WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Zeenat

World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 2.786

Volume 4, Issue 03, 288-298.

Review Article

ISSN 2278 – 4357

BIOMEDICAL APPLICATION OF MAGNETIC NANOPARTICLES FOR CANCER TREATMENT Z. N. Kashmiri* Department of Zoology, Sindhu Mahavidyalaya, Nagpur (MS), India.

Article Received on 29 Dec 2014, Revised on 24 Jan 2015, Accepted on 17 Feb 2015

ABSTRACT Cancer is described as the most hazardous class of disease describing a cluster of cells undergoing uncontrolled growth in the body. Over the last decade major advances have been made in the treatment of cancer.

*Correspondence for

Radiation and chemotherapy are the traditional ways for cancer

Author

treatment but the toxic drug molecules do not act selectively to cancer

Dr. Zeenat Kashmiri

cells and as such a enormous range of undesirable side effects have

Department of Zoology,

been experienced. Nano-sized formulations of cytotoxic agents have

Sindhu Mahavidyalaya,

proved to passively target different cancer and promote increased drug

Nagpur (MS), India.

efficacy due to the accumulation via enhanced permeability and

retention resulting in deeper drug penetration. Nanoparticles with easily modified surfaces have been investigated extensively in recent years and play a pivotal role in biomedicine. Recently magnetic nanoparticles have been increasingly explored for clinical applications, such as drug delivery, magnetic resonance imaging and magnetic fluid hyperthermia for diagnosis and cancer therapy. This article highlights the application of magnetic nanoparticle in cancer treatment. KEYWORDS: Radiation, chemotherapy, magnetic nanoparticle, biomedicine. INTRODUCTION Nanoscience and nanotechnology has become a versatile and promising platform for creating novel materials with enhanced properties and potential applications in cancer therapy. Nanotechnology, a wide research field which includes chemistry, engineering, biology and medicine, has excellent potential for early detection, accurate diagnosis, and treatment of cancer.[1] The term nanomedicine refers to the use of nanotechnology in the treatment, diagnosis and monitoring of diseases. For cancer diagnostics and therapy there are currently a number of techniques based on different types of nanoparticles.[2]

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Magnetic drug targeting is a particularly promising application in this field. The goal of the carrier systems involved is to achieve enrichment of effective substances in diseased tissue. Numerous nano systems can be used as carrier, but magnetic nanoparticles are important. On the one hand, the particles serve as carrier for the active substances, while on the other hand they can also be visualized using conventional imaging techniques and can therefore be used for theranostic purpose.[3] II) NANOSCIENCE AND CANCER TREATMENT Cancer is a major cause of death in world and one in four deaths in the United States is due to cancer. Nanoscience raises new promises in the diagnosis and treatment of various cancers. It also facilitates important advances in detection, diagnosis, and treatment of human cancers and has led to a new discipline of nano-oncology.[4] Nanoparticles offer a new method of tumor targeting, already available in clinical practice, which can concomitantly improve the efficacy and decrease the toxicity of existing or novel anticancer agents. This makes them an ideal candidate for precisely targeting cancer cells. Molecular imaging is now considered as a high area in cancer diagnosis.[5] The common feature of all nanoparticle-based cancer therapies is the need of specific nanoparticles

for

achieving

the

desired

therapeutic

effect.

However,

each

diagnostic/therapeutic technique requires a different chemical or physical property of the particles involved, which depends on the specific function played by the nanoparticles in that therapy (e.g., vector, porous receptacle, heating agent, magnetic moment carrier, etc.). Sometimes the particle function is activated using an external agent (magnetic fields, light, radiation, etc.) that interacts with the NPs. Therefore the requirements for nanoparticles as biomedical agents span a broad range of novel materials, synthesis strategies, and research fields. III) MAGNETIC NANOPARTICLES Magnetic nanoparticles (MNPs) are one sub-class of broad cancer-therapy designed nanoparticles. The first therapeutic applications of magnetic devices to humans can be chased back to the 16th century, when Austrian physician Franz Anton Mesmer (1734-1815) developed his theories about magnetic fluids.[6] He sustained the influence of invisible ‘universal fluids’ on the human body, and proposed his theory of ‘animal magnetism’ gaining notoriety across Europe. Since then Mesmerism (a therapeutics based mainly on hypnotism) has triggered a sustained flood of both research and ‘supernatural’ quackery. Pushed by

