know how in magnetic nanoparticles to the field of transfection devices and reagents for biomaterial delivery into cells for the life science research and development market and reagents for biomaterial delivery into cells for the life science research and development market.
Their aim is to provide superior performance magnetic based tools to address global markets and to underpin the research and development of current and future nanoparticle, magnetic particle, cancer therapy, drug delivery, genetic screening and gene therapy programs.
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