Seite - 111 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Alcantaraet al. Molecular imagingofbreast cancer etal.,2014). Inadditiontotheimagingofbreastcancerprolifera- tionandprogression, theN-[11C]methylcholine (11C-choline) is used as a radiotracer (Contractor et al., 2009) since the choline ismodified to phosphocholine due to the increase of the activ- ity of the enzyme choline kinase-α as noted above in the MR spectroscopysection. MOLECULARIMAGINGTECHNIQUESFORBREASTCANCER The term“molecular imaging” refers to thenon-invasive visual- ization andmeasurement of biological processes at the cellular and molecular levels in a living system using endogenous or exogenousmarkers. There aremanydifferent imagingmodalities that canbeused for molecular imaging, the most relevant ones being: nuclear imaging (PET and SPECT), optical imaging andmagnetic reso- nance imaging. Thedirectobservationofendogenousmarkerscanbeachieved withmagnetic resonance in vivo spectroscopic imaging (MRSI) (Begley et al., 2012; Bolan, 2013) or some advanced optical methods, such as Raman spectroscopy (Kallaway et al., 2013). The first one is based on classical nuclear magnetic resonance (NMR) spectroscopy, which allows the detection and quantifi- cation of molecules containing magnetic nuclei, typically 13C, 31P, 19F or 1H, being 1H NMR the most widely used in vivo. ThecombinationofNMRsequenceswithfieldgradients inMRI scanners allows for the spatial localization of the observable metabolites, giving rise toMRSI. Both 1H and 31PMRSI have been used for the metabolic characterization of breast tumors at a high magnetic field (Klomp et al., 2011). Raman spec- troscopy is based on inelastic scattering of photons after inter- action with vibratingmolecules and thus provides information about tissue composition (Brozek-Pluska et al., 2012; Li et al., 2014). The termmolecular imaging,however,mostcommonlyrefers totheuseofexogenousmarkers(contrastagents) tovisualizeand measure in vivoprocesses. For breast cancer diagnosis, PET and SPECThavebeenwidelyused inclinicalpractice,whereasMRIis expected to have amajor impact in the near future, and optical imaging ismainlyused inpreclinical studies. PETANDSPECT PETimagingusesradioactiveisotopesthatemitpositrons, suchas 18F, 15O, 13N,or 11C;whereas SPECT imaginguses isotopes that emitgammaphotons,suchas99mTc,123I,or125I.Positronstravel short distances in tissues, in the order of millimeters, and col- lide with surrounding electrons (annihilation), producing two highenergygammarays that travel inoppositedirections toone another and are detected by the PET camera. The time delay between thedetectionofpairedoppositedirection isused tocal- culate the location of the annihilation event. In SPECT, a single photon is emitted per event and detected by rotating gamma cameras. Most PET radioisotopes are short-lived, ranging from a few minutes to 2h, which implies the availability of an on-site cyclotron to produce them and therefore increases the cost of PETimagingdramatically.SPECTradioisotopesare longer-lived, in the order of hours (6h for 99mTc), allowing for longer image acquisitiontimes.Ontheotherhand,PETshowshigher sensitiv- ityascomparedtoSPECT. BothPETandSPECTprovideinformationaboutphysiological activity, such as glucosemetabolism, blood flow and perfusion, andoxygenutilization(Kjaer,2006).However, they lackanatom- ical detail, which has led to the development of hybrid systems that combine PET and SPECTwith other imagemodalities, CT andMRI. Both whole-body and dedicated PET/CT scanners are cur- rently available.Dedicated systemshavehigher sensitivity allow- ing for the detection of small tumors and thus being more accurate for molecular imaging, whereas whole-body scanners providevaluable informationfor locoregionalanddistantstaging (Koolen et al., 2012). PET/MRI is amore recent technology that offers the advantage of lower exposure to radiation and higher contrast resolution, togetherwith thepossibility of adding func- tional information fromotherMRImodalities, which has great potential formolecular imaging.However, further technological developments are still needed to get optimal performance of a fully integrated PET/MRI system (Pace et al., 2014). SPECT/CT hasshowntobeavaluabletool forsentinel lymphnodedetection (Husarik andSteinert, 2007; Lerman et al., 2007;VanDerPloeg etal., 2009;CoffeyandHill, 2010). OPTICALIMAGING Optical molecular imaging of the breast is based on the use of near-infrared (NIR) light to excite exogenousfluorescent probes that have been designed to selectively target breast tumor cells (Levi et al., 2007;Poellinger, 2012).TheuseofNIR-fluorophores for immunohistochemical characterization of excised tumor specimens is a common in vitro diagnostic technique. The goal of molecular imaging, however, is to detect these fluorophores in vivo, thus avoiding the need for biopsies. There are technical limitations, though, that need to be addressed if thesemethods are to be used on patients, like tissue penetration and back- ground signal contamination. To date, the use of NIR optical imaging invivo is limitedtotumorxenografts inpreclinical stud- ies(Oliveiraetal.,2012;Sanoetal.,2012;VanDeVenetal.,2012) or intraoperative imagingfortumormargindetectionandlymph nodemapping(Leeetal., 2010;Verbeeketal., 2014). MOLECULARMAGNETICRESONANCEIMAGING MRIhas attracted a great deal of interest in the eraofmolecular imaging, as it is themost versatile diagnostic imagingmodality, able to provide excellent anatomical detail, together with func- tional and metabolic information (Figure3). Furthermore, its non-ionizingnatureoffers thepossibilityofperforming longitu- dinal follow-upstudieswithoutanyrisk for thepatient. Themajority of theMRI signal comes from the water pro- tons (1H) and the contrast from the local differences in water content, water motion and magnetic relaxation times, T1 and T2, of the water protons. Although intrinsic contrast is suffi- cient formostMRI applications, the use of exogenous contrast agentsisoftenrequiredforaccuratediagnosis.MostMRIcontrast agentsarebasedoneithergadoliniumchelatesor superparamag- neticnanoparticles (SPIONs), thesebeing thebase formolecular imaging. www.frontiersin.org December2014 |Volume2 |Article112 |111