Low Z target switching to increase tumor endothelial cell dose enhancement duringgold nanoparticle-aided radiation therapyRoss I Berbeco Alexandre Detappe Panogiotis Tsiamas David Parsons Mammo Yewondwossen andJames Robar Citation Medical Physics 43 436 (2016) doi 10111814938410 View online httpdxdoiorg10111814938410 View Table of Contents httpscitationaiporgcontentaapmjournalmedphys431ver=pdfcov Published by the American Association of Physicists in Medicine Articles you may be interested in Gold nanoparticle induced vasculature damage in radiotherapy Comparing protons megavoltage photonsand kilovoltage photons Med Phys 42 5890 (2015) 10111814929975 Low-Z linac targets for low-MV gold nanoparticle radiation therapy Med Phys 41 021701 (2014) 10111814859335 Monte Carlo investigation of the increased radiation deposition due to gold nanoparticles using kilovoltageand megavoltage photons in a 3D randomized cell model Med Phys 40 071710 (2013) 10111814808150 Comment on ldquoEnhanced relative biological effectiveness of proton radiotherapy in tumor cells withinternalized gold nanoparticlesrdquo [Appl Phys Lett 98 193702 (2011)] Appl Phys Lett 100 026101 (2012) 10106313675570 Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized goldnanoparticles Appl Phys Lett 98 193702 (2011) 10106313589914

Low Z target switching to increase tumor endothelial cell doseenhancement during gold nanoparticle-aided radiation therapy

Ross I Berbecoa) and Alexandre DetappeDepartment of Radiation Oncology Brigham and Womenrsquos Hospital Dana-Farber Cancer Instituteand Harvard Medical School Boston Massachusetts 02115

Panogiotis TsiamasDepartment of Radiation Oncology St Jude Childrenrsquos Hospital Memphis Tennessee 38105

David Parsons Mammo Yewondwossen and James RobarDepartment of Radiation Oncology and Department of Physics and Atmospheric ScienceDalhousie University Halifax Nova Scotia B3H 1V7 Canada

(Received 1 July 2015 revised 13 October 2015 accepted for publication 28 November 2015published 31 December 2015)

Purpose Previous studies have introduced gold nanoparticles as vascular-disrupting agents duringradiation therapy Crucial to this concept is the low energy photon content of the therapy radiationbeam The authors introduce a new mode of delivery including a linear accelerator target that cantoggle between low Z and high Z targets during beam delivery In this study the authors examine thepotential increase in tumor blood vessel endothelial cell radiation dose enhancement with the low ZtargetMethods The authors use Monte Carlo methods to simulate delivery of three different clinicalphoton beams (1) a 6 MV standard (CuW) beam (2) a 6 MV flattening filter free (CuW) and(3) a 6 MV (carbon) beam The photon energy spectra for each scenario are generated for depths intissue-equivalent material 2 10 and 20 cm The endothelial dose enhancement for each target anddepth is calculated using a previously published analytic methodResults It is found that the carbon target increases the proportion of low energy (lt150 keV) photonsat 10 cm depth to 28 from 8 for the 6 MV standard (CuW) beam This nearly quadrupling of thelow energy photon content incident on a gold nanoparticle results in 77 times the endothelial doseenhancement as a 6 MV standard (CuW) beam at this depth Increased surface dose from the low Ztarget can be mitigated by well-spaced beam arrangementsConclusions By using the fast-switching target one can modulate the photon beam during deliveryproducing a customized photon energy spectrum for each specific situation C 2016 AmericanAssociation of Physicists in Medicine [httpdxdoiorg10111814938410]

Key words radiation therapy nanoparticle dose enhancement vascular disruption

1 INTRODUCTION

While nanoparticle-based cancer therapy has been an activearea of research for several years current approaches arebeset by significant challenges including inadequate diffusionof nanoparticles into the tumor and the poor tissue penetrationof the activating agent (optical IR UV kV x-rays etc)12

The treatment concept described in this paper overcomesthese challenges and offers a simple clinical workflow forimproving cancer therapy in combination with high energyexternal beam radiation therapy

We propose to target tumor blood vessels with gold nanopar-ticles (GNPs) prior to radiation therapy with a clinical linearaccelerator There is a growing body of evidence that vasculartargets could be more important for anticancer therapy thanclonogenic cell death alone3ndash11 Garcia-Barros et al proposedthat damage to tumor vasculature during radiation therapy(specifically apoptosis in the endothelial cells) may be a moreimportant mechanism for tumor eradication than clonogeniccell death3 A recent review by Park et al enumerated the

experimental evidence that radiation-induced tumor vasculardamage is contributing to the success of stereotactic radi-ation therapy procedures4 Murphy et al have shown thatnanoparticle-mediated drug delivery to tumor vasculature caneven have an antimetastatic effect12 Accordingly for radia-tion therapy combined with GNP a higher concentration ofGNP near the vasculature provides a biological advantageover a homogeneous distribution throughout the tumor13

Serendipitously accumulation in the vasculature is expectedfor nanoparticles of a certain size14 Nanoparticle concen-tration and duration in the tumor vasculature can be furtheroptimized by molecular targeting1214

The photoelectric interaction of low energy (lt150 keV)photons with gold atoms leads to the emission of short-range electrons Auger interactions occur at very low energiesand emitted Auger electrons are quickly absorbed beforecontributing to the dose enhancement15ndash17 Using Monte Carlotechniques it has been found that the nanoscopic photoelectricdose enhancement for a clinical 6 MV photon beam can bemany orders of magnitude close to the GNP1819 Similarly

