Seite - 103 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Mahmoudi andHadjipanayis Applicationofmagneticnanoparticles forbrain tumors greatestconcentrationoftherapeuticwhile minimizingsystemic toxicities. MRICONTRASTENHANCEMENTOFBRAIN TUMORS MNPs also serve as a powerful aid for the imaging of brain tumors. Their inherent ferromagnetic qualities provide sensitive contrast enhancement with MR imaging (Liu et al., 2010). AccumulationofMNPs in brain tumors appears as a hypointen- sity on T2-weighted imaging including gradient echo imaging (Na et al., 2007). FunctionalizedMNPscanbeengineeredto targetbraincancer cellswhichcan in turn be identifiedwithMR imaging. For stan- dard visualization of tumors, MNPs can providemore sensitive imagingof tumors when used as a contrast agent for MRI (Kumaretal., 2010). Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONPs), a sub- class of superparamagneticMNPs, are the most effective types ofMNPs that can be used for imaging purposes (Thorek et al., 2006). Their systemic half-life is two to three times greater than standard MNPs and are capable of being imaged byMRI for longerperiodsof time(Varallyayetal., 2002). In a recent study, itwas noted that USPIONPs can be used to detect areas withinbrain tumorswith increasedblood flow, which may be indicative of tumor recurrence (Gambarota and Leenders, 2011). They can also be used to iden- tify areas of pseudoprogression in brain tumors after standard adjuvant therapies such as radiotherapy and chemotherapy (Gahramanovetal., 2011). HYPERTHERMIA Hyperthermia for the treatment of dif- ferent cancers has been well described in the past. Elevation of targeted areas of the body above 40◦C can result in cancer cell death (Wust et al., 2002). In one study, researchers concluded that evenmoderate hyperthermia at a temper- ature around 45◦Cwas enough to cause tumor cells to undergo apoptosis (Pu etal.,2013).Furthermore,localorregional hyperthermia can result in elevatedblood flow, which may assist in the delivery of other treatments, such as chemother- apy, which could result in a synergistic antitumor effect (Kampinga, 2006; Issels, 2008). While local or regional hyperthermia can be effective in treating cancer involv- ing different parts of the body, treating brain tumors is difficult due to the sur- rounding skull (Jordan et al., 1999).Heat applied to thehead is shieldedby the skull which results in less thanoptimal temper- ature increases in the brain. Temperature elevation of the entire brain for pro- longedperiodsoftimewouldresult inside effects and toxicities to patients. To pro- vide amore targeted hyperthermia effect for brain tumors,MNPsmaybedelivered intratumorally prior to treatment with alternating magnetic fields. This process, knownas thermotherapy,aimstodelivera greaterhyperthermiaeffect locallytobrain tumors while minimizing heating of the surroundingbrain. THERMOTHERAPY Due to the side effects and toxicities of subjecting the entire brain to hyperther- mia for extended periods of time, local- ized treatment is necessary for effective brain tumor therapy.Direct implantation of MNPs into brain tumors can bypass theBBBandallow for amaximumhyper- thermiceffectprovided inatargetedman- nerFigure1. Brainautopsiesof twoGBM patients after MNP injection, confirmed thattheMNPswereretainedwithintumor tissueafter implantation(VanLandeghem et al., 2009). Once injected into tumors, MNPsaresubjectedtoanalternatingmag- netic field (AMF) which produces heat via the BrownianNéel relaxation process (Thiesen and Jordan, 2008;Deissler et al., 2014). The localized hyperthermic effect, known as thermotherapy, involves the application of an alternating magnetic field (Maier-Hauff et al., 2011) Figure1. Whenapplyingamagneticfield to the tar- get area, the strength of the hyperthermic treatment isdependentonavarietyof fac- tors including the strength of the AMF, the size and concentration of theMNPs, and the time inwhich the field is applied to the tumor region (Yanase et al., 1997; Guedes et al., 2004;Meenachet al., 2010). Targeted treatment is necessary because prolonged application of hyperthermia to healthy tissue can result in unwanted side effects and toxicities (Fajardo, 1984). In order tominimizetheriskofsystemictox- icities, thehyperthermic treatment is only applied for a brief periodof time to allow fortheMNPswithinthetargetedregionto heatupandcausenecrosisordeathof the cancer cells. Inhumanpatientswithbrain tumors, itwasdetermined thathyperther- miawith temperatures from42◦Cto49◦C were safe and caused very few side effects for thepatient (Maier-Hauffetal., 2007). Thermotherapy does induce the death ofmalignant cells (Marcos-Campos et al., 2011). When a MNP is subjected to an alternatingmagnetic field, its internal temperature increases. This heat is then transferred locally to the abnormal cells situated around the nanoparticles which further results in tumor death (Fajardo, 1984).With thermotherapy, only the tar- getedtumorregionisexposedtoincreased temperatures, resulting in localizednecro- sis. When clinicians studied the benefits of using thermotherapy in conjunction with radiotherapy in relapsedGBM, they reportedanoverallsurvivalof13.4months compared to just 6.2months with radio- therapy andTemozolomide alone (Maier- Hauff et al., 2011). Current limitations to the use of MNPs for thermotherapy of brain tumor patients include the high MNP concentration required to generate hyperthermia precluding the use ofMRI, aswellastheeffectivedeliveryoftheMNPs (Wankhedeetal., 2012). The decreased resistance to heat observed in GBM cells is not as clearly presented when conducting experiments with invitrosamples(Issels,2008).Cancer cells that reside in tumors are more sus- ceptible to damage fromheat than cancer cells that are in vitro (Rhee et al., 1990). This contrasts heavilywith the significant difference in immunity that is observed when experiments are conducted using in vivomodels. One explanation for this difference is that the vascular network within the tumor is abnormal which can lead to areas that have a difference in pH aswell as decreased availability of oxygen (Issels,2008). CONCLUSION Thermotherapy involving the use of an AMF in conjunction with MNPs has proventobeaneffectivemethodfor treat- ing patients with GBM. Initial tests have shown that MNPs have minimal toxic- ities to patients, though further testing must be done to confirm these findings Frontiers inChemistry | ChemicalEngineering December2014 |Volume2 |Article109 | 103