Page - 113 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Alcantaraet al. Molecular imagingofbreast cancer and other body fluids (Utting et al., 2002). It was also reported that the concentration of DNA in the bloodstream of patients with breast cancer was higher than healthy con- trols (Fleischhacker and Schmidt, 2007). Thus, the detection of cf-DNA provides new opportunities for management of cancer patients, adding a useful new tool for diagnosis, stag- ing andprognosis (Esposito et al., 2014). Imagingof cf-DNA after chemotherapy treatment has been described by using fluorochrome-functionalizednanoparticles (Choetal., 2013). Very recently, cf-DNA fromplasma samples has been imaged by AFM and allowed to confirm the specific size pattern of tumor-derivedcf-DNA(Mouliereetal., 2014). 3. Increased specificity and improved clinical translation of radiotracers forpositronemission tomography/single-photon emissioncomputed tomography(PET/SPECT).Since thedis- covery of GLUT family proteins overexpression associated with certain tumors, a variety of radiolabeled glucose deriva- tives havebeendeveloped as SPECTandPET tumor imaging agents. [18F]FDG is by far the most widely used in PET imaging for cancer diagnosis. Unfortunately, clinical usage is limited due to the need for the presence of cyclotron in 18F production.Generatorproduced isotopes, suchas99mTcand 68Ga,are readilyavailableandaffordable.Theavailabilityofa generatorandkitchemistrytoprepare99mTcand68Ga-based molecular probes may have a significant impact on nuclear medicine (Liu et al., 2014). It has been shown that 99mTc- glucaratemaybehaveasasuitablealternative to18F-FDGasa promisingbreast tumorimagingagentandneedstobefurther investigated (Gambini et al., 2011). Thus, using generator- produced isotopes to label glucose analogs is themajor focus ofongoingresearch. 4. Identification and assessment of using imaging biomarkers currently associated with other cancer indicators in addi- tional hallmarks such as hypoxia, invasion and changes in metabolism.Duringthepastdecades,researchershavetriedto elucidate themechanisms that underlie cancer-related death. However, this remains a challenge, as genomic instability causes a constantly changing genetic profile of tumors, and local variations in themicroenvironment causeheterogeneity in tumorcellbehavior(Polyak,2014). 5. How to validate novel imaging biomarkers in adequately powered multi-center clinical trials. While applied molec- ular biology to cancer has made great advancements, the development of clinically validated biomarkers for primary breastcancerhasremainedanunconquerabletask.Chemo-N0 (1993–1998)wasthefirstprospectiverandomizedmulticenter trial inNode-negativebreast cancerdesigned toprospectively evaluate the clinical utility of a biomarker. Its results estab- lisheduPA/PAI-1as aclinicallyusefulbiomarker forassessing long-term prognosis in early breast cancer and benefit from adjuvant chemotherapy in thehigh-riskgroup; it is thuswell- suitedforroutineriskassessment innode-negativebreastcan- cer (Harbeck et al., 2013). TheNodeNegative Breast Cancer Trial (NNBC), initiatedby the SwedishBreastCancerGroup, was able to validate a prognostic index consisting of a pro- liferation factor, PR-status, and tumor size. The index may be helpful for prognostic considerations and for selection of patients in need of adjuvant therapy (Klintman et al., 2013). Although still in their infancy, circulatingmi-RNAs and cf- DNAare beginning to be recognized as vital to future strate- gies on therapies for breast cancer (Ng et al., 2013; Esposito et al., 2014).mi-RNAshave become the rising stars for novel moleculartargetingtreatmentsbecauseoftheirabilitytoregu- latemultiplegenesinmolecularpathways(Sietal.,2013).Very recently, a Phase 1 clinical study ofMRX34, the firstmiRNA to advance into a human clinical trial for liver cancer, was approved(MirnaTherapeutics,2014). 6. Methods of reporting intratumoral heterogeneity and locate themostbeneficialareasforbiopsiesandradiotherapy.Within the plethora of imagingmodalities, diffusionweightedmag- netic resonance imaging (DW-MRI) has shown promise for the detection and characterizationof breast cancer. Apparent diffusioncoefficient (ADC)values allowquantificationof the diffusionsignal,andcanfacilitateindifferentiatingbenignand malignant breast tumors aswell as identifying early response in tumors undergoing preoperative treatment (Partridge and McDonald, 2013 and the references cited therein). On the other hand, the heterogeneous nature of cancer still presents an important challenge in cancer imaging and therapeutics (Seoane and De Mattos-Arruda, 2014). This heterogeneity also confers to the different breast cancer subtypes a spe- cific invasional kineticpattern, ashasbeen recently shownby Yamaguchi et al. usingMRI studies (Yamaguchi et al., 2014). Although breastMRI accuracy for assessing residual disease is good and surpasses other diagnostic techniques, overes- timation and underestimation of residual disease have also beenobserved.This is largelybecauseof thevarioustreatment types and breast cancer subtypes (Lobbes et al., 2013).With some limitations and taking into consideration that many of the experiments have been performed in mice, intravi- tal microscopy (IVM) is another technique that has proven its power to elucidate the cellular andmolecular events that underlie the hallmarks of cancer. Fluorescence-guided surgi- calprocedureshavealsobenefitedfromIVM,whichtranslates intomore promising uses in the clinical setting (Ellenbroek andVanRheenen,2014). 7. Extension of methods that identify and define subtypes of cancerous tumors—DCIS, TNBC and luminal types—with non-invasive procedures (which may identify mixed lesions missedbyhomogenizedorlimitedsampleanalyses)andassess heterogeneity betweenmetastases. In recent years, there has beenanexplosioninthefieldofnanomedicinewiththedevel- opmentofnewnanoparticles for thediagnosis and treatment of cancer, and the related term “nanooncology” has been adopted bymany (Thakor and Gambhir, 2013). The devel- opment of new contrast agents for MRI opens a new way fornon-invasivebreast cancer characterization. Special atten- tion ismade to ironoxidenanoparticles, currently oneof the best options in clinic due to its lack of toxicity (Kievit and Zhang, 2011; Rosen et al., 2012).Meier et al. usedmagnetic nanoparticles(SPIONs)decoratedwithfolicacidtoimageFR- positive humanbreast cancer cell lines non-invasively (Meier et al., 2010).Very recently, Sun et al. havedevelopedSPIONs functionalizedwith extradomain-Boffibronectin (EDB-FN) www.frontiersin.org December2014 |Volume2 |Article112 |113