436 Med Phys 43 (1) January 2016 0094-2405201643(1)4367$3000 copy 2016 Am Assoc Phys Med 436

437 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 437

endothelial cells in close proximity to GNP are expected toreceive a highly selective boost exceeding the predictions forhomogeneously distributed GNP20

Chemical vascular-disrupting agents (VDAs) have beendeveloped and tested clinically and preclinically It hasbeen shown that chemical VDA improves the effects ofradiation therapy in preclinical models21ndash23 However recenthuman clinical trials of chemical VDA have resulted inunacceptable toxicities limiting translation45112425 By usingbiocompatible GNP coupled with precise image-guidedradiation therapy we anticipate a reduction in associatednormal tissue toxicities

The concept of GNP as vascular-disrupting agents whencombined with external beam radiation therapy was firstintroduced in a theoretical study by Berbeco et al13 Ananalytical calculation was performed based on a conservativegeometry of a GNP localized adjacent to endothelial cellsThe results of that study demonstrated the feasibility ofproviding substantial radiation dose enhancement to tumorendothelial cells during clinical radiation therapy proceduresExperimental evidence has also shown that gold nanoparticleaided radiation therapy can lead to increased cell deathin vitro26ndash28 and increased tumor vascular damage in vivo2930

A recent study by Kunjachan et al demonstrated tumorvascular disruption after radiation combined with vascular-targeted gold nanoparticles in a multitude of experimentalassays31

Clinical radiation beams produced by a linear acceleratorhave substantial skin sparing and deep tissue penetrationproperties However an existing obstacle to gold nanoparticle-enhanced radiation therapy is the low proportion of low energy(lt150 kV) photons in a clinical beam that will interact moststrongly with the GNP In a nominal 6 MV beam only 8 ofthe photon spectrum is comprised of photons with energiesless than 150 kV at 10 cm depth in tissue

To overcome this obstacle we propose a modificationof the linear accelerator target to deliver more low energyphotonsmdashie a ldquosofterrdquo beam The goal is to design a targetthat balances increased GNP interactions with maintenanceof normal tissue dose constraints We will show that a 6 MVbeam produced using a carbon target will almost quadruplethe proportion of low energy (lt150 keV) photons at 10 cmdepth which corresponds to 77 times the endothelial doseenhancement of a standard clinical beam We will also show

that the corresponding 52 relative increase in surface doseis entirely mitigated by the use of multiple beam angles acommon practice in clinical radiation therapy

A prototype switching target has been built anddemonstrated on a clinical linear accelerator (Fig 1) Thedevice is compact occupying for testing purposes a singleport of the carousel of the linear accelerator (21iX VarianMedical Systems Inc) The two targets included in theprototype are composed of coppertungsten (CuW) andcarbon (C) respectively The switching mechanism operates atsim250 ms and is controlled externally A complete descriptionof the device will be presented in a separate publicationOne application of the switching target is intermittent highcontrast beamrsquos-eye-view (BEV) imaging during radiationtherapy3233 However a similar device can be used in thefuture to customize the photon energy spectrum for eachtreatment field depending on the patient anatomy targetlocation and geometry of normal tissues In principle boththerapy and BEV imaging functions of the low Z switchingtarget can be used simultaneously a concept that is beyond thecurrent scope of work In the following study we examine thedosimetric advantage of including a low Z linear acceleratortarget in gold nanoparticle aided radiation therapy

2 METHODS AND MATERIALS2A Monte Carlo photon spectrum generation

A Varian 2100EX Clinac was simulated using BEAMnrcThe model was modified from previous work32 to accountfor changes present in the most recent High EnergyAccelerator Monte Carlo Data Package provided by VarianMedical Systems under a nondisclosure agreement Thesemodifications largely consisted of the inclusion of the metalplating on the dielectric windows of the monitor chamber Tosimulate the low Z target the CuW target and flattening filterwere removed and the carbon target placed 9 mm from theberyllium exit window Directional bremsstrahlung splittingwas used with a splitting radius of 10 cm for a jaw defined10 times 10 cm2 at a source-to-surface distance (SSD) of 100 cmwith a bremsstrahlung splitting number of 2000 AE=ECUTand AP=PCUT values of 0521 and 0010 MeV respectivelywere used Phasendashspaces were scored at the water surface andat depths of 2 10 and 20 cm Dose was similarly calculated

F 1 (A) The switching target (CuW and C) with electric motor and external control (B) the switching target in the carousel of a Varian linear accelerator atDalhousie University

Medical Physics Vol 43 No 1 January 2016

438 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 438

T I Thermal conductivity of target materials

Target material Thermal conductivity (W mminus1 Kminus1)

Diamond 900ndash2300Graphite 119ndash165Copper 401Tungsten 173

at mentioned depths using DOSXYZnrc BEAMdp was usedto determine spectral distributions of the phase space files

Previous theoretical and experimental investigations ofberyllium (Z = 4) and aluminum (Z = 13) targets demon-strated the production of large amounts of low energyphotons34 However these target materials are not practicalfor clinical applications For example beryllium has a lowneutron activation energy and is toxiccarcinogenic whenmachined Aluminum is inexpensive and convenient tomachine but has a low melting point (660 C) In addition ithas been shown that reducing the atomic number of the targetto values lower than carbon (eg beryllium) has the effectof increasing the relative photon content at very low energiesleading to increases in surface dose without substantial lowenergy photons at clinically relevant depths32