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advances in the synthesis of biocompatible magnetic nanoparticles (MNPs) in a reproducible way, the concept of targeting magnetic nanospheres inside microscopic living organisms regained interest and finally became a reality. Since the size of MNPs is comparable to the DNA or subcellular structures, this field opened the door for cell separation strategies using magnets as external driving forces.[7] The ability to remain in solution indefinitely of nanoparticles in physiological conditions is one of the most vital factors for their successful usage in biomedicine. This is dependent on the physical and chemical composition of the nanoparticles, the charge in particular. When discussing nanoparticles, size and colloidal stability i.e. the capability of particles to resist aggregation, particularly for magnetic nanoparticles, in physiological environments is a crucial factor to show whether a particle has the potential for clinical application. Although characterization of a particle’s properties such as surface charge, surface area and crystallinity have been successively taken into account.[8], an in depth understanding of the basic mechanism including nanoparticles-protein interactions and their colloidal behaviour in different

physiological

environments

is

needed.[9]

The

therapeutic

outcome

of

chemotherapeutic treatments has considerably improved in the last decade but one of the main reasons for failure is correlated with the presence of multidrug resistance-associated protein in cancer cells. Once in biological media, proteins and other biological molecules quickly compete to bind onto the nanoparticle surface, leading to the formation of a protein corona. Applications of MNPs are based on the following physical principles 1. The application of controlled magnetic field gradients i.e., a magnetic force, around the desired target location for remotely positioning MNPs in organs or tissues, ex.-targeting, magnetic implants, magnetic separation applied to the sequencing of DNA, etc. 2. The utilization of the magnetic moment of the MNPs as a disturbance of the proton nuclear resonance, ex- contrast media for Magnetic Resonance Imaging, MRI. 3. The magnetic losses of nanometric particles in colloids for heating purposes (magnetic hyperthermia). Magnetic nanoparticles have been used for cell sorting, MRI, drug delivery and magnetic hyperthermia therapy.[10-11]

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IV) BIOMEDICAL APPLICATIONS OF MAGNETIC NANOPARTICLES a) Magnetic Drug Targeting Normally during chemotherapy less than 0.1 to 1% of the drugs are taken up by tumor cells, with the remaining 99% going into healthy tissue.[12] Chemotherapy encompasses treating patients with a diverse collection of drugs that attempt to preferentially destroy cancer cells either by inhibiting cellular division or by interrupting essential cell signaling pathways.[13] Most of the chemotherapeutic drugs are processed and excreted through kidney or liver which may result in unbearable toxicity levels in a patient which unable the drug to metabolize and excrete it. Local injection may solve the above problems, but it is restricted to sizeable tumors and limited by the accessibility to the tumor region. In order to chase metastatic cells in a whole organism, molecular recognition mechanisms must be used. Therefore, a promising alternative for cancer treatment relays on the ability of therapeutic agents to selectively reach the desired target after intravenous administration.[7] Magnetic drug targeting (MDT) in cancer therapy is aimed to concentrate chemotherapeutics to a tumor region while simultaneously the overall dose is reduced. This can be achieved with coated super paramagnetic nanoparticles bound to a chemotherapeutic agent. These particles are applied intra arterially close to the tumor region and focused to the tumor by a strong external magnetic field. The interaction of the particles with the field gradient leads to an accumulation in the region of interest i.e. tumor. The particle enrichment and thereby the drug-load in the tumor during MDT has been proven by several analytical and imaging methods. Moreover, in pilot studies we investigated in an experimental in vivo tumor model the effectiveness of this approach. Complete tumor regressions without any negative side effects could be observed. There are several other targeting techniques capable of directing therapy to desired locations. These include the use of magnetic fields,[14] ultrasound,[15-16] electric fields,[17] photodynamic therapy,[18] environment reactive targeting,[19] and antigen recognition.[20] Therapeutic magnetic elements have been created by the attachment of chemotherapy,[21] or gene therapy[22] to ferromagnetic particles,[23] by filling polymer capsules or micelles (capsules that self-assemble from lipid molecules with both drugs and magnetic materials or by growing cells in a cell-culture medium with magnetic nanoparticles to let the cells ingest the particles and thereby become magnetic.[24]

