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Conniotet al. Nanocarriers for immunecell targetingand tracking thepolymeroriginatenanoparticles,when theorganic solvent is eliminated(LassalleandFerreira,2007). Nevertheless, it is important to bear in mind that the cho- senmethodwill influencethecharacteristicsof theobtainedNPs, suchasthesizeandthesurface.Besides, it iscrucial tohaveagreat knowledgeabout thedifferentexperimentalvariables, inorder to achieve the intended formulation characteristics (Gorner et al., 1999;LassalleandFerreira,2007). A large number of polymers from different origins have alreadybeendescribedasusefulmaterials forpolymericNPpro- duction and used in preclinical studies. Polymers can be from natural origin, as chitosan, or synthesized, as polylactic acid and poly-lactic-co-glycolic acid (PLGA) (Krishnamachari et al., 2011; Mizrahy and Peer, 2012). Particulate adjuvants, such as PLGA and PCL NPs, have generated a lot of interest due to theirbiodegradability,biocompatibilityandmechanical strength. (Danhier et al., 2012) has nicely reviewed the main properties andapplicationsofPLGA-basednanocarriers.TheseNPscanalso actasadjuvants,maintainingtheantigenicityandimmunogenic- ity of encapsulated proteins. In fact, PLGA, used for decades in humans, is the most studied polymer for vaccine formulation and it was shown to increase antibody and cellular responses to antigen-loaded PLGANP (Johansen et al., 2000; Shen et al., 2006; Chen et al., 2014a). PCL has a great potential for devel- oping antigen controlled releasematrices by its lowdegradation rate, hydrophobicity, good drug permeability, in vitro stability and low toxicity. The adjuvant effect of PCL NPs to induce immune responses against an infectious disease was previously confirmedby several studies (Benoit et al., 1999; Florindo et al., 2008, 2009b; Labet and Thielemans, 2009). If the encapsulated antigen fails to induce DC activation, these NPs can be mod- ified withmaturation signals at their surface for direct ligand- receptorinteraction,asmannosereceptorisoverexpressedatDCs and macrophage cell surface. Chitosan NPs, for instance, are an interesting strategy for gene delivery, namely small interfer- ingRNA(siRNA).As chitosan is positively charged, electrostatic interactions occur with negatively charged siRNA, and thus the biomolecule is safely carried to its in vivo target (Aslan et al., 2013). Nanocarriers producedusing polypeptide-based polyanionic, zwitteronic and polycationic polymers (e.g., polyglutamic acid, polyarginine) have also been described (Christian et al., 2009). These are endosomolytic polymers and have been used to pro- mote thecytosolicdeliveryof thesebiomolecules.Althoughclin- ical trials with peptide-based cancer nanovaccines have shown littlesuccess,morerecentresearchhasbeendevelopedtoimprove them,usingnovelpolymericNPssystems. It has been reported that PLGANPs loadedwithmelanoma antigens can elicit effective anti-tumor activity by CTLs in vivo (Zhanget al., 2011;Maet al., 2012).DC-targeting chitosanNPs, carrying IL-12,were alsoused inapreclinical study.Theadmin- istrationof thisnanovaccine inananimalmodel resulted in sup- pression of tumor growth and increased induction of apoptosis (Kimetal., 2006). Regarding immune cell tracking, biodegradable PLGA NPs have been used in a combined multimodal imaging strategy for a DC-targeting nanovaccine. Superparamagnetic iron oxide particles and a fluorescently labeled antigens were incorporated within the samenanosystem, allowingnot only the analysis and quantificationofNPsuptake, but also the subcellular trackingof NPs(Cruzetal., 2011). Polymericmicelles Polymeric micelles are self-assembled spherical nanocarriers formed by amphiphilic block copolymers in aqueous medium (Figure3C).Ahydrophobic coreandahydrophilic surface com- pose these structures, and their size ranges from 10 to 100nm (Torchilin,2001; JhaveriandTorchilin,2014). Polymermicelleshavebeeninvestigatedasdeliverysystemsfor poorlywater-soluble/hydrophobicdrugsdue to thehydrophobic core. It has been shown thatmicelles can enhance the bioavail- ability of hydrophobic molecules, which is reassured because they protect the drug from in vivodegradation (Torchilin, 2001; Jhaveri and Torchilin, 2014). Other advantages of polymeric micelles are the low toxicity, the prolonged circulation time and good levels of accumulation in tumor areas (Ganta et al., 2008). In an experiment with nudemice xenograftmodel, PLGA-PEG polymeric micelles have shown increased tumoral uptake (Yoo andPark,2004). Novel pH-responsive polymer micelles formed by an N-(2-hydroxypropyl)methacrylamidecoronaandapropylacrylic acid(PAA)/dimethylaminoethylmethacrylate (DMAEMA)/butyl methacrylate (BMA) core have already been investigated for antigen trafficking modulation in DCs. The results showed that this nanosystem facilitates the antigen delivery to DCs in the lymph nodes and enhances CD8+ T cell responses, being thus a potential carrier for cancer vaccines (Keller et al., 2014). Also,micelles formed byDMAEMA and pyridyl disulfide ethyl methacrylate (PDSEMA), carrying bothCpGODNandprotein antigens, have shown to elicit and increase cellular andhumoral immune response by modulating and stimulating antigen cross-presentation,as summarizedbyWilsonetal. (2013). Dendrimers Dendrimers consist in hyperbranched spherical nanocarriers formed by a central core, branchingmonomers and functional- izedperipheral groups.Dendrimers canbeproducedby conver- gentordivergentpolymerizationofbranchingunits, resulting in a structurewith ahydrophilic surface andahydrophobic central core (Figure3D) (Lee et al., 2005). Their main physicochemi- cal featuresare lowviscosity,hyperbranchedmolecular topology, marcromolecular size,highdensityofchemical functionalityand multiple end groups that can be chemically functionalized (Lee etal.,2005).Also, thedepolymerizationofdendrimerscanbetai- lored inorder to control the release profile of the loaded agents, as described in a reviewbyWong et al. (2012). Besides vaccines, therapeutic and targeting carriers, dendrimers have also been reported as diagnostic tools due to their ability to protect imag- ingagents,decreasing its toxicityandenhancingspecificity (Yang etal., 2009). Nowadays, the most described family of dendrimers is the well-studied polyamidoamine (PAMAM). Poly(propyleneimine) and peptide dendrimers, such as poly(L-glutamic acid) dendrimers, have also been studied (Nanjwade et al., 2009). www.frontiersin.org November2014 |Volume2 |Article105 | 78