For these reasons we chose to investigate carbon in thecurrent work Carbon has a low atomic number (Z = 6) andno melting point (sublimes at sim3600 C) Table I shows thethermal conductivity of potential target materials Althoughthe efficiency of bremsstrahlung is approximately Z2 overallwithin the bounds of the primary collimator (eg plusmn14) thedependence on Z is weak3536

We generated Monte Carlo photon spectra for the followingcases (1) ldquostandardrdquo flat 6 MV beam with a CuW target(2) flattening filter free (FFF) beam with a CuW target and(3) FFF beam with a C target This last beam is referred toas ldquo6 MV (Carbon)rdquo in this study We used a 10 times 10 cmaperture at isocenter and 100 cm SSD for all beams Asthe beams penetrate deeper in tissue beam hardening (dueto selective absorption of low energy primary photons) orsoftening (due to patientphantom scatter) can decrease orincrease the proportion of low energy photons To study thiseffect we generated spectra at 2 10 and 20 cm depth intissue In addition to studying the relative endothelial doseenhancement we also investigated the effect of the carbontarget beam on entrance dose

The Monte Carlo methods of photon beam generationwith low Z targets used in this study have been previouslyvalidated experimentally32 In those studies photon depthdose measurements were acquired for both carbon andaluminum targets and excellent agreement with the MonteCarlo predictions was demonstrated

2B An analytical calculation method for endothelialdose enhancement

We used a previously published method for estimatingendothelial dose enhancement1337 Briefly the tumor vascularendothelial cells are modeled as flat rectangular slabs

F 2 Simplified model of endothelial cell layer between intravascularcavity and tumor cells The gold nanoparticles are attached to the vascularside of the endothelium The range of photoelectrons generated within theGNPs is shown as a ldquosphere of interactionrdquo with the nanoparticle at the centerThe extra dose deposited in the nearest endothelial cell by GNP photoelec-tron emissions (shaded region) is used to calculate the dose enhancementReprinted with permission from Berbeco Ngwa and Makrigiorgos Int JRadiat Oncol Biol Phys 81(1) 270ndash276 (2011)

For the calculation gold nanoparticles are placed justoutside the endothelial cell (Fig 2) This is a conservativemodel as endothelial cell uptake of gold nanoparticlespreviously demonstrated in vitro and in vivo will increase theexpected dose enhancement Only photoelectric interactionsare included as Auger effects will be extremely shortrange (simseveral nanometer) and substantial self-shieldingis expected The photoelectric interaction cross section isprovided in tables by NIST38 The range and dose depositionof emitted photoelectrons is calculated using the method ofCole39 The generation of photoelectrons will depend greatlyon the energy of the incident photon Photons above roughly250 keV contribute very little to the dose enhancement Onlydose deposited within the ldquosphere of interactionrdquo is includedin the calculation

Beam ldquosofteningrdquo with a low Z target is expectedto increase GNP therapeutic effectiveness13183740ndash42 Ourprevious theoretical calculations combining Monte Carlo withthe analytical microdosimetry calculation described above1337

predict a roughly 50ndash150 increase in dose to the tumorendothelial cells for a 6 MV standard (CuW) beam Factorsthat affect the therapeutic efficacy include depth in tissue13

removal of the FFF and the energy of the electron beamincident on the target

The Monte Carlo generated spectra for the targets listedabove are used to evaluate relative increase in endothelialdose enhancement Like other reported calculations of goldnanoparticles in radiation therapy this analytical calculationhas not been validated in vivo However the concept ofincreasing DNA damage for larger proportions of low energyphotons in a therapy beam has been validated in vitro27 Dueto the lack of any clear absolute metric of the consequencesof endothelial dose enhancement we report our results asrelative endothelial dose enhancement where the standardCuW target is the reference In this way we are able toshow the relative advantage of the lower atomic numberlinear accelerator target The relative enhancement of eachtarget is calculated at each depth providing the increasein endothelial dose enhancement factor (EDEF) for thelow Z target under the same treatment conditions as theconventional target The explicit expression for the calculation

Medical Physics Vol 43 No 1 January 2016

439 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 439

F 3 Photon energy spectra at depth= 2 10 and 20 cm for 6 MV deliverywith a standard flat beam (CuW target) a FFF (CuW target) beam and acarbon target beam Note the substantial increase in low energy photons at alldepths for the carbon target relative to the CuW target

of the relative improvement in EDEF is EDEFnew targetEDEFstandard flat(CuW)

3 RESULTS

The photon energy spectra calculated with the Monte Carlofor 6 MV standard (CuW) 6 MV FFF (CuW) and 6 MV(carbon) are shown in Fig 3 These spectra are generatedfor depths of 2 10 and 20 cm in tissue Figure 4 showsthe percentage of low energy photons (25ndash150 keV) for eachtarget and depth combination Relative to the 6 MV standard(CuW) beam the 6 MV FFF beam shows a substantialincrease in low energy photons for all depths At 10 cmdepth the 6 MV standard beam is composed of 8 lowenergy photons compared to 11 for the FFF beam The6 MV carbon target beam has a much larger proportion of lowenergy photons at all depths than either of the CuW beams(standard or FFF) At 10 cm depth the 6 MV carbon targetbeam is composed of 28 low energy photons This is nearlyfour times the low energy photon content of the standard 6MV beam and more than two and a half times that of the 6 MVFFF beam Of note the 6 MV carbon target beam becomesharder at greater depths whereas both 6 MV standard and FFFbeams become softer at greater depths in tissue