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b. Hyperthermia Hyperthermia is a general term for the rise of temperature above the physiologic level (in the 40°C-45°C range) within a targeted tumor without damaging the surrounding healthy tissue. Tumorous cells die at elevated temperatures, in particular in the range of 42-46°C and since local hyperthermia does not require surgery to administer, the therapy is a very efficient and non-invasive approach for treating cancer. The therapy is so effective that local hyperthermia is used as a supplementary treatment to radiotherapy and chemotherapy. Hyperthermia can be rendered by several different heat sources such as external water baths, radiation applicators, or inserted probes. Unfortunately, these heat sources do not provide enough control or precision of how or how much heat is applied to the target area.[25-26] The discovery of generating a localized heat field by exposing magnetic particles to a magnetic alternating current field opened the doors to magnetic hyperthermia.[27] The study of different energy dissipation and effects of electromagnetic fields on different particles has shown the superiority of this therapy in providing site-specific heating that minimizes damage to the surrounding tissues.[28] The treatment begins with the injection of magnetic nanoparticles, specifically Fe3O4, that are about 10nm in radius and coated with cancerspecific biomolecules, into the blood stream near the tumor where the nanoparticles attach and accumulate.[29-30] Once adhered to cancerous cells, the nanoparticles are subjected to an alternating magnetic field for 15-60 minutes to gain and maintain a temperature in the range of 42-46°C.[31] Figure 1 details the process of magnetic hyperthermia.

Fig. 1: Basic process of magnetic hyperthermia (Courtesy: Shido et al. 2010). The choice of the target temperature, as well as the physical source of heat generation, depends on factors such as tumor location, volume to be heated and micro environmental

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factors (e.g. degree of vasculature or local pH). The synergistic interaction between heat and radiation therapy is recognized by the medical community, and has been already validated in preclinical studies.[32] However, there are no yet models that can describe the interplay between physical and biochemical cell mechanisms involved in thermo sensitisation, heatinduced protein expression or cell apoptosis, on a microscopic basis. Recent efforts for elucidating these mechanisms have demonstrated that cell membrane and cytoskeleton are important loci of cell damage by both ionizing radiation and hyperthermia.[33-34] c. Cell Separation Filtration, centrifugation are the earlier methods used for the separation of biological substances which are based on different driving forces. Filtration is the oldest protocol for cell separation, and still it remains a key technique use by researcher and industries due to new developments of synthetic micro- and nano-porous materials. Centrifugation is another classical method based on the application of a centrifugal force1 to separate biological units from their surrounding medium on either a batch or a continuous-flow basis. Differential centrifugation is based on the size of the particles in differential centrifugation, and is the preferred technique for isolation of cells in clinical applications, whereas the alternative density gradient centrifugation is employed for purification of subcellular organelles and macromolecules.[7] The magnetic-based cell separation techniques based on the presence of a tagging element i.e. magnetic nano-particles that can be attached to the cell membrane with high specificity. For Drug Delivery, MRI or hyperthermia applications, the problems of functionalization and tagging are key issues that influence the final specificity of the whole process. The physical basis for magnetic cell separation methods is the force F generated on the attached MNPs when a magnetic particle with magnetic (dipole) moment m is placed in a non-uniform magnetic field B. It is important to notice that a uniform magnetic field B0 on a magnetic dipole does not exert net forces on it but only a torque that aligns it parallel to the field. Miniaturization of magnetic cell sorters,[35] flow-through technique known as High Gradient magnetic separation[36] are the methods based on magnetic cell separation. The concept of miniaturized device is that heterogeneous cell population, targeted with MNPs of different sizes, can be injected into a microfluidic chamber where a magnetic field gradient perpendicular to the fluid velocity generates a force capable to deflect each population proportionally to its magnetic moment. The inhomogeneous field is achieved by placing a

