Seite - 10 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Condeetal. Biofunctionalizationandsurfacechemistryof inorganicnanoparticles et al., 2008). Consequently, MNPs do not agglomerate in the absence of the magnetic field, which is essential for in vivo applications(Yooetal.,2011).Thischaracteristic israther impor- tant in applications, suchasmagnetichyperthermia.TheMNPs’ capacity of converting the energy of an alternatemagnetic field intoheat(Rosensweig,2002)andtheextrasensitivenessof tumor cells to an increase in temperature (van der Zee, 2002) are the two pillars of magnetic hyperthermia in cancer. Since the late 50’s, whenGilchrist et al. (1957) first reported the use ofMNPs toheat tissue samples, to nowadays,magnetic hyperthermia has evolvedconsiderablyandisakeyareaofinterest incancertherapy with several studies showing the benefit of employingmagnetic materials in hyperthermia strategies (Jordan et al., 1993, 2001; Johannsen et al., 2010; Laurent et al., 2011). Several groups havereportednoteworthyresults inclinical trialswheremagnetic hyperthermia shows effectiveness in tumor cell destructionwith impressive targeting, thus minimizing significantly side effects (Johannsenetal., 2005;Liuetal., 2011;Zhaoetal., 2012b). There are a wide variety of methodologies used for MNP synthesis, including physical or wet chemical approaches. Concerningwetchemicalapproaches, therearesomemethodolo- gies,suchascoprecipitation(Perezetal.,2002)orreversemicelles precipitation(Liuet al., 2000) thatprovidedirectlywater soluble MNPswith an organic layer with chemicalmoieties for narrow sizedistributionofMNP.However, commonsynthetic strategies traditionally renderMNPssolubleonly inorganic solvents.Their use in bioapplications imply an additional stepwhere adequate chemical moieties are introduced by several strategies (e.g. use of amphiphilic polymers, silanization, replacing and/ormodify- ing thesurfactant layer) inorder toallowsilanization, theirwater transferenceandfurtherbiofunctionalization. QUANTUMDOTS Quantum dots (QDs) are nanoparticles composed of semicon- ductormaterials fromIII-Vor II-VIgroupsof theperiodic table, such as ZnS, ZnSe, CdS, CdSe, CdTe, InP, and others (Donega, 2011).Their reduced size induces a shift of the electronic excita- tions tohigher energy, concentrating the oscillator strength into justa fewtransitions, conferringuniquequantum-confinedpho- tonic andelectronicproperties (Alivisatos, 1996;Alivisatos et al., 2005). Although physically larger than organic dyes and fluo- rescent proteins, their cumulative optical properties offer great biological utility.With tunable core sizes, it is possible to attain a broad adsorption profile, narrow size, and symmetric photo- luminescence spectra depending of the fundamental materials. QDsalso showstrongresistance tophotobleachingandchemical degradation, aswell as significant photostability andhighquan- tumyields(Ghanemetal.,2004;Xuetal.,2006;Algaretal.,2011). Their potential as biological labels was first demonstrated by Nie and Alivisatos groups in 1998, turning the focus into bioapplicationsofQDs.Themethod relies on a ligand exchange strategy is based on the replacement of the original hydropho- bic ligands adsorbedonto the surfaceofQDswithbiofunctional molecules, suchasproteintransferrins.TheseQDsweresuscepti- ble to effective receptor-mediated endocytosis in culturedHeLa cells. Since these first demonstrations of QDs potential, their uniquepropertieshavebeencontinuouslyoptimizedandapplied inaplethoraofbioapplications, rangingfromfluorescentprobes, biosensorstotherapeuticsandtheranosticagents(Akermanetal., 2002;Smithetal.,2006;Lietal.,2009;Liuetal.,2010;Ruanetal., 2012;Singhetal., 2012). OnceQDs that showparamount optical properties are those synthesized in organic media, numerous methods have been developed for creating hydrophilic QDs (Medintz et al., 2008). Thefirst approach is commonlydesignatedas “ligandexchange” (Gill et al., 2008), where the hydrophobic layer of the organic solventmaybe replacedbybiofunctionalmolecules containinga softacidicgroup(i.e., thiol, sodiumthiolycolate)andhydrophilic groups(i.e.,carboxylic,aminicgroups)(Wangetal.,2008).Asec- ond approachusually consists in adding aparticular shell to the nanoparticles that can be further functionalizedwith additional biomoleculesorpolymers(Kooleetal., 2008;Zhangetal., 2008). BIOFUNCTIONALIZATIONOFINORGANICNANOPARTICLES Nanoparticles with unique and broad-based optical properties, ease of synthesis and facile surface chemistry and functionaliza- tionwithin appropriate size scale are generatingmuch enthusi- asminbiotechnologyandbiomedicine,withparticularemphasis in clinical diagnostics and therapy. However, for the biological application of these NPs, it is necessary their functionalization with one or several biomolecule (Figure1), such asDNA/RNA, oligonucleotides (i.e., ssDNA/RNA, dsDNA/RNA), peptides and antibodies, fluorescentdyes, polymers (i.e., PEGs), drugs, tumor FIGURE1 |Schematic representationofamultifunctionalnanocarrier. These innovativeNPscomprisenucleic acidssuchasRNAandDNAused forgenesilencingapproachesand incolorimetric assays, respectively. Aptamersandanticancerdrugmoleculesarealsoused fordelivery to the target tissue.Carbohydratesmaybeuseful assensitivecolorimetric probes.PEG isused to improvesolubility anddecrease immunogenicity. Responsivenanocarrierscanalso trigger reactionuponexternal stimuli through the functionalityof valuable tumormarkers, peptides, carbohydrates,polymersandantibodies that canbeused to improve nanocarrier circulation,effectiveness, andselectivity.Multifunctional systemscanalsocarryfluorescentdyes that areusedas reporter molecules tethered to theparticlesurfaceandemployedas trackingand/or contrast agents. www.frontiersin.org July2014 |Volume2 |Article48 | 10