F 4 The percentage of low energy photons (25ndash150 keV) for a standard(CuW target) beam a FFF (CuW target) beam and a carbon target beam

F 5 The expected increase in the EDEF for 6 MV FFF (CuW) and 6 MV(carbon) respectively Results are shown relative to a 6 MV standard (CuW)beam At 10 cm depth the carbon target provides 77 times the EDEF

As expected from the Monte Carlo photon energy spectrumresults the relative improvement in EDEF for the carbon targetbeam is substantial at all depths The calculation of relativeincrease in EDEF is made independently for each depthcondition using the entire photon energy spectrum Figure 5shows the relative EDEF for the carbon target beam comparedto the 6 MV FFF beam At 2 cm depth the carbon target beamprovides 186 times the endothelial dose enhancement as a 6MV standard beam This reduces to 77 times at 10 cm depthand 40 times at 20 cm depth as the relative difference in theproportion of low energy photons decreases at the deepestdepths The 6 MV FFF beam would supply more than twiceas much endothelial dose at 2 cm decreasing to 15 times at20 cm depth

Due to the relative nature of the calculation in this paper thesize and concentration of the nanoparticles do not influencethe results In addition no assumptions have been made aboutcoating (eg PEG) or targeting (eg RGD)

The Monte Carlo data were also used to investigate theincrease in surface dose and loss of penetration depth forstandard and proposed beams The percent depth dose (PDD)curves for the 6 MV standard (CuW) 6 MV FFF (CuW)6 MV (carbon) normalized to deliver 100 dose at 10 cm

F 6 PDD for 6 MV standard (CuW) 6 MV FFF (CuW target) 6 MV(carbon) 25 MV (C) normalized to 100 at 10 cm depth

Medical Physics Vol 43 No 1 January 2016

440 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 440

F 7 Normalized percent skin dose as a function of number of parallelopposed treatment beams from different gantry angles A 25 MV (carbon)beam requires eight beam angles to limit the surface dose to the same levelas four beam angles of a 6 MV standard (CuW) beam (296) while stilldelivering 100 dose to the tumor

depth are shown in Fig 6 We define the surface dose as thecentral axis dose at 1 mm as a percentage of dmax

The loss of penetration depth and reduced skin sparingeffects of beams with more low energy photons contributeto higher entrance dose Beams of 6 MV FFF (CuW) and6 MV (carbon) contribute 21 and 52 more surface dosethan a standard flat 6 MV beam respectively HoweverFig 7 shows the reduction in surface dose by the use oftreatment plans consisting of multiple angles as are mostcommonly used clinically We simulated parallel opposedbeams to include both entrance and exit doses representinga worst-case scenario Cylindrical symmetry is assumed witha separation of 20 cm The normalization is 100 to apoint on the central axis at 10 cm depth To achieve thesame or less surface dose (296) as a 4-field standard flat6 MV delivery a 6 MV (carbon) beam requires five beams toreach the same level of skin sparing as a 4-field 6 MV standard

(CuW) delivery while still delivering 100 dose to the tumorat 10 cm depth In these figures we also show the results fora 25 MV (carbon) beam Currently used for imaging onlythis beam could have therapeutic use in the future

4 DISCUSSION

In this study it has been demonstrated that a 6 MV photonbeam generated using a clinical linear accelerator with acarbon target will provide a substantial increase in low energyphotons compared to conventional beams with a CuW targetThese additional low energy photons will translate into amultifold increase in endothelial dose enhancement whenincident upon gold nanoparticles in close proximity A fullstudy of 3D treatment planning with a 6 MV carbon targetbeam will be the subject of a future study

One potential application of this work is the use of afast-switching target (FST) to generate custom photon energyspectra Different clinical scenarios of gold nanoparticle-aidedradiation therapy will call for different mixes of lowhighenergy photon spectra This will depend on beam anglefield size patient thickness and proximity of normal tissuesdose fractionation and other clinical parameters Togglingbetween different targets during beam delivery will generate acustomized photon energy spectrum (Fig 8) The optimalspectrum can be determined prior to treatment deliverysimilar to the modulation of multileaf collimators in intensity-modulated radiation therapy

This study is focused on photon beams with a peak energyof 6 MV Lower energy beams with alternative targets couldoffer similar advantages in increased proportion of low energyphotons Some currently available linear accelerators are ableto deliver imaging beams of 25 MV using a low Z targetPreviously published studies have shown that 40ndash50 ofthe primary photons from a 25 MV (carbon) beam are inthe diagnostic range33 However these beam lines are notapproved for human radiation therapy and will also likely

F 8 Conventional delivery (left) is contrasted with FST delivery (middle and right) These drawings depict incoming 65 MeV electrons colliding with thelinear accelerator target generating photons for radiation therapy The resultant photon energy spectra for 10 cm depth in tissue are shown for each deliverymode respectively These spectra are shown in greater detail in Fig 3 (Left) Conventional (conv-CuW) delivery is shown with the standard CuW target anda flattening filter (Middle) FST delivery with only the high Z (FFF-CuW) target the flattening filter is removed (Right) FST delivery with only the low Z

(FFF-C) target the flattening filter is removed

Medical Physics Vol 43 No 1 January 2016

441 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 441

suffer from a low dose-rate An additional challenge willbe the balance of tumor coverage and skin sparing fordeep-seated tumors Simulated PDD and surface dosecalculations are shown in Figs 6 and 7 for comparisonwith the 6 MV beams

