Seite - 74 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking DCtherapy involves the isolation, culture and stimulationof patient’smonocytes andmacrophages ex vivo using TAAs (Cho et al., 2011). When administered back to the patient, antigen- loaded DCs will bypass the in vivo uptake of tumor antigens. DCs are already activated and therefore they are able tomigrate to the secondary lymphnodes wherein theywill trigger T cells. However, the relative short half-life of TAA-MHCcomplexes on DCmembrane surface, and the low percentage (3–5%) ofDCs that canmigrate to the lymphnodesandcontactwithTcells can contribute to the low rate of success of these vaccines (DeVries etal.,2003;Hamdyetal.,2011).Also,beingproducedspecifically for a particular patient, ex vivoDC-based vaccines are a highly complex, laborious, time-consuming and expensive approach. Futhermore,thevaccinequalitymightdependontheclinicwhere it is produced, once there are several variable parameters in the process, suchasdoseofDCsandposology (Hamdyet al., 2011). The type of DCs stimulated, antigen loading method and DC maturation level are also important aspects to be characterized tobetterunderstandtheadjuvant roleofDCs. Invivo To overcome the lack of clinical efficacy of ex vivoDC-based cancervaccines, it isextremelyrecommendedtodevelopanalter- nativeway to target antigens directly toDCs in vivo, which can beachievedusingpeptide-basedvaccines.Thesearemainlybased onMHCIpeptides,whichare simple toproduceandadminister, and guaranteeDCactivation and expansion for prolongedperi- ods of time (Figure1) (Cheong et al., 2010; Silva et al., 2013). However, thecytoplasmicdeliveryof theantigenis limitedbylow membranepermeabilityandfrequentdestructionafterintracellu- larentry,beingtheir immunogenicityconsiderablylowerthanthe traditionalvaccines.Hence, theirassociationtopotentadjuvants, FIGURE1 |Nanoparticulate cancer vaccines. (A)NPs are able to deliver several TAAs and adjuvants simultaneously, enabling a coordinated activation of DCs. NPs can also be functionalized in order to actively target DCs in vivo, increase their cellular internalization and immunogenicity or even target specific intracellular compartments. (B)NP-based cancer vaccines can be targeted toDCs in vivo and after their internalization induce thematuration of these cells. TAAs and adjuvants are simultaneously released inside the sameDCwhich guaranties its coordinated activation. TAAs are presented troughMHCclass I and class IImolecules toCD8+ and CD4+ naïve T cellswhich recognize the processed antigens through TCRs. Activated CD8+ T cells differentiate into CTLs,which can destroy tumor cells, andmemory T cells, that are important to avoid recidivism and metastasis. CD4+ T cells should differentiate in Th1 cells, whichwill potentiate the action of CTLs andwill also activate cells of the innate immune system, such asNK cells, granulocytes andmacrophages that play a role in the tumor destruction process aswell. www.frontiersin.org November2014 |Volume2 |Article105 | 74