Seite - 49 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Cooperet al. Nanoparticles for radiation therapy on the value of E. The photoelectric effect dominates below the electron rest energy of 511keV, beyond which inelastic Compton scattering becomes more prevalent. As the photon energydecreases, it isnolongerable toeject inner-shellelectrons, producing the characteristic sawtooth patternwithK, L, andM edge structures.When ionizedbyX-rayorγ ray energy,mid- to high-Z elements (roughly Br and up) can produce a cascade of low-energyAuger electrons that can locally enhance the effective radiationdose(Kobayashietal.,2010).Denseinorganicnanopar- ticles canalsoprovide radiationdose enhancement thatdepends uponthecompositionandsizeoftheparticles,uptakeofparticles intocells, andtheenergyof theappliedradiation. GNRT Aunanoparticles have beenunder investigation for several years as possible agents for selective amplification of radiation dose in tumors, a concept called “goldnanoparticle-assisted radiation therapy” or GNRT (McMahon et al., 2008; Brun et al., 2009; Cho et al., 2009; Rahman et al., 2009; Van den Heuvel et al., 2010;Leungetal., 2011;Zhangetal., 2012).Reviewsof thiswork can be found in Jelveh andChithrani (2011), Butterworth et al. (2012),Jainetal.(2012),BabaeiandGanjalikhani(2014),Suetal. (2014). The earliest studies usedbulkormicro-sized gold to enhance radiation dose. Although this could be effective in vitro at a range of energies, micron-sized particles are not taken up well in vivo, even after intratumoral injection (Herold et al., 2000). Later experiments focused onAu nanoparticles or nanoclusters (1.9nmdiameter).When injected intravenously, theseultrasmall particles rapidly accumulated in cancer tissue, with 2.7g Au/kg body weight resulting in 7mg Au/g in tumor almost immedi- ately after injection. Irradiationwas performed about 60s after injection,andwithtypical250kVpX-raytherapy,1-yearsurvival was86%(compared to20%withX-raysaloneand0%withgold alone) (Hainfeld et al., 2004). This result was followed by theo- retical andexperimentalpapers examining themechanismofAu nanoparticle action as well as attempting to optimize Au parti- cleconcentration, size,andtheenergyanddoseofappliedX-rays (Choet al., 2009;Zhanget al., 2009;VandenHeuvel et al., 2010; Leungetal., 2011). IMPROVINGGNRTBYTARGETING Asignificantproblemwithultrasmall,nontargetednanoparticles is rapid excretion by the kidneys. The amount of Au needed in early studies (>2g Au/kg body weight) represents a very large amount of Au for human use. This is impractical, costly, and maycausetoxicity.Achievingtherapeutic levels intumorwithless deliveredtotalAuisneeded. Inaddition, irradiationinthemouse studieswas performed immediately after particle injection. This is not practical in the clinic andmay notworkwell in humans. Particleswith longer circulation times,whichcanbedelivered in multipledoses, aredesirable forclinical applications.Optimizing the size, surface chemistry, and targeting of the Au nanoparti- clesmay improve circulation times andaccumulation in specific tumors. The increasedmetabolic rateof tumors relative tonormal tis- sueresults inahighdemandforglucose.Severalstudieshaveused FIGURE1 |Approaches tocreatingtumor-targetedAunanoparticles. Moleculesnot toscale. (A)Thioglucose-conjugatedAunanoparticles. (B)Aunanoparticlesconjugated toHerceptin (anti-HER2antibody). (C)Au nanorodsconjugated to folic acid. (D)PEI-coatedAunanoparticles conjugated tocholine. thioglucose-conjugated Au nanoparticles (Figure1A) in order to increase uptake by cancer cells. One study using ∼14nm Au demonstrated significantly increased uptake of thioglucose- conjugatedparticlesbyanovariancancer cell line after 8–96hof incubation (Geng et al., 2011). A significant increase in inhibi- tionwas seen in the presence of 5nMparticles using 90kVpor 6MVX-rays; dose enhancementwas significant relative to con- trolbeginningat5Gyandextendingto20Gy,whereall cellswere inhibited even in the absence of particles. Another study com- paredcysteamineandthioglucose-coated15nMAunanoparticles inbreast cancerandnormalbreast cell lines (Konget al., 2008b). Cysteamine-coatedparticleswere takenup3- to4-foldmoreeffi- ciently than glucose-coated particles. However, when applied to cells at concentrations that led to similar intracellular Au con- centrations, glucose-coated particles led to increased radiosen- sitization relative to cysteamine-capped particles. Interestingly, radiosensitization byAuwas not seen in a nonmalignant breast cell line,althoughthecellsgrewatthesamerateasthecancercells andtookupanequalnumberofparticles.Theabilityof167Csand 60Cosources to inhibit the cancer cellswas alsodemonstrated in thispaper. Theuseof largerAuparticles (57nmand84nm)coatedwith thioglucosehasbeenstudiedinanotherreport(Songetal.,2013). These particles were taken up in equal numbers byHeLa cells. Frontiers inChemistry | ChemicalEngineering October2014 |Volume2 |Article86 | 49