Seite - 102 - in Cancer Nanotheranostics - What Have We Learnd So Far?

OPINIONARTICLE published:03December2014 doi: 10.3389/fchem.2014.00109 Theapplicationofmagneticnanoparticles for the treatment ofbrain tumors KeonMahmoudi1 andCostasG.Hadjipanayis2* 1 Georgia Instituteof Technology, School of Biology,Atlanta,GA,USA 2 BrainTumor Nanotechnology Laboratory, Department ofNeurosurgery, WinshipCancer Institute of Emory University,Emory UniversitySchool of Medicine, Atlanta,GA,USA *Correspondence: chadjip@emory.edu Editedby: Jesús M. DeLa Fuente, UniversidaddeZaragoza, Spain Reviewedby: Manuel Ocana,Consejo Superior de Investigaciones Científicas, Spain MaríaLuisa García-Martín,AndalusianCentre for Nanomedicine andBiotechnology, Spain Keywords:nanotheranostics,magneticnanoparticles,hyperthermia,nanoparticles, imaging,glioblastoma INTRODUCTION Glioblastoma (GBM), a World Health Organization (WHO) grade IV astrocy- toma, is the most common and diffi- cult primary brain tumor to treat (Braun et al., 2012). Even when detected early, the median survival rate for patients is 12–15 months (Adamson et al., 2009; Johnson and O’Neill, 2012). The chal- lenge intreatingGBMarises fromitsresis- tance to therapies such as radiotherapy andchemotherapy.GBMtumorsarequite infiltrative into the surrounding normal brainpermittingtumorstorecur locally in themajorityofpatients. Thecurrent standardof care treatment for GBM involves surgery and radiation, withconcurrent andadjuvant chemother- apy (Stupp et al., 2005). Surgery permits the bulk of aGBM tumor to be removed in most cases. All patients have resid- ual tumor cells residing away from the resection cavity that eventually lead to local tumor recurrence and the demise of the majority of patients (Hou et al., 2006). The infiltrating GBM cells reside centimeters away from the main tumor mass in normal brain making it diffi- cult for complete surgical removal (Kim et al., 2014). Chemotherapy and radio- therapy of patients after surgery attempts to target these cells to prolong overall patient survival. The blood brain barrier (BBB) represents another challenge to the treatment of GBM tumors by preventing the accumulation of most chemothera- peutics into the brain to target the infil- trative cancer cells (Salazar et al., 1976; Bidros and Vogelbaum, 2009). Surgery and adjuvant therapies pose risks to the patient such as neurologic deficits and systemic toxicities. Known side effects of radiation therapy with chemotherapy for braintumorsincludechronicfatigue,nau- sea, and cognitive deficits (Loehrer et al., 2011). The BBB remains a formidable challenge in the treatment of GBM and malignant brain tumors. Its selective permeability is due to the presence of specialized endothelial cells, astrocytes, pericytes, and neuronal terminals (Tajes et al., 2014). The semi-permeable mem- brane that comprises the BBB prevents sufficient exposure of tumors to most chemotherapeutic drugs that are com- monly used to fight tumor progression (Liu et al., 2010). Local disruption of the BBB is found within GBM tumors. The tumor vessels inGBM tumors are abnor- mal both structurally and functionally (Batchelor et al., 2007). The abnormal tumor vessels further impair delivery of therapeutics and create a hypoxic microenvironment that can reduce the effectiveness of radiation and chemother- apy. Antiangiogenic therapy attempts to normalize the tumor vasculature and improve the tumor microenvironment (Jain, 2001, 2005). Outside of the main tumormass, theBBBis intactwherebrain cancer cells infiltrate into the surrounding normal brain. The oral chemotherapy agent, temozolomide (Temodar), can penetrate the BBB and has resulted in prolongation of overall survival patient survival by several months (Stupp et al., 2005). The challenges associated with the treatment of GBM tumors require novel approaches foragreater impactonpatient survivalandqualityof life forpatients. MAGNETICNANOPARTICLES(MNPs) MNPs aremost commonly comprised of ferromagnetic iron-oxide (Fe3O4). They are invisible to the naked eye, typi- cally measuring 1–100nm in diameter (Sandhiya et al., 2009). MNPs can be designed to target cancer bymodification of their surfacewith theadditionofapep- tide or antibody specific to cancer cells (Hadjipanayis et al., 2010). For biomedi- cal applications, they can deliver targeted therapy to specific regions of the body. MNPscanbeadministered into theblood streamsystemicallyanddirectedtoatarget with application of an external magnetic field (Pankhurst et al., 2003).Particles can be engineered to carry a drug, which can be released once the particles reach their target. In vivo experiments have shown the effects of MNPs within a magnetic fieldongliomacells lastingup to100min postexposure (Braun et al., 2012). In a separate study with rabbits, intravenous injection of specially designedMNPs and subsequent exposure to an externalmag- netic field resulted in permanent remis- sion of squamous cell carcinoma tumors (Chertok et al., 2008).While intravenous administration is feasible with tumors in otherpartsof thebody, theBBBremainsa formidable challenge for systemicdelivery of agents for treatment of brain tumors. For the treatment of patientswithGBMs, direct intratumoral delivery provides the www.frontiersin.org December2014 |Volume2 |Article109 |102