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permanent magnet on one side of the chamber so that an effective gradient is produced towards the magnetic pole.[37] This parameter gives an estimation of how fast a given particle responds to a given magnetic force. The time to reach the collecting capillaries can be controlled by the input velocity, which in turn allows separation of different size windows. The ‘flow-through’ technique known as high gradient magnetic separation consists of a quadrupolar arrangement of magnets mounted concentrically on a tubular setup with thin annular geometry. This configuration is specifically designed to produce a radially symmetric magnetic field gradient in a plane perpendicular to the velocity field. As the cell mixture is carried along the channel by the input flow and passes through the magnetic field, the specific cell types tagged with immune specific MNPs are driven toward the outer wall where some cell collector device retains the desired cells. The magnetic techniques for cell separation still face challenges regarding the purity of the final product since the starting liquid usually contains additional bioparticles, cell debris, non tagged cells and other by-products, which can show similar behavior than the desired cells, depending on the driven force used. In spite of these difficulties, magnetic separation has been successfully tested for precise separation of specific cells in blood.,[38] gram positive pathogens[39] and protein purification.[40] d. Magnetic Resonance Imaging (MRI) Magnetic resonance imaging is a medical imaging technique that records changing magnetic fields, it is also called Nuclear Magnetic Resonance (NMR). It give different kinds of images based on the pulse sequence and capable of complete body scans, but commonly used for brain. It is the most successful among the imaging techniques currently available as it is a non-invasive, non-destructive modality that can reconstruct both 2D and 3D images of an internal living structure, without limitation in volume or depth of the analyzed target. [7] Resonant technique is based on the existence of physical entities for example, electrons, nuclei, or molecules that can be promoted from their ground state (taken as the zero-energy, E0) to higher- energy excited states with E1, E2,…….En. In MRI, the resonant physical entities are the hydrogen nuclei (protons) that exist abundantly in living tissues.

MRI

involves a magnetic coupling between the magnetic-component of the EM waves and the magnetic moment of the resonant hydrogen nucleus (nuclear spin). Therefore the MRI is a nuclear resonance technique that gives information based on the magnetic properties of the

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biological samples. The signal from relaxation of the excited protons is captured through currents induced over a specific arrangement of pick-up coils, and finally the whole relaxation process is reconstructed computationally to obtain temporal or spatial images of the desired organ/tissues.[41] MRI is most valuable technique for cancer diagnosis and therapy. CONCLUSION In comparison with traditional cancer therapy, magnetic field operated therapeutic approaches can treat cancer in an unconventional but more effective and safer way. For designing new metallic nanoparticle based therapies for cancer treatment, a deeper understanding of the molecular mechanisms underlying early stages of cancer is a requisite, however, quick diagnosis and treatment of cancer using magnetic nanoparticle may hold the key to improved clinical outcomes and quality of patient’s life. REFERENCES 1. Ferlauto AS, Alvarez F, Fonseca FC, Goya GF, Jardim RF. J Metas-table Nanocryst Mater, 2004; 4: 20-21. 2. Menezes GA, Menezes PS, Menezes C. Nanoscience in diagnostics: A short review. Internet Journal of Medical Update, 2011; 6(1): 16-23. 3. Tietze R, Lyer S, Durr S, Alexiou C. Nanoparticles for cancer therapy using magnetic forces. Nanomedicine, 2013; 7(3): 447-57. 4. Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer, 2005; 5(3): 161-71. 5. Yezhelyev MV, Gao X, Xing Y. Emerging use of nanoparticles in diagnosis and treatment of breast cancer. Lancet Oncol, 2006; 7(8): 657-67. 6. Donaldson I.M.L. Mesmer's 1780 proposal for a controlled trial to test his method of treatment using ‘animal magnetism. J R Soc Med, 2005; 98: 572. 7. Goya G F, Grazú, M R and Ibarra H. Magnetic Nanoparticles for Cancer Therapy. Current Nanoscience, 2008; 4: 1-16. 8. Susuki M, Shinkai M, Yanase M, Ito A, Honda H, Koboyash T. Enhancement of uptake of magnetoliposomes by magnetic force and hyperthermic effect on tumor, Jpn. J. Hyperthermic Oncol. Jpn J Hyperthermic Oncol, 1999; 15: 79-87.

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