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Magnetic nanoparticle targeting of lysosomes: a viable method of overcoming tumor resistance? “Magnetic nanoparticles ... are currently one of the hottest topics in nanomedicine owing to their potential applications in both cancer therapy and imaging.” Keywords: drug resistance • iron oxide nanoparticle • lysosomal death pathway • nanoscale thermal phenomena • receptor targeting
Nicole Iovino
It is estimated that one in every three females and one in every two males will be diagnosed with cancer over their lifetime. Despite billions of US dollars invested into research, cancer still remains second only to heart disease as the leading cause of death in the USA and the number one killer of Americans between the ages of 35 and 65 years [1] . Although treatment options have improved significantly over the past 50 years, modern therapies still fall short especially when it comes to drug resistance and harmful side effects. Cancer’s resilience to modern drugs is dependent upon its unregulated growth and high mutation rates, which quickly select for cells that are able to overcome environmental pressures leading to eventual drug resistances. Many traditional chemotherapies target complex biological pathways that are often hijacked by mutations. In addition, many of these targeted pathways are common to both malignant and healthy cells. This lack of discrimination leads to drugs that are not well tolerated and are accompanied by several adverse side effects. In recent years, attention has shifted to targeted therapies that exploit differences between healthy and malignant cells in order to minimize side effects and maximize efficacy. One promising target for such therapies is the lysosome. Although present in nearly all living cells, many malignant cells have been found to have an increased number of lysosomes and with increased hydrolase activity [2] . These transformations play an important role in a tumor’s angiogenesis, invasiveness and metastasis [3] . These changes
Ana C Bohorquez
10.2217/NNM.14.52 © 2014 Future Medicine Ltd
also make the tumor more susceptible to the so-called lysosomal death pathway, which is based upon evidence that disruption of the lysosomal membrane can lead to cell death [3–5] . Although doubts were originally cast upon the importance of this pathway as a means to destroy cancer cells due to the presence of intact lysosomes in apoptotic bodies, as observed by electron transmission microscopy, the topic has gained special interest following new evidence of lysosomal membrane permeabilization (LMP). When a cell undergoes LMP, the lysosomal membrane can be compromised even while remaining intact allowing some leakage of proteolytic enzymes from within the lysosome into the cytosol. The most important class of these enzymes are the cathepsins. LMP can be induced by several agents including reactive oxygen species, detergents and bile salts [3] . Boya et al. demonstrated experimentally that cathepsin molecules, which under normal conditions are restricted to the lysosome, become dispersed throughout the cytoplasm following LMP by monitoring anticathepsin fluorescent-labeled antibodies as they conjugated to cathepsins within cultured cells [3] . It is now believed that upon minor leakage into the cytoplasm, cathepsins induce cell death by activating Bid, a mediator of the classical caspase apoptotic pathway, and by degrading Bcl-2 family antiapoptotic proteins; both of which are upregulated in cancer [6] . Massive leakage causes acidification of the cytoplasm and loss of integrity of the cell membrane, leading to necrosis [7] . Chung et al. found that lysosomal disruption
Nanomedicine (2014) 9(7), 937–939
College of Medicine, University of Florida, Gainesville, FL 32611, USA J Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
Carlos Rinaldi Author for correspondence: J Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA and Department of Chemical Engineering, University of Florida, Gainesville, FL 32611, USA Tel.: +1 352 294 5588 Fax: +1 352 273 9221 carlos.rinaldi@ bme.ufl.edu
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Editorial Iovino, Bohorquez & Rinaldi can lead to cell death using NH4HCO3, a substance that when heated releases CO2 bubbles to mechanically disrupt the lysosome [8] . NH4HCO3 was delivered to the cells via liposomes, which were taken up through endocytosis and trafficked towards the lysosome. Upon heating, the lysosomal membrane was mechanically disrupted by these bubbles, cell viability was greatly reduced and necrosis was confirmed by a significant increase in the levels of lactate dehydrogenase in the cell medium [8] .
“...magnetic nanoparticles are showing great
potential as a method of overcoming tumor resistance by two important mechanisms: by enhancing the efficacy of other chemotherapeutic agents, such as cisplatin and bortezomib, even in resistant cell lines; and by bypassing the classical caspase-dependent apoptotic pathways, which are susceptible to mutations by thermally or mechanically inducing lysosomal membrane permeabilization.
