Page - 51 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Cooperet al. Nanoparticles for radiation therapy Photothermal therapy consisted of 3min of irradiation with a 30mW,808nm laser source.Apoptosiswas seen after treatment in thepresenceof thegoldparticles. A recent study (Hainfeld et al., 2010) calculated the radiation dose required to control 50% of tumors (TCD50) in a mouse squamous cell carcinomamodel.Goldnanoparticleswere deliv- ered intratumorally, and24h later the tumorwasheated to48◦C for5minat 1.5W/cm2 followedbyX-ray irradiationat 100kVp (7.5Gy/min).TCD50wasreducedfrom55Gyto less than15Gy. These studies illustrate one of the biggest problems of the approach,which is theneed for simultaneousdeliveryofheating and radiation,whichposes logistic problems in the clinic (Wust etal.,2002).Otherdrawbacks includea lackofspecificityandthe difficultyofheatingdeeptumors. ALTERNATIVESTOGOLD:BISMUTHANDIRON Alternatives toAuarebeingsought thataremoreeffectiveand/or less costly.Bismuth(Bi,Z=83)andplatinum(Pt,Z=78)have been shown in at least one theoretical study to yield a dose enhancement factor higher than Au, with Bi being the high- est. Dose enhancement is predicted to increase with decreasing nanoparticle size, because the smaller nanoparticles accumulate closer to thenucleus,where they can cause the greatest damage. The dose enhancement is also expected to be greater when the averageenergy is close to theK-edgeof theelement (Ngwaet al., 2010;HossainandSu,2012).Aradiochromicdosimeterwasused in another study to experimentally measure the dose enhance- ment of bismuth oxide (Bi2O3) nanoparticles. Using a 100kV X-ray sourceandan irradiationdoseof10Gy, the radiationdose inawater-equivalentmatrixdopedwith0.5mMof50nmBi2O3 nanoparticles was>80% higher than in the control compart- ment(Alqathamietal., 2013).Anotherstudy(Zhangetal., 2014) looked at thedark toxicity, biodistribution, and radiation effects ofbismuth selenide (Bi2Se3)nanoplatelets in cell lines andmice. The platelets were not significantly toxic to either cells ormice, withover93%oftheBiclearedfromthebody90daysafter treat- ment.Significantradiationdoseenhancementwasobservedafter irradiationdosesofupto8Gy. Gadolinium (Gd, Z=64) represents another alternative to goldnanoparticles. Inaddition tohavinga relativelyhighatomic number,Gd is already routinelyusedas a contrast agent inMRI. Gd2O3 core nanoparticles encapsulated in a polysiloxane shell have shown potential as an image guided radiotherapeutic tool in a gliosarcoma ratmodel (LeDuc et al., 2011). Accumulation of the nanoparticles in the tumor after saphenous vein injec- tion was demonstrated usingMRI, and the tumor-bearing rats weretreatedwithmicrobeamradiationtherapy,withasignificant increase in survival in the nanoparticle-treated group. Another studyusing a rat brain tumormodel confirmed that ultra-small Gd-based nanoparticles accumulate in brain tumors after IV injection(Miladietal., 2013). Magnetic particles such as iron oxide may also be used for combined hyperthermia and radiation. By using an alternating magneticfieldtoexcitemagneticnanoparticles, localtemperature increases can be achieved. The advantages of iron oxide include low toxicity, ease of synthesis, and the ability to perform image guidanceusingMRI.Dextran-coated ironoxidehasbeen shown toreducetumorgrowthinasyngeneicmousebreastcancermodel whenhyperthermiaandradiationwerecombined(Giustinietal., 2011). Several studies have looked at radiosensitization properties of iron oxide nanoparticles. Using 6MeV X-rays on a human prostatecarcinomacell line(DU145),1mg/mlofFe3O4nanopar- ticles resulted inadoseenhancement factorof approximately1.2 (Khoeietal., 2014).Anotherstudysuggestedthat superparamag- netic ironoxidenanoparticles(SPIONs)canradiosensitizetumor cells by catalyzing ROS formation. Uncoated, citrate-coated, or malate-coated SPIONswere added toMCF-7, 3T3, andCaco-2 cells. Uncoated SPIONS caused dark toxicity, with no increase inROSupon 1 or 3Gy irradiation. In contrast, coated SPIONS were non-toxic in the absence of radiation, but resulted an increase of up to 300% in the fluorescence intensity of theROS reporter dichlorofluorescein diacetate (DCF-DA) (Klein et al., 2014). SCINTILLATINGNANOPARTICLESFOR RADIATION/PHOTODYNAMIC“HYBRID”THERAPY INTRODUCTIONANDCONCEPT A 2006 study proposed a new approach to nanoparticle-based therapies aiming to combine and enhance the effects of radi- ation therapy and photodynamic therapy (PDT) through the use of scintillating nanoparticles conjugated to photosensitizer molecules(ChenandZhang,2006).Theconcept is simple:attach adyeusedforPDTtoananoparticlethatemits lightwhenexcited bytherapeuticradiation(scintillates). If thescintillationemission overlapstheabsorbancespectrumofthedye,thedyewillgenerate singletoxygenas itdoeswith light-excitedPDT(Figure2).Many conventional photosensitizers are based on naturally occurring porphyrin, chlorin, andbacteriochlorin structures comprised of highly conjugated heterocyclic macrocycles (Figure3A). These moleculeshaveastrongabsorbancepeak in theUVtobluerange (Soret band) as well as numerous weaker peaks in the visible (Figure3B). This idea has attracted significant attentionover the past few years (Cheng andLo, 2011) because it promises to combine the tissuepenetrationdepthofradiationwiththeefficacyandbenign side effect profile of PDT. PDT results in less damage tonormal tissue thandoesradiationtherapy;doesnot inducescarring;may be repeated multiple times; andmay spark immune responses that help destroy the tumor. However, because of the limited tissue penetration depth of visible and even near-IR light, this therapy is restricted toonly themost superficial cancers, such as non-melanomaskincancerandbladdercancer. The challenge is to develop stable, nontoxic nanoscintillators thatmay be delivered to cells. Several varieties of doped insula- tor and semiconductor nanoparticles have been proposed to fill thisrole.WhilescintillationhasbeendemonstratedforCdSe/ZnS quantum dots (Létant andWang, 2006), they have poor radia- tionhardnessanddegraderapidlyunderγ rayexposure(Withers et al., 2008). As the toxicity of thesematerials is also primarily related to their chemical degradation, alternatives are necessary. The development of such alternatives is mostly in early stages. Althoughmany of the approaches to surface chemistry and tar- getingthathavebeenusedforgoldcouldbeappliedtotheseother Frontiers inChemistry | ChemicalEngineering October2014 |Volume2 |Article86 | 51