Seite - 123 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Liuet al. AuNS forcancer imagingand therapy resonance imaging (MRI), X-ray computer tomography (CT), highresolutionoptical imagingwith labeledfluorescencedyesas well as photothermal therapy (PTT) andphotodynamic therapy (PDT).Furthermore,goldnanospheresandnanoshellshavebeen usedinclinical trials fordrugdeliveryandphotothermaltherapy, respectively (Gad et al., 2012). Therefore, novel nanoplatforms areofgreat interest forcancerdetectionandtreatment. Gold nanostars (AuNS), with multiple sharp branches (Figure1A), have superior tip-enhanced plasmonic properties in the near-infrared (NIR) tissue optical window, which is suitable for in vivo biomedical applications. Plasmonic AuNS have been applied for in vivo lymphatic systemmapping with photoacoustic tomography(PAT)(Kimetal., 2011a).AuNSwith silica shells have been found to be internalized into living cells and can be used for intracellular imaging (Rodriguez-Lorenzo et al., 2011; Fales et al., 2013; Yuan et al., 2013a). In addition, AuNS surface-enhanced Raman scattering (SERS) nanoprobes have been applied for immuno-SERSmicroscopy of the tumor suppressorp63, imaged inprostatebiopsies (Schutzet al., 2011). SERS takes advantage of a unique phenomenon on certain metal nanoparticles, surface plasmon resonance (SPR). Surface plasmon refers to oscillating electrons within the conduction band when the metallic nanostructure surface is excited by an external electromagnetic field. The oscillating electrons can generateasecondaryelectromagneticfield,which isaddedtothe external electromagnetic field to result in SPR. Incident photon energy, when in resonancewith the surface plasmon,magnifies the local electromagnetic field that dramatically enhances the intrinsicallyweakRaman signal. The SERS enhancement factor is typically 106–108-fold and can be up to 1015-fold in hot spots, where the electromagnetic field is extremely intense (Liu et al., 2015b). By combining resonance enhancement, surface-enhanced resonance Raman scattering (SERRS) shows even greater Raman signal enhancement than SERS alone. Silica-coated AuNS SERRS nanoprobes have been used for visualizingbraintumormarginsandmicroscopictumorinvasion (Harmsen et al., 2015). Our group has developed a novel toxic surfactant-freeAuNSsynthesismethodthatgreatly improvesthe biocompatibility and the versatility of surface functionalization (Yuan et al., 2012b). In this review paper, wewill focus on the latest progress achieved in our laboratory related toAuNS and discuss theirbright future for theranosticapplications. Multimodal Imaging AuNS provide a powerful tool for 3D in vivo tracking and disease detection with whole body scans. For CT imaging, goldnanoparticles are superior to traditional iodinated contrast agents, since goldhas ahigher atomicnumber (Z= 79) andk- edgevalue(80.7keV).Inaddition,theX-rayattenuationofiodine isdecreasedbywaterwhilethatofgoldisnot.Goldnanoparticles canabsorbX-ray,whichsubsequentlygeneratephotoelectricand Compton effects. These effects lead to formation of secondary electrons and reactive oxygen species (ROS), the yield ofwhich correlates with the surface area of nanoparticles (Misawa and Takahashi, 2011). Since star-shaped geometry exhibits greater surface area than the spherical counterpart of equivalent size, AuNS can be an improved sensitizer for radiation therapy. For MRI imaging,Gd3+ ions have been linked to theAuNS surface through 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. As shown in Figure1B, tumor cells loaded withmultifunctionalAuNSprobes display high intensity under CTandMRIexamination (Liu et al., 2013a). PETscanprovides anextremelysensitive3Dimagingmethod.Thesensitivitycould reachpicomolar forPETcompared tomicromolar forMRI.We performed PET imaging with 64Cu-labeled AuNS nanoprobes for dynamic imaging up to 24h (Figure1D). In vivo tracking results showedthat thedevelopedAuNSnanoprobesaccumulate gradually intumorwith3.3:1tumor-to-muscleratioat theendof 24h (Liu et al., 2015b). These studies exemplify the potential of AuNSforwholebody imaging. In addition, AuNS have been exploited as a powerful optical contrast agent undermultiphotonmicroscope for high- resolution imaging. With an exceptionally high two-photon photoluminescence (TPL) [more than one million Göeppert- Mayer (GM) two-photon action cross-section (TPACS)], AuNS offer superior signal contrast than quantum dots or other organic fluorophores for multiphoton optical imaging (Yuan et al., 2012b). Furthermore, a recent study investigated TPL of single gold nanoparticle with different shapes and the TPACS were reported to be 83,500, 1.5 × 103, 4.2 × 104, 4.0 × 106GM for nanosphere, nanocube, nanotriangle, nanorod and nanostar, respectively (Gao et al., 2014). The TPACS of AuNS is almost two orders higher than that of gold nanorod, which is the highest one among other shapes. With an intense TPL emission, AuNS can be used not only for real-time in vivo tracking, but also for sensitive tumor detection following systemic injection of AuNS (Yuan et al., 2012c). As shown fromTPL imaging inFigure1C, transactivator of transcription (TAT)-functionalized AuNS nanoprobes have much stronger signal in cells than thatofAuNSwithoutTATfunctionalization. TAT is awell-known cell-penetrating peptidewith capability to increasenanoparticlecellularuptake.AlthoughtheTPLimaging depth is limited by the extent of laser penetration, optical microscopy offers the highest spatial resolution among most animal imaging modalities. AuNS are also suitable to be used under PATwith high extinction coefficient (∼1010M−1cm−1) (Xia et al., 2012a; Yuan et al., 2014). Being a potent contrast agent for PAT, which is an optical-ultrasound hybrid imaging technology, theparticokinetics andbiodistributionof theAuNS can be studied with deeper imaging depth and larger field of view. Furthermore, AuNS have been applied for SERS detection with tip-enhancedplasmonics.ThereportedSERSenhancement factor is several orders higher than that of gold nanospheres (Yuan et al., 2013a). SERS applies nanometallic structures to enhance “fingerprint”Raman spectra,whichprovides amethod formolecular sensingwith high sensitivity (Liu and Sun, 2011; Liu et al., 2013b,c; Yuan et al., 2013b; Zhao et al., 2014a). Our group demonstrated the first analytical application of SERSinchemicalanalysisusingnanostructuredmetal substrates 30 years ago, and has been working on various types of SERS nanoplatforms, including nanogratings, nanorod arrays, nanowiresandAuNS,forbiochemicalsensing(Meieretal.,1985; Frontiers inChemistry |www.frontiersin.org August2015 |Volume3 |Article51 123|