”
Magnetic nanoparticles (MNPs) are currently one of the hottest topics in nanomedicine owing to their potential applications in both cancer therapy and imaging. Several properties make them a promising new tool, such as increased biocompatibility and ease of conjugation with molecular targets and fluorescent tags. Most importantly they are unique in their ability to dissipate heat when subject to an alternating magnetic field (AMF). One promising application of this phenomenon is so-called magnetic fluid hyperthermia (MFH), in which a MNP colloidal solution is injected directly into a tumor and subjected to an AMF to generate energy as a form of heat and kill cancer cells. This approach is based upon evidence that tumor cells are much more susceptible to heat than normal cells and when heated to 42–45°C shows a significant loss in viability compared with its noncancerous counterpart [9–11] . The use of nanoparticles as a source of heat has been shown to have clear advantages in comparison to hot water bath hyperthermia when studying breast and colorectal cancer cell lines [12] . Similarly, in vitro studies using the anticancer drug cisplatin in combination with MFH have shown a synergistic effect with respect to increased apoptotic cell death due to a membrane permeabilization effect [13] . A similar synergistic effect was also observed with the combination of the anticancer proteasome inhibitor bortezomib with MFH [14] . This suggests the potentiality of MNPs to overcome drug-resistant cancers by enhancing traditional chemotherapies [15] . Furthermore, evidence of the potential advantages of MFH in treating cancer is not limited to in vitro experiments; in vivo animal studies
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and even clinical trials have shown promising results in the treatment of gliomas [16, 17] . In fact, MFH is currently being used in Germany to treat glioblastoma, an extremely fatal cancer of the CNS. Observations of membrane permeabilization due to energy dissipation by MNPs are believed to be due to nanoscale thermal phenomena occurring in the vicinity of the nanoparticle surface upon application of an AMF. Evidence of this was shown experimentally using iron oxide nanoparticles functionalized with a thermoresponsive polymer that fluoresces at a higher intensity when heated. Polo-Corrales and Rinaldi observed that when these nanoparticles were placed in an AMF, they fluoresced at an intensity that corresponded to a temperature much higher than that of the medium they were suspended in [18] . Riedinger et al. also found evidence supporting nanoscale thermal phenomena using iron oxide nanoparticles coated with polymers of different lengths and a fluorescent dye terminally attached via a thermally labile linker, which released the dye when the medium temperature exceeded 45°C through external heating. They then observed release of the dye upon application of an AMF, without the need for a temperature rise in the medium. They further estimated that temperature reached a maximum at distances less that 0.5 nm from the surface of the nanoparticle and decreased exponentially with increasing distance thereafter [19] . Nanoscale thermal phenomena due to energy dissipation by MNPs has also been successfully applied to destroy cancer cells using receptor-targeted MNPs. This was first demonstrated by Creixell et al. [11] using nanoparticles targeting the EGF receptor and later by Sanchez et al. [20] using nanoparticles targeting the G-protein coupled receptor. In both cases, significant reductions in cancer cell viability were observed upon application of an AMF without a perceptible temperature rise. Domenech et al. identified LMP and lysosomal death pathways as being at least partially responsible for the observed reduction in cell viability [21] . They demonstrated that upon application of the AMF, the number of lysosomes in a cell population decreased and the percentage of cytosolic cathepsin B increased when EGF receptor-targeting nanoparticles were used. Sanchez et al. also found evidence that LMP was at least partially responsible for their observations of a decrease in cell viability [20] . These studies suggest the potential of using receptor targeted MNPs to induce LMP and lysosomal death pathways in cancer. Our understanding of MNPs and their potential in cancer therapy has evolved from nanoparticles producing heat on a macroscopic scale, to nanoparticles producing heat on a nanoscale, which in turn has contributed to our understanding of how MNPs can
future science group
Magnetic nanoparticle targeting of lysosomes: a viable method of overcoming tumor resistance?
activate lysosomal death pathways via LMP. Moreover, we now have a precise method of aiming iron oxide ‘missiles’ at the lysosome by exploiting receptors that are upregulated in cancer cells as molecular targets. Receptors vary among different types of cancers and their mutations; there is therefore a lot more work to be carried out to identify the receptor targets that are suitable for LMP. More importantly, MNPs are showing great potential as a method of overcoming tumor resistance by two important mechanisms: by enhancing the efficacy of other chemotherapeutic agents, such as cisplatin [13] and bortezomib [14] , even in resistant cell lines; and by bypassing the classical caspase-dependent apoptotic pathways, which are susceptible to mutations by thermally or mechanically inducing LMP [7] . The next exciting steps of developing a cancer therapy based
Editorial
upon MNPs targeting the lysosomal death pathway is moving these applications forward to more clinical studies including cancers that are resistant to chemotherapeutic drugs. We are very confident that we will see positive results and that this method will prove to be a viable method of overcoming tumor resistance. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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