Collateral advantages of the fast-switching target researchinclude novel clinical imaging concepts We anticipate thatboth volumetric and planar imaging with the therapy beamwill be greatly improved by the target modifications presentedhere resulting in improved patient setup and beamrsquos-eye-viewin-treatment imaging3443ndash45 For example fast and periodicimaging of a lung tumor with a low Z target could be usedto update predictive models of respiratory motion withoutinterruption of the treatment delivery Previously publishedimaging work with low Z targets demonstrated a markedimprovement in image contrast using a 235 MV beam with acarbon target33

5 CONCLUSION

Our results indicate that replacing the CuW target witha carbon target in a clinical linear accelerator should resultin a multifold increase in the radiation dose enhancement totumor blood vessel endothelial cells when GNP is in closeproximity The resulting disruption of tumor vasculature canprovide a new therapeutic tool for clinical situations wherethe deliverable radiation dose is limited by adjacent normaltissue The concept of customizing photon spectra via a fast-switching target is a novel concept which could offer a furtherpersonalized solution for each unique clinical scenario

ACKNOWLEDGMENTS

This project was supported in part by a grant fromVarian Medical Systems Inc (JR) and the National CancerInstitute of the National Institutes of Health under AwardNos R03CA164645 and R21CA188833 (RIB) The contentis solely the responsibility of the authors and does notnecessarily represent the official views of the National CancerInstitute or the National Institutes of Health

a)Author to whom correspondence should be addressed Electronic mailrberbecopartnersorg

1D K Chatterjee T Wolfe J Lee A P Brown P K Singh S R BhattaraiP Diagaradjane and S Krishnan ldquoConvergence of nanotechnology withradiation therapy-insights and implications for clinical translationrdquo TranslCancer Res 2(4) 256ndash268 (2013)

2W Ngwa H Korideck A I Kassis R Kumar S Sridhar G M Makrigior-gos and R A Cormack ldquoIn vitro radiosensitization by gold nanoparticlesduring continuous low-dose-rate gamma irradiation with I-125 brachyther-apy seedsrdquo Nanomed Nanotechnol Biol Med 9(1) 25ndash27 (2013)

3M Garcia-Barros F Paris C Cordon-Cardo D Lyden S Rafii AHaimovitz-Friedman Z Fuks and R Kolesnick ldquoTumor response toradiotherapy regulated by endothelial cell apoptosisrdquo Science 300(5622)1155ndash1159 (2003)

4H J Park R J Griffin S Hui S H Levitt and C W Song ldquoRadiation-induced vascular damage in tumors Implications of vascular damage inablative hypofractionated radiotherapy (SBRT and SRS)rdquo Radiat Res177(3) 311ndash327 (2012)

5D W Siemann ldquoThe unique characteristics of tumor vasculature andpreclinical evidence for its selective disruption by tumor-vascular disruptingagentsrdquo Cancer Treat Rev 37(1) 63ndash74 (2011)

6P Carmeliet and R K Jain ldquoMolecular mechanisms and clinical applica-tions of angiogenesisrdquo Nature 473(7347) 298ndash307 (2011)

7J N Rich ldquoCancer stem cells in radiation resistancerdquo Cancer Res 67(19)8980ndash8984 (2007)

8T Reya S J Morrison M F Clarke and I L Weissman ldquoStem cellscancer and cancer stem cellsrdquo Nature 414(6859) 105ndash111 (2001)

9L E Ailles and I L Weissman ldquoCancer stem cells in solid tumorsrdquo CurrOpin Biotechnol 18(5) 460ndash466 (2007)

10H J Mauceri N N Hanna M A Beckett D H Gorski M J StabaK A Stellato K Bigelow R Heimann S Gately M Dhanabal G A SoffV P Sukhatme D W Kufe and R R Weichselbaum ldquoCombined effects ofangiostatin and ionizing radiation in antitumour therapyrdquo Nature 394(6690)287ndash291 (1998)

11D W Siemann D J Chaplin and M R Horsman ldquoVascular-targetingtherapies for treatment of malignant diseaserdquo Cancer 100(12) 2491ndash2499(2004)

12E A Murphy B K Majeti L A Barnes M Makale S M Weis KLutu-Fuga W Wrasidlo and D A Cheresh ldquoNanoparticle-mediated drugdelivery to tumor vasculature suppresses metastasisrdquo Proc Natl Acad SciU S A 105(27) 9343ndash9348 (2008)

13R I Berbeco W Ngwa and G M Makrigiorgos ldquoLocalized dose enhance-ment to tumor blood vessel endothelial cells via megavoltage x-rays andtargeted gold nanoparticles New potential for external beam radiotherapyrdquoInt J Radiat Oncol Biol Phys 81(1) 270ndash276 (2011)

14S D Perrault C Walkey T Jennings H C Fischer and W C W ChanldquoMediating tumor targeting efficiency of nanoparticles through designrdquoNano Lett 9(5) 1909ndash1915 (2009)

15F Van den Heuvel J P Locquet and S Nuyts ldquoBeam energy considerationsfor gold nano-particle enhanced radiation treatmentrdquo Phys Med Biol55(16) 4509ndash4520 (2010)

16S J McMahon W B Hyland M F Muir J A Coulter S Jain K TButterworth G Schettino G R Dickson A R Hounsell J M OrsquoSullivanK M Prise D G Hirst and F J Currell ldquoBiological consequences ofnanoscale energy deposition near irradiated heavy atom nanoparticlesrdquoSci Rep 1 18 (2011)

