Seite - 112 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Alcantaraet al. Molecular imagingofbreast cancer FIGURE3 |BreastMRI imagesat1.5T.Aconventional breastMRI image (withoutcontrast agent) (A).Abreastprosthesiscanbeseen in the right breast (B). In contrast to nuclear and optical imagingmodalities, which are based on the direct detection of molecular probes, molec- ular magnetic resonance imaging is an indirect method that detects the effect of the contrast agents on themagnetic proper- ties of the surroundingwatermolecules. This is a crucial aspect in understanding MRI-based molecular imaging, as explained below. Themajor drawbacks of MRI for molecular imaging appli- cations are, on the one hand, its inherent low sensitivity, due to the small difference in atoms between the high and the low energystates,andontheotherhand,thelackofspecificityofcon- ventionalMRI contrast agents. Thus,molecular imaging probes have to be able to strongly increase sensitivity and at the same time showhigh specificity. In this regard, SPIONs (Lodhia et al., 2010; Ittrich et al., 2013; Jin et al., 2014) have important advan- tages over othermagnetic contrast agents because they produce signal enhancement through local field inhomogeneities, which affects theT2of a largenumberofwatermolecules, thus leading to very strong signal enhancement. Nonetheless, other types of contrast agents have also beenproposed formagnetic resonance molecular imaging, such asGd-basednanoparticles (Huang and Tsourkas, 2013). Finally, the functionalization of these nanosys- tems using technological approaches adds both specificity and biocompatibility. Some studies have already shown the great potential ofmag- netic resonance for molecular imaging of breast cancer using targetednanoparticles (Li et al., 2013;Yanetal., 2013).Although these studies havebeenonly conducted in animalmodels, it can be expected that, in thenear future, the rapidly growingfield of nanomedicinewill facilitate the translation of thesemethodolo- gies to theclinics. PERSPECTIVES Although molecular imaging is able to visualize breast tumor morphology and functional andmetabolic processes within the tumor at several levels, the sensitivity of the differentmolecular imaging techniques is varied depending on the type of marker used in signaling the biological processes. At present, themain milestones for futuremolecular imaging development in breast cancerare: 1. To enhance knowledge of molecular drivers behind breast cancer subtypes,progressionandmetastasis. 2. To develop validated markers for chemosensitivity and radiosensitivity. 3. To validatemultimodality imagingbiomarkers forminimally invasivediagnosisandmonitoringofresponsesinprimaryand metastaticdisease. 4. Todevelopinterventionsandsupporttoimprovethesurvivor- shipexperience. In 2012, the charity Breast Cancer Campaign facilitated a series of workshops where specialists and other stakeholders revealed the main gaps in the prevention and treatment of breast can- cer (Eccles et al., 2013). Top problems in molecular imag- ing of breast cancer (and recent research on the field) to be highlightedare: 1. There is a need to increase the use of functional screening techniques to learn about tumor heterogeneity, identify fea- tures associatedwith response or resistance to treatment and accelerate therateatwhichpromisingonesenterclinical eval- uation.The“EuropeAgainstCancer”programmehas created qualityassuranceguidelinesusedforallmammography-based screening for breast cancer. They were created to maximize resultswhileminimizingnegativeeffects.TheMammography QualityStandardsAct (MQSA) in theUnitedStateshasman- dated that all mammography clinics be certified (VonKarsa andArrossi,2013).Resistancetochemotherapyhasbroughtto light the issueof tumorheterogeneity.Approximately 70%of humanbreast tumorsareERpositiveanddependonestrogen forgrowth.TheuseofselectiveERmodulators,suchastamox- ifen, in ER-expressing tumors was one of the first examples for successful targeted therapybasedon the tumor’smolecu- lar classification(Swabyetal., 2007).What inducesendocrine resistanceinthesetumorshasbeenoneofthelongeststanding andmost intense areasofbreast cancer research.The somatic evolutionoftumorprogressionwasdiscoveredin2012,butthe results raisedadditionalquestions that couldnotbeanswered at that time(GreavesandMaley,2012).Oneof themostexcit- ing outcomes of comprehensive cancer-genome-sequencing studiesisthatwefinallyhavethetoolstofollowclonalandsub- clonal evolutionof tumors and see the complexity of cancers asawhole(Polyak,2014). 2. Evaluation of emerging imaging biomarkers of primary and metastatic breast cancer. A biomarker is a crucial tool for measuring the progress of disease and the effects of treat- ment for better clinical outcomes in breast cancer patients. The current questions of therapeutic choices can focus now on the understanding that breast cancer is truly a collection of genetically-specific heterogeneous diseases, each demon- strating different clinical behavior and therapeutic response (DeMattos-Arrudaetal.,2013).Severalbiomarkershavebeen proposed as newbreast cancer targets, includingMicroRNAs (mi-RNA) (Mulrane et al., 2014), proteins (Kondo, 2014), antibodies (Knowles andWu, 2012), or glycans (Adamczyk et al., 2012). One promising direction is the detection and imaging of circulating cell-free DNA (cf-DNA). Since 2002, cf-DNA has been shown to represent a good non-invasive biomarker, as it can be isolated fromhuman plasma, serum Frontiers inChemistry | ChemicalEngineering December2014 |Volume2 |Article112 | 112