Seite - 79 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking Linear poly(glutamic acid) is a poly(amino acid) polymer with considerable potential for antigendelivery toDCs, and adjuvant properties forDCmaturation, able to induce CTLs (Yoshikawa et al., 2008). Additionally, it has been shown to be safe for use in clinic (Chipman et al., 2006) providing the necessary safety profile for human use. These glycopeptide dendrimers have shown promise for antitumor and antiviral prophylactic or therapeutic vaccines, as well as antiviral agents (Niederhafner et al., 2008). Several formulations have reached clinical trials as vaccines against breast (Gilewski et al., 2007), prostate (Slovin et al., 2003), and small cell lung cancers (Krug et al., 2004)with encouraging results. Even though, further investigation must be done in order to guarantee the long-term safety, before they becomeclinicallyavailable (Aslanetal., 2013). INFLUENCEOFNANO-BASEDTECHNOLOGYPROPERTIESINCELLULAR UPTAKE Arguably, theweakest link inpreclinical experimentationofnan- odelivery systems is the continued failure to document dynamic processes (over time) using complex biosystems asmodels, i.e., a systems biology approach. The outcome of different classes of nanomedicines under preclinical and clinical evaluation has demonstrated that theirmainbiological consequencesof cellular or subcellular targetingandaccess are closely related tomaterials intrinsicproperties (Ehmannetal., 2013). The uptake of TAAs, carriedwithin nano-platforms, byDCs is in fact influencedby severalparticulatephysicochemicalprop- erties. Size, shape, surface charge, hydrophobicity and recep- tor interactions are generally underlined (Foged et al., 2005; Bachmann and Jennings, 2010). Particulate vaccines, such as whole-cellvaccines,virosomes,VLPsorformulateddeliveryplat- forms such as liposomes, micro and NPs have great surfaces with electrostatic or receptor-interacting properties, leading to an increased interaction when compared to soluble antigens (Bachmann and Jennings, 2010). Also, it has been reported that particulate size can direct the DC subset target. However, the ideal dimensions of NPs for APCuptake are still under discus- sion. In fact, small size platforms (<200nm)may drain freely to LNs, being thus taken up by LN-residentDC subsets such as CD8α+,whichseemsanadvantage forcancer immunotherapeu- tic approaches. However, delivery systems greater than 200nm appear to be takenupby circulantmonocytes,whichdifferenti- ateafterparticleuptakeandmigratetoLNsafterwards(Manolova etal.,2008).AccordingtoFogedandcolleagues,NPsizeshouldbe 0.5μmor less tobequickly and efficiently incorporatedbyDCs (Fogedetal., 2005). Size NPsize appears to influence the cellular uptakemechanismand theendocyticpathwayofNPs,dictating theirultimate intracellu- lar fate and thusoverall biological effect.NPsmaybeassimilated by receptor-mediated endocytosis, clathrin-dependent and/or caveolae-mediated, and phagocytosis, or through a receptor independentmechanism—macropinocytosis.Particulatesystems witha largerdiameter (>0.5μm)tend tobeassimilated through macropinocytosis and/or phagocytosis by some specific cells, as macrophages and Langerhans cells in the skin. Smaller particles usuallyenterthecell throughendocytosis.NPswithsize<150nm are generally taken by cells via classic receptor-mediated endo- cytosis (clathrin-dependent)or endocytosis caveolae-mediated if ranging from50 to80nm(PelkmansandHelenius, 2002).These NPs with size equivalent to viruses are usually able to initiate a virus-like immune response with activation of CTL and Th1. On the other hand, larger particles normally generate a similar immuneresponsetothatinducedbybacteria,withTh2activation andantibodyproduction(Xiangetal., 2006). Shape Besides size, it has also been reported that particle shape may influence cellular uptake and biodistribution. Although it has been suggestednon-spherical particlesmaybe valuable for their increasedbloodcirculation time,due toreducedphagocytosisby unspecificcells, theyalsodemonstrateddecreasedcellularuptake, whencomparedtosphericalNPs.AccordingtoGrattonetal.,rod- shapedNPs show the highest uptake performance, followed by spheres, cylindersandfinallycubicalNPs(Grattonetal., 2008). Surfacecharge NP surface charge also seems to play an important role in their particle internalizationandthuswill alsodeterminethenatureof the induced immune response (Xianget al., 2006).As cellmem- brane charge is negative, positively charged molecules/systems will show high affinity to it. After cellular uptake, it has been observed that negatively charged or neutralNPs tend to localize within lysosomes, whilst positively charged NPs showed ability to escape from these. Cationic NPs were found in the perin- uclear area and have been reported as effective for uptake by macrophages andDCs (Thiele et al., 2003; Yue et al., 2011).On the other hand, the interaction of those delivery systems with cell dependsonmultiple factors and some studies have reported the presence of neutral NP at endoplasmic reticulum, suggest- ing their ability to escapedegradation at lysossomal/endossomal compartment(Zhouetal., 2014). NANOCARRIERSFORTUMORANDIMMUNECELLTARGETING Passive targeting Passive targeting results from the transport of nano-based sys- tems across the abnormal leaky vasculature of tumors, into the tumor interstitium or cells, by their movement within fluids— convection—or by passive diffusion. Whereas convection is observed for larger molecules, compounds with lowmolecular weight cross themembranesbydiffusion,dependingonlyon the concentrationgradient (Iyeretal., 2006;Danhieretal., 2010). As blood vessels architecture and its regulation are com- promised, caused by unpaired angiogenesis, nanocarriers tend to accumulate selectively in tumor interstitium due to the “Enhanced Permeability and Retention (EPR) effect.” The increased size of gaps in endothelial cells creates pores rang- ing from 10 to 1000nm, which along with the poor lymphatic drainage, contributes to the EPR effect, that was first described byMatsumura andMaeda (1986); Yuan et al. (1995); Danhier et al. (2010). This effect has become very important for the design of targeted nanocarriers for cancer therapies. It has been reported that NP levels of accumulation in tumor interstitium Frontiers inChemistry | ChemicalEngineering November2014 |Volume2 |Article105 | 79