17M Douglass E Bezak and S Penfold ldquoMonte Carlo investigation of theincreased radiation deposition due to gold nanoparticles using kilovoltageand megavoltage photons in a 3D randomized cell modelrdquo Med Phys 40(7)071710 (9pp) (2013)

18P Tsiamas B Liu F Cifter W F Ngwa R I Berbeco C Kappas KTheodorou K Marcus M G Makrigiorgos E Sajo and P ZygmanskildquoImpact of beam quality on megavoltage radiotherapy treatment techniquesutilizing gold nanoparticles for dose enhancementrdquo Phys Med Biol 58(3)451ndash464 (2013)

19B L Jones S Krishnan and S H Cho ldquoEstimation of microscopic doseenhancement factor around gold nanoparticles by Monte Carlo calcula-tionsrdquo Med Phys 37(7) 3809ndash3816 (2010)

20S H Cho ldquoEstimation of tumour dose enhancement due to gold nanoparti-cles during typical radiation treatments A preliminary Monte Carlo studyrdquoPhys Med Biol 50(15) N163ndashN173 (2005)

21R Murata D W Siemann J Overgaard and M R Horsman ldquoImprovedtumor response by combining radiation and the vascular-damaging drug56-dimethylxanthenone-4-acetic acidrdquo Radiat Res 156(5) 503ndash509(2001)

22D W Siemann and A M Rojiani ldquoThe vascular disrupting agent ZD6126shows increased antitumor efficacy and enhanced radiation response inlarge advanced tumorsrdquo Int J Radiat Oncol Biol Phys 62(3) 846ndash853(2005)

23W R Wilson A E Li D S M Cowan and B G Siim ldquoEnhancement oftumor radiation response by the antivascular agent 56-dimethylxanthenone-4-acetic acidrdquo Int J Radiat Oncol Biol Phys 42(4) 905ndash908 (1998)

24D W Siemann and M R Horsman ldquoVascular targeted therapies inoncologyrdquo Cell Tissue Res 335(1) 241ndash248 (2009)

25D W Siemann E Mercer S Lepler and A M Rojiani ldquoVascular targetingagents enhance chemotherapeutic agent activities in solid tumor therapyrdquoInt J Cancer 99(1) 1ndash6 (2002)

26D B Chithrani S Jelveh F Jalali M van Prooijen C Allen R G BristowR P Hill and D A Jaffray ldquoGold nanoparticles as radiation sensitizers incancer therapyrdquo Radiat Res 173(6) 719ndash728 (2010)

27R I Berbeco H Korideck W Ngwa R Kumar J Patel S Sridhar SJohnson B Price A Kimmelman and G M Makrigiorgos ldquoDNA dam-age enhancement from gold nanoparticles for clinical MV photon beamsrdquoRadiat Res 178(6) 604ndash608 (2012)

Medical Physics Vol 43 No 1 January 2016

438 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 438

T I Thermal conductivity of target materials

Target material Thermal conductivity (W mminus1 Kminus1)

Diamond 900ndash2300Graphite 119ndash165Copper 401Tungsten 173

at mentioned depths using DOSXYZnrc BEAMdp was usedto determine spectral distributions of the phase space files

Previous theoretical and experimental investigations ofberyllium (Z = 4) and aluminum (Z = 13) targets demon-strated the production of large amounts of low energyphotons34 However these target materials are not practicalfor clinical applications For example beryllium has a lowneutron activation energy and is toxiccarcinogenic whenmachined Aluminum is inexpensive and convenient tomachine but has a low melting point (660 C) In addition ithas been shown that reducing the atomic number of the targetto values lower than carbon (eg beryllium) has the effectof increasing the relative photon content at very low energiesleading to increases in surface dose without substantial lowenergy photons at clinically relevant depths32

For these reasons we chose to investigate carbon in thecurrent work Carbon has a low atomic number (Z = 6) andno melting point (sublimes at sim3600 C) Table I shows thethermal conductivity of potential target materials Althoughthe efficiency of bremsstrahlung is approximately Z2 overallwithin the bounds of the primary collimator (eg plusmn14) thedependence on Z is weak3536

We generated Monte Carlo photon spectra for the followingcases (1) ldquostandardrdquo flat 6 MV beam with a CuW target(2) flattening filter free (FFF) beam with a CuW target and(3) FFF beam with a C target This last beam is referred toas ldquo6 MV (Carbon)rdquo in this study We used a 10 times 10 cmaperture at isocenter and 100 cm SSD for all beams Asthe beams penetrate deeper in tissue beam hardening (dueto selective absorption of low energy primary photons) orsoftening (due to patientphantom scatter) can decrease orincrease the proportion of low energy photons To study thiseffect we generated spectra at 2 10 and 20 cm depth intissue In addition to studying the relative endothelial doseenhancement we also investigated the effect of the carbontarget beam on entrance dose

The Monte Carlo methods of photon beam generationwith low Z targets used in this study have been previouslyvalidated experimentally32 In those studies photon depthdose measurements were acquired for both carbon andaluminum targets and excellent agreement with the MonteCarlo predictions was demonstrated

2B An analytical calculation method for endothelialdose enhancement

We used a previously published method for estimatingendothelial dose enhancement1337 Briefly the tumor vascularendothelial cells are modeled as flat rectangular slabs

