Seite - 48 - in Cancer Nanotheranostics - What Have We Learnd So Far?

REVIEWARTICLE published:14October2014 doi: 10.3389/fchem.2014.00086 Goldnanoparticlesand theiralternatives for radiation therapyenhancement DanielR.Cooper,DeveshBekah andJayL.Nadeau* DepartmentofBiomedicalEngineering,McGillUniversity,Montreal,QC,Canada Editedby: JesúsM.DeLaFuente,Universidad deZaragoza,Spain Reviewedby: PedroVianaBaptista,Universidade NovadeLisba,Portugal WolfgangParak,Universität Marburg,Germany *Correspondence: JayL.Nadeau,Departmentof BiomedicalEngineering,McGill University, 316LymanDuffBuilding, 3775UniversityStreet,Montreal, QCH3A2B4,Canada e-mail: jay.nadeau@mcgill.ca Radiation therapy is oneof themost commonly used treatments for cancer. Thedoseof delivered ionizing radiation can be amplified by the presence of high-Zmaterials via an enhancementof thephotoelectriceffect; themostwidelystudiedmaterial isgold (atomic number79).However,a largeamount isneededtoobtainasignificantdoseenhancement, presentingachallengefordelivery. Inorder tomakethis techniqueofbroaderapplicability, thegoldmustbe targeted,oralternative formulationsdevelopedthatdonot relysolelyon thephotoelectriceffect.Onepossibleapproach is toexcitescintillatingnanoparticleswith ionizing radiation, and then exploit energy transfer between these particles and attached dyes inamanneranalogous tophotodynamic therapy (PDT).Dopedrare-earthhalidesand semiconductorquantumdotshavebeen investigated for thispurpose.However, although thespectrumofemitted light after radiationexcitation is usually similar to that seenwith light excitation, the yield is not. Measurement of scintillation yields is challenging, and inmany cases has been done only for bulk materials, with little understanding of how theprinciples translate to thenanoscale.Another alternative is touse local heatingusing gold or iron, followedbyapplicationof ionizing radiation.Hyperthermia pre-sensitizes the tumors, leading to an improved response. Another approach is to use chemotherapeutic drugs that can radiosensitize tumors. Drugsmay be attached to high-Z nanoparticles or encapsulated. This article discusses eachof these techniques, giving anoverviewof the current stateofnanoparticle-assisted radiation therapyand futuredirections. Keywords:nanoparticle, scintillator, radiationtherapy,photodynamic therapy,photosensitizer, radiosensitizer INTRODUCTIONANDBACKGROUND Radiation therapy (XRT) is a critical component of the mod- ern approach to curative and adjuvant treatment of cancers. XRT controls the growth of cancerous cells by bombardment with ionizing radiation, causing DNA damage by direct ion- ization or through generation of free radicals by ionization of water or oxygen molecules. Sufficient damage to DNA in this fashion can arrest cell growth and preventmetastasis. The pri- mary drawback is collateral damage: there is little distinction in absorption between healthy andmalignant tissues, and thus doses must be limited in order to mitigate unwanted dam- age to the tumor surroundings. External beam radiotherapy (EBRT)utilizesX-ray beamsproducedbyorthovoltageunits, or linear accelerators that may be spatially oriented, with beams shaped using multileaf collimators in order to maximize the specificity for the target. Distinct energy ranges are available for different EBRT targets: 40–100kV (kilovoltage or “super- ficial” X-rays) for skin cancers or other exposed structures; as well as 100–300kV (orthovoltage) and 4–25MV (mega- voltage or “deep” X-rays) for sub-surface tumors. Techniques such as 3-dimensional conformal and intensity-modulated radi- ation therapies have vastly improved the targeting capabilities of external beam therapy, but naturally there is still a strong desire to be able to further reduce the doses required for effective treatment. The SI derived unit for absorbed dose is the gray (Gy), equivalent to one joule of energy deposited by ionizing radiation per kilogram of matter (1Gy = 1J/kg = 1m2/s2). Brachytherapy, or internal radiotherapy, utilizes a radioactive source toprovide a steadyorpulseddoseof radiation to a small tissuevolume. It is typicallyusedforcervical,prostate,breastand skin cancers. Radioactive sources include 125I and103Pd, which produceγ raysof∼20–35keV, 192Ir (γ rays, 300–610keV), 137Cs (γrays,662keV),60Co(γrays,1.17and1.33MeV),198Au(γrays, 410–1009keV), 226Ra (γ rays, 190–2430keV), and 106Ruwhich decays primarily throughβ− emission at 3.54MeV. Seeds of the listedmaterials canprovidedosesofupto12Gy/hour(highdose rateorHDRbrachytherapy), thoughtypical lowdoserate (LDR) treatmentsamount toaround65Gyover5–6days. Heavy elements can be potent radiosensitizers (Kobayashi et al., 2010). It hasbeendemonstrated thatplatinum-containing DNA-crosslinkingdrugssuchasCisplatincanenhancetheeffects of ionizing radiation through the “high Z effect,” or what has come to be known as Auger therapy. Heavy elements have sig- nificantly higher photoelectric cross-sections than soft tissue for sub-MeV energies, approximated for “X-ray energies” by the equation: σpe ∝ Z n E3 where σpe is the cross-section, E=hν is the photon energy, Z is the atomic number, and n varies between 4 and 5 depending www.frontiersin.org October2014 |Volume2 |Article86 | 48