Seite - 85 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking TheSPIONPsareknownas safe systemsdue to theirbiodegrad- ability nature and usual rapidmetabolization in vivo (Yu et al., 2012). Therefore, the SPIO-based cell labeling is mostly suit- able for short-term studies. On the other hand, false positives maybedetectedafter the accumulationof thedetectionagent in macrophages after thedestructionof labeled cells (Ahrens et al., 2003; Thorek and Tsourkas, 2008). This disadvantage is in fact commontodifferent imagingreagent-labeled techniques. The 19FMRI is a highly sensitive technique that allows the direct quantification of labeled immune cells, as T cells and phagocytic cells, either in vivo or ex vivo (Srinivas et al., 2009; Helferetal.,2010).UnlikeSPIONPs,this labelingmethodusually doesnotdetectfalsepositivesand,onceisnotmetabolized invivo, constitutes a suitable approach for long-termstudies (Janjic and Ahrens,2009;Srinivasetal., 2012). The droplet surface of these PFC colloidal systems has been changedwithchargedentities topotentiate theirefficientdelivery atintracellularlevel.Therefore,thesafetyoftheselabelingsystems is increased,whichhasbeenshownusingdifferent immunecells, asDCsandTcells(Ahrensetal.,2005;Srinivasetal.,2009;Helfer etal., 2010;AhrensandBulte,2013). Recent studies have shown thepromising combinationof 19F labeling techniques with fluorescence orNIR probes, as well as withnuclearmagneticresonance(NMR)(Pateletal.,2013).Even though, theuseof these colloidal system for cell tracking is con- siderablyrecentandfurtherstudiesareurged inorder toconfirm these indications. ANIMALMODELSFORTHETRANSLATIONOF IMMUNOTHERAPEUTICAPPROACHES The successful translation of alternative immune-based approaches for cancer therapy into theclinic ishighlydependent onthedevelopmentofpreclinical animalmodels that adequately mimic human disease progression. Several models have been developed and successfully used to study cancer mechanisms of disease and the efficacy of conventional therapeutic options (Budhuetal., 2014). Accordingly, models currently used to evaluate therapeutic antitumorefficacyatpreclinical levelarebasedontransgenicsys- tems and the transplantation of in vitro grown cancer cells into healthyanimalsor inhumanizedmousemodels—humantumor xenograftmodels (Ostrand-Rosenberg, 2004). The implantation of human cell lines dictates the use of immunocompromised mice–T-cell deficient—toallow the establishmentof cancer dis- ease. Besides beingoneof themost usedmodels to study cancer disease and the effect of cytotoxic therapies, those are definitely not suitable to test the efficacy of immunotherapeutic strategies as it is not possible to evaluate the effect of adaptive immune response in tumordevelopment (Legrandet al., 2009).However, different approaches are currently being explored to improve theirapplicationtowardthereconstitutionoftheimmunesystem using human cells (Carpenito et al., 2009; Legrand et al., 2009; Pedroza-Gonzalez et al., 2011). Still, the evaluation of the out- comeof different immunotherapeutic options has beenpossible due to development of differentmouse cancer cell lines, which can be furthermodified if needed: B16melanoma, CT26 colon carcinoma, TRAMP (transgenic adenocarcinoma of the mouse prostatemodel) prostate cancer, 4T1 breast cancer, EL4 T lym- phoma (Greenberg et al., 1995). Even tough, there is usually a rapid tumor growth after the subcutaneous administration of those cells and therefore thesemodels do notmimic the long- lasting host-tumor interactions resultant from the spontaneous implementation of this disease. On the other hand, the trans- plantable tumors are very versatile for prophylactic studies as it allows establishment of different vaccination settings, allowing an immune response before the inductionof cancer disease and consequent immunosuppressiveoutcomes. The spontaneousandmulti-step tumordevelopment, includ- ing the cross-talkbetweencellswithin tumormicroenvironment is possible in genetic modified animals (Dougan et al., 2011). However, these animals need to be evaluated for longer periods of time. In addition, the presence of mutations in a perma- nent manner, in contrast to what happens in cancer disease, has been associated with higher variability and tolerance and consequently, lowereffectivenessofdifferent immunotherapeutic options(Hurwitzetal., 2000;Ercolinietal., 2005). Asaresult, thereisanurgentneedforanimalmodelsrecapitu- latingcancerdisease,andall results shouldbediscussedhavingin considerationanimalmodelspecificitiesandlimitations. Inaddi- tion,different typesofanimalmodelsshouldbetestedinorderto better characterize the obtained antitumor evidences for clinical translation. CONCLUSIONSANDFUTUREPERSPECTIVES Despite the improvement observed in chemotherapy and radio- therapy forcancer treatment, thebattleagainst thisdisease seems tohavemorechances tobeachieved throughthecombinationof different therapeuticmodalities. Immunotherapeuticapproaches have emerging as promising tools to address the heterogene- ity of this disease, namely those immune cell mediated cancer therapies. It is possible to underline the advances obtainedwith the approval of anti-CTL4 monoclonal antibody by the FDA, and great expectations have arisen from the use of different approaches to modulate the function of immune cells within tumor site. Among those strategies, the outcome of cancer vac- cines canbehighlighted.Tomonitor andguide thedevelopment ofcellulartherapiesandthe insitumanipulationofimmunecells, the improvement of non-invasive imaging strategies to obtain detailed information regarding the biological processes within the complex tumor microenvironment is imperative. We fore- see the use of non-toxic nanotechnology-based systems able to combine the specific (i) targeting of immune cells, promoting thecontrolleddeliveryofdifferentmolecularentities tomodulate the cell-cell interactions; and (ii) tracking through the inclu- sion of different probes to improve safety, specificity and sen- sitivity of cell-labelingmethods and imaging approaches. These immunotheranostics are expected to enable a rational definition oftreatmentplansforaparticularpatient,resultinginbetterclin- icaloutcomesandenhancedcontrolofthedisease,whichcanalso promote their translation intomarketedsystems. ACKNOWLEDGMENTS This work was supported by Fundação para a Ciência e a Tecnologia, Ministério da Ciência e da Tecnologia, Portugal Frontiers inChemistry | ChemicalEngineering November2014 |Volume2 |Article105 | 85