Page - 110 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Alcantaraet al. Molecular imagingofbreast cancer treatmentthanthedecreaseoftumorsize.Furthermore, thecom- bination of spectroscopy and diffusionMRI data have demon- strated a high specificity to characterize benign andmalignant lesions(Tsougosetal., 2014). CONTRASTAGENTS In spite of the multiple image diagnostic tools commented on above, radiologists still find some difficulties when diagnosing earlystagebreasttumormalignanciesduetothelackofsensibility given for these techniques.Earlydetectionhasbecomeoneof the most important issues in the cancer treatment, and researchers have improvedthis issuebydevelopingexternal substancescalled contrastagentsthatenhancethesensibilityofimagesintheregion of interest. This fact allows improvement to the quality and the follow-up of molecular processes at the cellular andmolecular levels of the region under study. The more common contrast agents used in clinical studies are gadolinium- and iodine-based structures formagnetic resonance imaging andmammography (X-ray)respectively,howeverothercontrastagents suchasradio- tracers are being investigated as potential biomarkers for daily clinicalpractice. MAGNETICRESONANCEIMAGINGCONTRASTAGENTS As noted above, the gadolinium-based contrast agents are the most commonly used in clinical practice, generating a positive image of the nearby tissues. The presence of gadolinium ions shortens the T1 relaxation time, thus generating an increase of the intensity in the images (bright signal or positive image) that help to distinguishmalignancies fromother benign pathologies (ZhouandLu, 2013).However, gadolinium is ahigh toxicpara- magneticcation(Gd3+)thatneedstobeprotectedfromthebody, so gadolinium ismainly reactedwith chelate ligands thusmin- imizing the toxicity effects from the free gadolinium (Gd3+). Therefore, themost typically used gadolinium chelates asMRI contrast agents in clinical practice are gadopentetate dimeglu- mine (Gd-DTPA, Magnevist®), gadoterate dimeglumine (Gd- DOTA, Dotarem®), gadoteridol (Gd(HP-DO3A), Prohance®), and gadodiamine (Gd(DTPA-BMA), Omniscan®). These con- trast agents, approved by the Food and Drug Administration (FDA), present excellent biodistributionwithin the extracellular space, and fast renal clearance from the body with half-lives of 1–2h.Albeit themostusedgadolinium-basedcontrastagentsare theGd-chelates, complexgadolinium-basedcontrast agentshave been developed to improve their T1 relaxation time and phar- macokinetics. These complexes providewell-defined advantages overGd-chelates due to slow rotationalmotion, they are a com- bination ofGd-chelates, such asGd-DTPA andGd-DOTA, and dendrimers (Li et al., 2013) or liposomes (Huang andTsourkas, 2013; Zhou and Lu, 2013). For instance, poly(amidoamine) PAMAMdendrimers indifferent generationshave shownhigher r1 relaxivity and size-dependent pharmacokinetics, low genera- tion(2–4)presented renal clearance, andhighgeneration (5–10) presentedminimal renal clearance. A recentmodification in the designof contrast agentdendrimers resulted in thedevelopment of dendrimer nanoclusters (DNCs), as a combination of small PAMAMdendrimers.TheseDNCswereeasilysynthesizedinhigh yields andalso exhibitedhigher r1 values than the small units of PAMAM-based contrast agents (Cheng et al., 2010). TheseGd- chelateswerealsocombinedwith liposomesvia encapsulation in the inner core or immobilization at the liposome surface, being the immobilizationmost used since the relaxivity is higher than intheencapsulatedmethod,thusexhibitingalowwaterexchange rate with the gadolinium encapsulated in the inner core of the liposome. X-RAYCONTRASTAGENTS Iodine-basedcontrast agents improve thevisualizationof images in radiography andCT by increasing the density of tissues and also the vessels. Similarly to dynamic MRI using Gd chelates, relevant information can be extracted from the different uptake kinetics of these contrast agents that helps in differentiating malignant lesions frombenign tissues. In case ofmalignant tis- sues,theiodineisrapidlyabsorbedanddesorbed(morecontrast), while in the benign ones the absorption takes place slowly (less contrast), thus giving differences in the tissue density of the images. Iodine contrast agents could be sorted into two groups depending on the binding to the iodine: covalent (non-ionic) or ionic contrast agents (Robbins andPozniak, 2010). The ionic contrast agents present are better contrast agents than the non- ionic ones due to their higher osmolality,with the consequently increaseddeliveryordisassociationofiodine(Barrettetal.,1992). However, the ionic iodine contrast agents inducesmore toxicity (moresideeffects)mainlydue to the largeamountof iodine ions delivered(higherosmolality injected incomparisonwithserum), beingalsorecentlyreportedthatthesecontrastagentscouldaffect the thyroid in some patients (Rhee et al., 2012). Therefore, in order tominimize the toxicity, the contrast agents used for the clinical practice present values close to the serum, and non- ionicbondssuchasIohexol300mgIodine/mL(Omnipaque)and Iodixanol320mgIodine/mL(Visipaque). POSITRONEMISSIONMAMMOGRAPHY(PEM) PEM is high-resolution PET scanner that provides functional imaging specifically for breast cancer detection (Kalles et al., 2013). PEM can isolate and enhance breast images with more accuracy than full-body PET scans andworksmuch like a full- body PET scan (see Section PET and SPECT). In this tech- nique, thecontrast agentsused in theevaluationofbreast cancer are radiotracers (Penuelas et al., 2012), in particular radioac- tive labeled sugar-like molecules. These radiotracers help the diagnostic accuracy of the cancer, especially in the early stages, metastasis,andalsocancerprogressionduringthetreatment.18F- fluorodeoxiglucose (FDG) (Caldarella et al., 2014) is the most typical radiotracer used as a contrast agent in PEM. FDG is an analog of glucose that is accumulated, after injection,mostly in cancer tissues, since those present a faster metabolism in com- parisonwith the normal tissues allowing amore clear vision of the suspectedmalignant tissues by PEM.Another radiotracer is the3′-deoxy-3′-[18F]fluorothymidine(18FLT).Thisradiotracer is not still used as a routinebreast cancer contrast agent in clinical practice, but it hasbeen tested as abiomarker for imaging cellu- lar proliferation. 18FLT is a structural analogofDNAnucleoside thymidine that is trapped in the cell thus informing about the stage ormonitoring the evolution of the tumor cells (Caldarella Frontiers inChemistry | ChemicalEngineering December2014 |Volume2 |Article112 | 110