Nanotechnology in Glioblastoma Multiforme

Nanotechnology in the CNS
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Neurooncology, or the study of cancer within the nervous system, is a field in which there is new and constant research being published to help improve both diagnostic tools and treatments. Nanotechnology is one of these such new techniques and it has recently began to be used in both areas, specifically with recurrent glioblastoma multiforme, a type of cancer within the central nervous system. Thus far, there are very limited or effective treatments for GM within the CNS and an earlier diagnosis has proven to be difficult, however improvements in diagnosis and treatment are possible with the introduction of nanoparticles.

Nanoparticles are structures 1-100nm in size with new and/or enhanced properties compared to the original quantum and molecular structure of the compound and are encased by either a monosaccharide or polysaccharide[1]. They have a wind range of use including improving magnetic resonance imaging contrast and passing the blood brain barrier to either directly stimulate and denature tumors or provide transport and protection for an anti-cancer drug[2].

1 Diagnosis

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In this diagram the inner magnetite core is presented as well as the polysaccharide outer layer.
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1.1 USPIOs

A new nanoparticle, a superparamagnetic iron oxide particle, has emerged to help create a clearer and more precise diagnosis of glioblastoma multiforme with MRI scans. These iron oxide particles have an iron oxide center, based on the natural occurring minerals magnetite (Fe3O4) and maghemite (Fe2O3), the former of which has received the most attention within the biomedical technology community[1]. They are then encased in a hydrophilic coating consisting of either a synthetic monomer or polymer casing or a polysaccharide[1]. Polyethylene glycol is another widely used coating as it increases the nanoparticle size as well as prevents them binding to RES particles, therefore preventing the excretion of the nano particles by the reticuloendothelial system (RES)[3]. They are primarily used as contrast agents to improve MRI scans and the most common of which are ultrasmall superparamagnetic iron oxide particles, or USPIOs, which are 10-50nm in diameter.

Because of the physical and magnetic properties of USPIOs, they have been highly targeted for their use in biomedical technology. The USPIO ferumoxytol, which for years has been used for iron replacement therapy[4], has been targeted as the most useful agent in MR imaging contrast. Ferumoxytol is a semisynthetic compound made from the naturally occuring magnetite coated in a polyglucrose sorbitol carboxymethylether[4]. Due to its limited strain on the cardiovascular system as well as the kidneys[1], reduced free iron radical release, long half-life (approximately 14 hours)[5] and a decreased allergic reaction[4] it is the ideal candidate for improving tumor diagnosis.

Within early time stages of injection, Ferumoxytol acts as a blood pooling agent as it remains in the vascular system and, once it leaks through permeable vessels, it is taken up by macrophages in the CNS and becomes an inflammatory marker[5]. This is hugely helpful to tumor identification as it will mark the inflamed areas surrounding and within the tumor.

1.2 MRI Diagnosis

Ferumoxytol [5]
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Ferumoxytol is shown here as a strong contrast agent in MRI scans, allowing for a clearer and more precise image.
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Ferumoxytol has been identified as key player to increase the effectiveness of MRI scan diagnosis of CNS tumors. USPIOs are readily taken up by phagocytes within the CNS such as astrocytes, dendritic cells and microglia and their strong magnetic susceptibilities allow for clear MRI scans of possible tumors[1]). The long half-life of ferumoxytol is hugely advantageous to MRI scans as it can remain at a constant concentration for longer periods of time, a requirement for accurate MRI scans. It is a negative contrast agent as it has a strong effect on the spin-spin relaxation time, or T2, of MRIs, however it can act by shortening T1, or the spin-latice relaxation time, as well and produce a positive signal with the correct pulse[5]. It can also be used to greatly enhance the performance of susceptibility-weighted MRIs due to its influence on T2 by increasing microvessel visibility within the CNS[5].

