Seite - 82 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking FIGURE6 |Ligand-cell interactionandNP internalization.NPscanbe functionalizedwithdifferent ligands to increasecell targetingandNP internalization. (A)FunctionalizationofNPswithantibodiesallows the targetingofantigensexclusivelyexpressedoroverexpressedby target cells (e.g., anti-CD205antibody to targetCD205onDCsoranti-HER2antibody to targetHER2onbreast cancercells). (B) Inorder to targetDCs,NPscanbe functionalizedwithmolecules thatmimicPAMPs,normally carbohydrates, nucleic acidsor lipids,whichare recognizedbyPRRsexpressedbyDCs.For instance,mannoseor fucose residuesare recognizedby themannose receptors—aC-lectin receptor.Bacterial lipopolysaccharideorflagellin target TLR4andTLR5onDCs, respectively. (C)Cell-penetratingpeptidesaresmall aminoacidsequencesnormallyusedbyvirusesorbacteria to facilitate cellular invasionby thosepathogensandcanbeused to increase the internalizationofNPs.FunctionalizedNPssee their internalizationby target cells increasedessentiallyby twomechanisms: inductionofendocytosis upon ligand-receptorbinding,whichhappens toNPs functionalizedwith ligandssuchasantibodies,PAMPsorsomepenetratingpeptides that induce receptor-mediatedendocytosis (e.g., integrins)or (D) throughdirect cell penetrationacross theplasmamembrane (e.g., antimicrobial peptidesor histidine-richpeptides) (E)orboth (e.g.,HIVTATpeptide). indirect mechanisms involving TLR-activated DCs (Silva et al., 2013).C-type lectin receptors (CLRs) belong to another class of PRRsexpressedbyAPCs.This receptor family is characterizedby thepresenceofdomains thatbind to carbohydrates (VanKooyk, 2008). CLRs are specific receptors particularly engaged in the internalization of antigens. CLRs enable the intracellular uptake andprocessingofantigens,aswellas influencetheircytosolic fate and the loading onMHCclass I and II (Unger andVanKooyk, 2011). Regarding the involvement of PRRs in several strategic immunepathways, thedesignofnano-basedsystemsfor immune cell targeting can be extremely interesting. Not only because a morespecificdeliverycanbeachieved,butalsobecausethecellu- lar internalizationof the targetednanosystemcanbemodulated and potentiated. Additionally, the attachment of PRRs ligands on the surface of nanocarriers may boost their immunogenic- ity,whichcanbeanoutstanding strategy for thedevelopmentof vaccines, since it allows the incorporationof an antigen and the “danger signal” in thesameplatform(Silvaetal., 2013). NANOCARRIERSFORIMAGINGAPPROACHES The importance of a deeper knowledge of the dynamic cancer immunological processes has long been realized. The study of theseprocesses in vivo,with living cells and thewholeorganism, is essential to answer this issuemore accurately. Cancer disease processeswill bebetterunderstoodand thus improved therapies can surely bedeveloped. For the visualizationof these biological dynamic processes in vivo, methods have to provide a real-time in situ fast response, as well as be non-invasive and with high sensitivityandstability (Wangetal., 2013b). www.frontiersin.org November2014 |Volume2 |Article105 | 82