Seite - 39 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Dawidczyket al. Nanomedicines for cancer therapy electromagnetic radiation in the visible range of the spectrum (plasmon absorbance), and have been explored for hyperther- miatherapy.GoldnanoparticlesconjugatedwithPEGandtumor necrosis factor alpha (TNFα are being developed for targeted cancer therapy(Libutti etal., 2010). Ferromagnetic materials, such as iron oxide (magnetite, Fe3O4), iron, cobalt, and nickel offer an additional degree of freedom in the synthesis of nanoparticles for nanomedicine (Arruebo et al., 2007). Very small ferromagnetic nanoparti- cles (typically< 10nm) have no intrinsicmagnetization in the absence of amagnetic field, and hence do not aggregate in col- loidal suspension.Thesesuperparamagneticnanoparticlescanbe manipulated in an external field providing a simplemethod for spatialmanipulation andwashing.Magnetic nanoparticles, such as superparamagnetic ironoxide(SPIO)nanoparticleshavebeen used formagnetic resonance imaging (MRI) and hyperthermia therapy(Yuetal., 2013). Carbon-based nanoparticles have exploited the small size and unique properties of buckyballs, carbon nanotubes, and grapheme (Yu et al., 2013). Combinations of organic and inor- ganicmaterials, takingadvantageof specificmaterials and struc- tureshavealsobeenwidelyexplored inmultifunctionalnanopar- ticleplatforms. Hybrid nanoparticles with organic and inorganic compo- nents or associated combinations of inorganic nanostructures provide further opportunities for introducing multiple func- tionalities. These systems can exploit the biocompatibility of organicnanoparticles,while still retaining the stability and func- tion of inorganic nanoparticles. Inorganic nanoparticle conju- gatesallowformultimodal imagingandtheranosticapplications. Examples include constructs such as liposomes filledwithmag- neticnanoparticles(SailorandPark,2012),coordinationpolymer nanoparticles(Novioetal.,2013),andmetal-organicframeworks (Horcajadaetal., 2012). TARGETINGMOIETIES(ANTIBODIES,APTAMERS,SMALLMOLECULES, ETC.) Active targetingof ananoparticle is away tominimizeuptake in normal tissue and increase accumulation in a tumor. Strategies for active targeting of tumors usually involve targeting surface membrane proteins that are upregulated in cancer cells (Huynh et al., 2010;HanahanandWeinberg, 2011).While this strategy is widelyused, tumorcellpopulationsareextremelyheterogeneous and expression levels can vary significantly. Targetingmolecules are typically antibodies (Dill et al., 1994; Arruebo et al., 2009; Chames et al., 2009), antibody fragments (Holliger andHudson, 2005),aptamers(Keefeetal.,2010;HuandZhang,2013),orsmall molecules (Figure1). Accumulationof adelivery systemat a tumor site by theEPR effect isdependentinpartontheconcentrationinthecirculation. Processes such as clearance by theMPSoruptake innormal tis- suedecrease the concentration in circulationandhencedecrease the accumulation in the tumor. Active targeting can provide an additional sink for a nanoparticle platform since expression of targetmolecules is usually differential in that the target is highly expressed in tumor cells but expressed at low levels in other cell types in the vascular system. Since the surface area of the FIGURE1 |Examplesoftargetingmolecules. (A)Antibodiesaretypically around150kDaorabout15×5nmwithtwoantigenbindingsites. (B) xPSM-A10isa18.5kDaaptamerwithabindingaffinityofabout10−8M−1 for theextracellularportionof theprostate-specificmembraneantigen(PSMA) (Lupoldetal.,2002). (C)Theglutamate lysineureasmallmoleculetargets PSMA(473Da) (Banerjeeetal.,2008). (D)TheRGDpeptidesequence (604Da)bindstocellsurface integrins,upregulated inmanytumortypes. vasculature ismuch larger than the tumor, activebinding innor- mal tissue can be significant, even for targets that are expressed at relatively low levels (Jain, 2005). Furthermore, targetingmoi- etiesmay themselvesbe targets for receptors onphagocytic cells, asdescribedabove. Antibodies Monoclonal IgG antibodies (mAbs) are widely used for protein recognition and targeting since they have two epitope binding www.frontiersin.org August2014 |Volume2 |Article69 | 39