F 2 Simplified model of endothelial cell layer between intravascularcavity and tumor cells The gold nanoparticles are attached to the vascularside of the endothelium The range of photoelectrons generated within theGNPs is shown as a ldquosphere of interactionrdquo with the nanoparticle at the centerThe extra dose deposited in the nearest endothelial cell by GNP photoelec-tron emissions (shaded region) is used to calculate the dose enhancementReprinted with permission from Berbeco Ngwa and Makrigiorgos Int JRadiat Oncol Biol Phys 81(1) 270ndash276 (2011)

For the calculation gold nanoparticles are placed justoutside the endothelial cell (Fig 2) This is a conservativemodel as endothelial cell uptake of gold nanoparticlespreviously demonstrated in vitro and in vivo will increase theexpected dose enhancement Only photoelectric interactionsare included as Auger effects will be extremely shortrange (simseveral nanometer) and substantial self-shieldingis expected The photoelectric interaction cross section isprovided in tables by NIST38 The range and dose depositionof emitted photoelectrons is calculated using the method ofCole39 The generation of photoelectrons will depend greatlyon the energy of the incident photon Photons above roughly250 keV contribute very little to the dose enhancement Onlydose deposited within the ldquosphere of interactionrdquo is includedin the calculation

Beam ldquosofteningrdquo with a low Z target is expectedto increase GNP therapeutic effectiveness13183740ndash42 Ourprevious theoretical calculations combining Monte Carlo withthe analytical microdosimetry calculation described above1337

predict a roughly 50ndash150 increase in dose to the tumorendothelial cells for a 6 MV standard (CuW) beam Factorsthat affect the therapeutic efficacy include depth in tissue13

removal of the FFF and the energy of the electron beamincident on the target

The Monte Carlo generated spectra for the targets listedabove are used to evaluate relative increase in endothelialdose enhancement Like other reported calculations of goldnanoparticles in radiation therapy this analytical calculationhas not been validated in vivo However the concept ofincreasing DNA damage for larger proportions of low energyphotons in a therapy beam has been validated in vitro27 Dueto the lack of any clear absolute metric of the consequencesof endothelial dose enhancement we report our results asrelative endothelial dose enhancement where the standardCuW target is the reference In this way we are able toshow the relative advantage of the lower atomic numberlinear accelerator target The relative enhancement of eachtarget is calculated at each depth providing the increasein endothelial dose enhancement factor (EDEF) for thelow Z target under the same treatment conditions as theconventional target The explicit expression for the calculation

Medical Physics Vol 43 No 1 January 2016

439 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 439

F 3 Photon energy spectra at depth= 2 10 and 20 cm for 6 MV deliverywith a standard flat beam (CuW target) a FFF (CuW target) beam and acarbon target beam Note the substantial increase in low energy photons at alldepths for the carbon target relative to the CuW target

of the relative improvement in EDEF is EDEFnew targetEDEFstandard flat(CuW)

3 RESULTS

The photon energy spectra calculated with the Monte Carlofor 6 MV standard (CuW) 6 MV FFF (CuW) and 6 MV(carbon) are shown in Fig 3 These spectra are generatedfor depths of 2 10 and 20 cm in tissue Figure 4 showsthe percentage of low energy photons (25ndash150 keV) for eachtarget and depth combination Relative to the 6 MV standard(CuW) beam the 6 MV FFF beam shows a substantialincrease in low energy photons for all depths At 10 cmdepth the 6 MV standard beam is composed of 8 lowenergy photons compared to 11 for the FFF beam The6 MV carbon target beam has a much larger proportion of lowenergy photons at all depths than either of the CuW beams(standard or FFF) At 10 cm depth the 6 MV carbon targetbeam is composed of 28 low energy photons This is nearlyfour times the low energy photon content of the standard 6MV beam and more than two and a half times that of the 6 MVFFF beam Of note the 6 MV carbon target beam becomesharder at greater depths whereas both 6 MV standard and FFFbeams become softer at greater depths in tissue

F 4 The percentage of low energy photons (25ndash150 keV) for a standard(CuW target) beam a FFF (CuW target) beam and a carbon target beam

F 5 The expected increase in the EDEF for 6 MV FFF (CuW) and 6 MV(carbon) respectively Results are shown relative to a 6 MV standard (CuW)beam At 10 cm depth the carbon target provides 77 times the EDEF

As expected from the Monte Carlo photon energy spectrumresults the relative improvement in EDEF for the carbon targetbeam is substantial at all depths The calculation of relativeincrease in EDEF is made independently for each depthcondition using the entire photon energy spectrum Figure 5shows the relative EDEF for the carbon target beam comparedto the 6 MV FFF beam At 2 cm depth the carbon target beamprovides 186 times the endothelial dose enhancement as a 6MV standard beam This reduces to 77 times at 10 cm depthand 40 times at 20 cm depth as the relative difference in theproportion of low energy photons decreases at the deepestdepths The 6 MV FFF beam would supply more than twiceas much endothelial dose at 2 cm decreasing to 15 times at20 cm depth

Due to the relative nature of the calculation in this paper thesize and concentration of the nanoparticles do not influencethe results In addition no assumptions have been made aboutcoating (eg PEG) or targeting (eg RGD)

The Monte Carlo data were also used to investigate theincrease in surface dose and loss of penetration depth forstandard and proposed beams The percent depth dose (PDD)curves for the 6 MV standard (CuW) 6 MV FFF (CuW)6 MV (carbon) normalized to deliver 100 dose at 10 cm

F 6 PDD for 6 MV standard (CuW) 6 MV FFF (CuW target) 6 MV(carbon) 25 MV (C) normalized to 100 at 10 cm depth