In MRI intracranial tumor diagnosis both T1 and T2 scans are enhanced by ferumoxytol and inflammatory areas are more readily identified in which previous agents, such as gadoteridol, could not do[6]. Another key player in tumor identification is detecting areas that are undergoing rapid growth, which indicates a tumor, and is often done by measuring the relative cerebral blood flow (rCBV). Ferumoxytol has shown the most promising results in this area as well, as it has much higher rCBV results than other agents and can therefore identify very early on areas in which rapid growth is occurring[7]. As well this identification of higher rCBV allows for identification between psuedoprogression and active tumors within patients[7], leading to a more effective diagnosis with MRI scans and therefore treatment.

1.3 Efficacy and Safety of USPIOs

Compared to other contrasting agents such as gadoteridol, ferumoxytol increases the visibility of vascular malformations within the brain allowing it to identify abnormalities which previous agents could not, as outlined in more detail above[5]. Within current research ferumoxytol and other compounds similar to it such as ferumoxtran-10 show no short or long term detrimental effects to brain cells or myelin within rat models[8]. As well, it has been shown that within pediatric use, after 7 years no ill effects were seen with the use of the particles[9].

However, there are still further areas that need to be improved upon in order to more efficiently use these particles in tumor diagnosis. An inability to differentiate their signaling from and an interference by the natural iron signaling in the brain is one of the challenges still facing this technology[1].

2 Treatment

2.1 Thermotherapy/Photothermal therapy

Effect of Thermotherapy on Tumor Diameter [3]
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Tumor a) received macrophages with nanoparticles b) no treatment
c) Nanoparticle macrophages with thermotherapy and d) empty macrophages plus thermotherapy

Widespread treatment of glioblastoma multiforme is relatively limited, ineffective and requires a great deal of individualization based on the patients previous medical history. A new therapy has been proposed; hyperthermia therapy, or thermotherapy, in which only tumor tissue only is exposed to high temperatures in the hopes of denaturing the cells. The use of USPIOs in this newly introduced therapy has shown to be quite effective in improving the life span of individuals with recurrent glioblastoma multiforme[2]. The magnetite based iron oxide nanoparticles are directly inserted into the tumor and then subsequently heated with an alternating magnetic field, thus denaturing the tumor cells[2].

Using neuronavagational control by direct injection, the USPIOs are directed to the tumor sites where they can easily bypass the tumor vasculature due to the tumors increased permeability[3]). It is prevented from leaving the tumor and thus remaining there throughout the treatment because of the impaired lymphatic drainage of the tumor[3]. From this point the densities of the nanoparticles are then measured by CT scans. The magnetic properties of their magnetite core are then stimulated by a magnetic field through the T1 and T2 relaxation process thus creating heat from its movement[2]. However, to ensure that damage to surrounding unaffected tissue does not occur from the heat, the heat in surrounding tissue never extends past 43oC[2]. The heat generated from the magnetic fields denature, and thus eliminate, the tumor cells. This new therapy was seen to extend the life of patients with glioblastoma multiforme by almost twice the amount[2].

2.1a Use of Macrophages for Delivery of USPIOs

The navigation of nanoparticles to tumor sites, where they can then be heated to denature the tumor cells, can often be difficult and creates a substantial challenge for this new therapy. However, macrophages can be used to transport the nanoparticles to the tumor site with much more accuracy and efficacy[3]. Macrophage-based vecotorization presents a very effective solution to this problem. These such cells can be easily obtained from the patient and re-injected with the nanoparticles, which they take up readily and without toxic effect, due to them being circulating cells[3]. As well, there is limited risk of a build-up of these vectors as there is a natural accumulation of macrophages at tumor sites, thus leading to no toxic effect due to their accumulation as well as easy tumor targeting[3]. They can easily by bass the blood brain barrier, allowing the nanoparticles access into the CNS and the targeted tumor[10].

2.2 Anti-Cancer Drug Delivery with Nanovescicles

2.2a USPIOs

Nanovescicles in the form of iron oxide particles can help with anti-cancer drug delivery by increasing the drugs half-life within the body as well as presenting a more feasible way for delivery. An example of such a drug, TNF-related apoptosis-inducing ligand, or TRAIL has been widely known in its effectiveness in killing tumor cells within the CNS without damaging healthy, unaffected cells. However without an aid to transport TRAIL directly to the tumor site, it is incredibly difficult to create an effective path for it. By bonding the TRAIL amino acid group to the iron oxide nanoparticles surface, it creates an efficient transport system for the anti-cancer drug[11]. This combination has shown a large increase in tumor apoptosis and decrease in tumor size compared with using TRAIL alone[11], presenting a strong argument for their use in anti-cancer drug delivery.

