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Conniotet al. Nanocarriers for immunecell targetingand tracking are10–50-foldhigherthaninnormaltissues, leadingtoimproved therapeuticefficacyandless sideeffects (Iyeretal.,2006;Danhier etal., 2010). Active targeting Nanotechnology-basedstrategieshavebeenexploredasplatforms for drug delivery, cancer vaccination and/or diagnosis, due to theircapacity forovercomingbiologicalbarriersandtomodulate payloads’ intracellular trafficking.Thesenanoparticulate systems present a good potential for site-selective delivery by binding recognitionligandstoNPsurface,whichcanenhanceNPendocy- tosis, influencing their intracellular traffickingandthus inducing prolongedeffects (Danhieretal., 2010). Surface functionalization of nano-based systems (Figure4) hasbeenusedtoimprovetissueandcell surfaceantigentargeting, thus moderating non-specific distribution and prolonging the bloodcirculationtimeofnano-basedsystems(Alexisetal.,2008). PEGylation is a widespread strategy to improve the half-life time of nanocarriers, through steric stabilization and “stealth” properties. It relies on the introduction of poly(ethylene glycol) (PEG) molecules by conjugation, grafting or adsorption onto the surface of nanosystems (Figure5). The terminal groups of PEG chains also present very suitable moieties to attach func- tional ligands and attain active-targeted carriers (Freichels et al., 2012). The conjugation of antibody fragments to PEG ends, using disulfide bonds, may consist in an interesting strategy to develop platforms for active targeting (Brocchini et al., 2008). D-α-tocopheryl polyethylene glycol succinate (TPGS) has been reportedasanalternative toPEG(PanandFeng,2008). Active-targeted nanosystems are based on the design of nanocarriers with bioactive ligands placed onto their surface or periphery. They will be recognized by overexpressedmolec- ular patterns at the tissues/cells intended to target, facilitating NP recognition and subsequent receptor-mediated endocytosis (Figure6) (Chenget al., 2007;Kumaret al., 2009;Danhier et al., 2010; Aslan et al., 2013;Nicolas et al., 2013;Wang et al., 2013a; Gaoetal., 2014).Surfacemodifications representanoutstanding tool for cell targeting allowing a specific contact of nanopartic- ulate systemswithcritical immunecells, as evidenced inStephan etal. (2010).Forexample, theligandDEC-205ishighlyexpressed by CD8+DCs, cells particularly efficient at “cross-presenting” exogenous antigens on MHCI, constituting a highly relevant pathway for the development of a cytolytic immune response. Moreover, recent studies have indicated that the triggering of CD40onAPCscanleadtoCD8T-cell effectors,without theneed ofcommonstimulationbyMHCII-relatedThcells viaCD40 lig- ands (Vonderheide et al., 2013).Mannose receptors at DCs are also associated to ligand internalization and further processing and presentation by immune cells, leading to amore extensive immune response (Lu et al., 2007; Carrillo-Conde et al., 2011; Silvaetal., 2013). These ligands, suchaspeptides, antibodiesandantibody frag- ments, carbohydrates and evenvitamins,maybe either attached before the nanocarrier production or afterwards. Liking ligands FIGURE4 |Examples of NP functionalization. NPs can be functionalized differently in order to attain distinct goals. PEG or TGPS functionalization provide stealth properties to NPs, avoiding capture by phagocytic cells and increasing their circulation time. Functionalization of NPs with imaging agents, such as fluorescent probes, radionuclides or contrast agents (e.g., gold or magnetic NPs), provide applicability of NPs to diagnostic, theranostic or even in vivo real-time imaging. The immunogenicity of NPs can be increased for immunotherapy or prophylactic vaccination. Different molecules can be used for that propose, such as PAMPs (several carbohydrates, lipids or nucleic acids) or immunogenic polymers (e.g., chitosan, alginate, poloxamers). Specific tissue and cell targeting can be achieved through the functionalization of NPs with antibodies directed to specific or overexpressed antigens. Cell-penetrating peptides can improve NP internalization. pH-sensitive coatings allow drug release in specific tissues or intracellular compartments in a pH-dependent manner. www.frontiersin.org November2014 |Volume2 |Article105 | 80