Seite - 9 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Condeetal. Biofunctionalizationandsurfacechemistryof inorganicnanoparticles direct delivery of therapeutic agents to diseased cells and tis- sues, and innovativemonitoring sensors forpredictivemolecular changes, increase theprocesses’ efficiencywhileminimizingcosts (Baptista, 2009;Minelli et al., 2010;Maet al., 2011;Condeet al., 2012c). Besides being an area of intense upfront basic research, nanotechnology holds the key to future technological applica- tions. It is a burgeoning field asmore and improved techniques are becoming available for clinical therapy and diagnostics with increased sensitivity and efficiency at lower costs (Baptista et al., 2008;Lammersetal., 2011). In spite of these advantages, NPs do have limitations. For example, their small size and large surface area can lead to particle-particle aggregationandmayresult in limited loadingof functional components andburst release. In fact, onlyNPswith the appropriate size and surface chemistry are not immediately recognizedbytheimmunesystemandshowincreasedcirculation times (Gil andParak, 2008; Shvedova et al., 2010).Nevertheless, their unique and broad-based optical properties, their ease of synthesis and facile surface chemistry and, most importantly, their appropriate size scale are overcoming these drawbacks and have been generatingmuch eagerness in clinical diagnostics and therapy(Sperlingetal., 2008). Herewewill reviewdifferentstrategiesofbiofunctionalization andcharacterizationmethodsof inorganicnanoparticles, aswell astheirmainadvantagesandlimitations.Ouraimistodiscussthe challenges ofworkingwithnanoparticleswhile giving anoverall overviewof thestate-of-the-art. INORGANICNANOPARTICLES GOLDNANOPARTICLES Historically, colloidal gold has been used since ancient times mainly as amethod for glass staining.However, it was not until Faraday’sworkthatgoldnanoparticles(AuNPs)begantobestud- ied in a scientific approach (Faraday, 1857). Since then, AuNPs havegeneratedever-increasinginterestandinthelast fewdecades more andmore controllable synthesismethods and applications indiversenanosystemshavebeendeveloped(Wagneretal.,2000; EdwardsandThomas,2007). AuNPs, also known as colloidal gold, are a suspension of sub-micrometer-sized goldmetal particle in a fluid and can be obtained with diameters between 3 and 200nm. AuNPs have gained increasing interest due to their special features, such as extraordinaryopticalandelectronicproperties,highstabilityand biological compatibility, controllable morphology and size dis- persion,andeasysurface functionalization(Sperlingetal.,2008). The optical properties of AuNPs are significant because absorptionandemissionarewithin thevisible rangeof light (El- Sayed, 2001).Ofparticular interest is the light extinctionprocess in theUV-visible range, which occurs when an electromagnetic wave passes through a metal particle exciting its electronic or vibrational states(KreibigandVollmer,1995).Thisphenomenon inducesdipolemoments thatoscillateat therespective frequency of the incidentwave, dispersing secondary radiation in all direc- tions. This collective oscillationof the free conduction electrons is called localized surfaceplasmonresonance (LSPR).TheSPR is thecollectiveoscillationof theelectrons in theconductionband. The oscillation frequency is usually in the visible region giving rise to the strongSPRabsorption (Schultz et al., 2000; Jain et al., 2006;Huangetal., 2007;Murphyetal., 2008). Sizealsoprovides importantcontrolovermanyof thephysical and chemical properties, including luminescence, conductivity, and catalytic activity. AuNPs’ absorption and scattering propor- tions depend on theAuNPs size (Cao et al., 2002). AuNPswith a diameter smaller than 20nm essentially show absorption, but when the size increase to80nmthe ratioof scattering toabsorp- tion also increases. As the size of theAuNPs increases, light can no longer polarize thenanoparticles homogeneously andhigher ordermodes at lower energy dominate. This causes a red-shift andbroadeningof the surface plasmonband. SmallAuNPs, like those with 13nmof diameter, absorb green light, which corre- sponds toa strongabsorptionbandat520nmin thevisible light spectrum.However, solutionsofAuNPs appear red in color. For smaller AuNPs (i.e., 5nmdiameter), surface electrons are oscil- latedby the incoming light inadipolemode,but theSPR isvery sensitive to the composition, size, shape, inter-particle distance andenvironment(dielectricproperties)of theAuNPs(Pellegrino etal., 2005;Sperlingetal., 2006). Inall synthesismethods reported so far, a reducinganda sta- bilizing agent is added toprevent theparticles fromaggregating. The type of stabilizer affects the selection of further biofunc- tionalization strategies, as for certain strategies a good colloidal stability at a broad range of pH and ionic strength is required. Although a wide variety of nanoparticles can be stabilized by a large range of stabilizers (ligands, surfactants, polymers, den- drimers, biomolecules) (Sperling and Parak, 2010), the most robust nanoparticles are covered by thiol molecules using the stronggold–SbondbetweenthesoftacidAuandthesoft thiolate base (Giersig andMulvaney, 1993). Thus, if a bifunctional thio- lated stabilizer or even amixtureof them isused (e.g. thiolated- PEGmoleculeshavingcarboxylic,amine,azidegroups,etc.), then it ispossible tostabilizeandintroducechemical functionalities in a single step.This allows furtherattachmentofbiomolecules ina controlledwaybycovalent immobilizationstrategies thatwewill discuss in the followingsections. MAGNETICNANOPARTICLES Magnetic nanoparticles (MNPs) constitute an important class of nanomaterials widely studied for their potential use in biomedicine fields, such as imaging, cell labeling, hyperthermia anddrugandgenedelivery(Pankhurstetal.,2003;Barakat,2009; Berry, 2009).MNPs can be classified asmetal, alloys or oxides, and are generally based on elements such as iron, cobalt, nickel, ormanganese among others (Pankhurst et al., 2009). From the aforementioned, iron-basedNPsare themost studied, since iron is believed to be biocompatible (Hanini et al., 2011).Other ele- ments, such as cobalt or nickel are reported to be more toxic (Fang andZhang, 2009). IronoxideNPs (IONPs) are composed ofmagnetite (Fe3O4)ormaghemite(γ-Fe2O3),nanocrystallites. Most ofMNPs’ applications are a consequence of theirmag- netic properties, which greatly differ from those of the bulk material.Whensmall enough,MNPspresent superparamagnetic behavior at room temperature,meaning that they becomemag- netized upon exposure to an external magnetic field but lack remnantmagnetization once the external field is removed (Jun Frontiers inChemistry | ChemicalEngineering July2014 |Volume2 |Article48 |9