2.2b Liposomes: The Interleukin-13 Model

Effect of IL-13 Liposomal treatment with doxorubicin on tumor growth [12]
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Tumor clearly decreases in size in mice which received the IL-13 liposome with doxorubicin, an anti-cancer drug (top row)
Tumor increases in size in animals that did no receive the targeted liposome (bottow row)

Liposomes are a second nanoparticle which are very useful in delivering anti-cancer drugs to gliomas within the CNS due to their ability to cross the blood brain barrier and directly deliver the drugs to the tumor site. However, the most effective model thus far in liposome vectors is the interleukin-13 (IL-13) conjugated liposome vector. In the human central nervous system, only glioblastoma tumors and not healthy cells express the IL-13 α2 receptor protein[12], making it an excellent target for liposomal binding and drug delivery. These liposomes will specifically target the tumor cells, enforcing an increase in cytotoxicity and cell death while preventing the death of healthy tissue. These glioma cells uptake the IL-13 liposome, which contains an anti-cancer drug, often doxorubicin, via endocytosis[13]. From this point, the drug can then induce cell apoptosis and destroy the glioma cell. Drugs injected by IL-13 liposomes show an increase in their retention and accumulation within the cancerous cells and produce stronger results for decreased tumor size and growth with less damage to the healthy cerebral tissue due to its more precise delivery system[12].

1. Weinstein, J.S. et al. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J. Cereberal Blood Flow & Metabolism. 30, 15-35 (2010).
2. Maier-Hauff, K. et al. Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J. Neurooncol. 103, 317–324 (2010).
3. Madsen, S.J. et al. Macrophage as cell-based delivery system for nanoshells in photothermal therapy. Ann Biomed Eng. 40(2), 507-515 (2011).
4. Lu, M. et al. FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease. American Journal of Hematology. 85(5), 315-319 (2010).
5. Dosa, E. et al. Magnetic resonance imaging using ferumoxytol improves the visualization of CNS vascular malformations. Stroke. 42(6), 1581-1588 (2011).
6. Dosa, E. et al. Magnetic resonance imaging of intracranial tumors: intra-patient comparison gadoteridol and ferumoxytol. Neuro Oncology. 13(2), 251-260 (2011).
7. Gharamanov, S. et al. Potential for differentiation of pseudoprograssion from true tumor progression with dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging using ferumoxytol versus gadoteridol: a pilot study. Int J Radiat Oncol Bio Phys. 79(2), 514-523 (2011).
8. Muldoon, L. L. et al. Imaging, distrubtaion, and toxicity of superparamagnetic iron oxide magnetic resonance particles in the rat brain and intracerebral tumor. Neurosurgery. 57(4), 785-796 (2005).
9. Thompson, E.M. et al. Dual contrast perfusion MRI in a single imaging session of pediatric brain tumors. J Neurooncol. 109(1), 105-114 (2012).
10. Baek, S.K. et al. Photothermal treatement of glioma; an invitro study of macrophage delivery of gold nanoshells. J. Neurooncol. 104(2), 439-448 (2011).
11. Perlstein, B. et al. TRAIL conjugated to nanoparticles exhibits increased anti-tumor activities in glioma cells and glioma stem cells in vitro and in vivo. Neuro Oncol. 15(1), 29-40 (2013).
12. Madhankumar, A.B. et al. Efficacy of interleukin-13 receptor-targeted liposomal doxorubicin in the intracranial brain tumor model. Mol Cancer Ther. 8, 647- 654 (2009).
13. Madhankumar, A.B. et al. Interleukin-13 receptor targeted nanovescicles are a potential therapy for glioblastoma multiforme. Mol Cancer Ther. 5, 3162-3169 (2006).

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