Medical Physics Vol 43 No 1 January 2016

440 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 440

F 7 Normalized percent skin dose as a function of number of parallelopposed treatment beams from different gantry angles A 25 MV (carbon)beam requires eight beam angles to limit the surface dose to the same levelas four beam angles of a 6 MV standard (CuW) beam (296) while stilldelivering 100 dose to the tumor

depth are shown in Fig 6 We define the surface dose as thecentral axis dose at 1 mm as a percentage of dmax

The loss of penetration depth and reduced skin sparingeffects of beams with more low energy photons contributeto higher entrance dose Beams of 6 MV FFF (CuW) and6 MV (carbon) contribute 21 and 52 more surface dosethan a standard flat 6 MV beam respectively HoweverFig 7 shows the reduction in surface dose by the use oftreatment plans consisting of multiple angles as are mostcommonly used clinically We simulated parallel opposedbeams to include both entrance and exit doses representinga worst-case scenario Cylindrical symmetry is assumed witha separation of 20 cm The normalization is 100 to apoint on the central axis at 10 cm depth To achieve thesame or less surface dose (296) as a 4-field standard flat6 MV delivery a 6 MV (carbon) beam requires five beams toreach the same level of skin sparing as a 4-field 6 MV standard

(CuW) delivery while still delivering 100 dose to the tumorat 10 cm depth In these figures we also show the results fora 25 MV (carbon) beam Currently used for imaging onlythis beam could have therapeutic use in the future

4 DISCUSSION

In this study it has been demonstrated that a 6 MV photonbeam generated using a clinical linear accelerator with acarbon target will provide a substantial increase in low energyphotons compared to conventional beams with a CuW targetThese additional low energy photons will translate into amultifold increase in endothelial dose enhancement whenincident upon gold nanoparticles in close proximity A fullstudy of 3D treatment planning with a 6 MV carbon targetbeam will be the subject of a future study

One potential application of this work is the use of afast-switching target (FST) to generate custom photon energyspectra Different clinical scenarios of gold nanoparticle-aidedradiation therapy will call for different mixes of lowhighenergy photon spectra This will depend on beam anglefield size patient thickness and proximity of normal tissuesdose fractionation and other clinical parameters Togglingbetween different targets during beam delivery will generate acustomized photon energy spectrum (Fig 8) The optimalspectrum can be determined prior to treatment deliverysimilar to the modulation of multileaf collimators in intensity-modulated radiation therapy

This study is focused on photon beams with a peak energyof 6 MV Lower energy beams with alternative targets couldoffer similar advantages in increased proportion of low energyphotons Some currently available linear accelerators are ableto deliver imaging beams of 25 MV using a low Z targetPreviously published studies have shown that 40ndash50 ofthe primary photons from a 25 MV (carbon) beam are inthe diagnostic range33 However these beam lines are notapproved for human radiation therapy and will also likely

F 8 Conventional delivery (left) is contrasted with FST delivery (middle and right) These drawings depict incoming 65 MeV electrons colliding with thelinear accelerator target generating photons for radiation therapy The resultant photon energy spectra for 10 cm depth in tissue are shown for each deliverymode respectively These spectra are shown in greater detail in Fig 3 (Left) Conventional (conv-CuW) delivery is shown with the standard CuW target anda flattening filter (Middle) FST delivery with only the high Z (FFF-CuW) target the flattening filter is removed (Right) FST delivery with only the low Z

(FFF-C) target the flattening filter is removed

Medical Physics Vol 43 No 1 January 2016

441 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 441

suffer from a low dose-rate An additional challenge willbe the balance of tumor coverage and skin sparing fordeep-seated tumors Simulated PDD and surface dosecalculations are shown in Figs 6 and 7 for comparisonwith the 6 MV beams

Collateral advantages of the fast-switching target researchinclude novel clinical imaging concepts We anticipate thatboth volumetric and planar imaging with the therapy beamwill be greatly improved by the target modifications presentedhere resulting in improved patient setup and beamrsquos-eye-viewin-treatment imaging3443ndash45 For example fast and periodicimaging of a lung tumor with a low Z target could be usedto update predictive models of respiratory motion withoutinterruption of the treatment delivery Previously publishedimaging work with low Z targets demonstrated a markedimprovement in image contrast using a 235 MV beam with acarbon target33

5 CONCLUSION

Our results indicate that replacing the CuW target witha carbon target in a clinical linear accelerator should resultin a multifold increase in the radiation dose enhancement totumor blood vessel endothelial cells when GNP is in closeproximity The resulting disruption of tumor vasculature canprovide a new therapeutic tool for clinical situations wherethe deliverable radiation dose is limited by adjacent normaltissue The concept of customizing photon spectra via a fast-switching target is a novel concept which could offer a furtherpersonalized solution for each unique clinical scenario

ACKNOWLEDGMENTS

This project was supported in part by a grant fromVarian Medical Systems Inc (JR) and the National CancerInstitute of the National Institutes of Health under AwardNos R03CA164645 and R21CA188833 (RIB) The contentis solely the responsibility of the authors and does notnecessarily represent the official views of the National CancerInstitute or the National Institutes of Health

a)Author to whom correspondence should be addressed Electronic mailrberbecopartnersorg

1D K Chatterjee T Wolfe J Lee A P Brown P K Singh S R BhattaraiP Diagaradjane and S Krishnan ldquoConvergence of nanotechnology withradiation therapy-insights and implications for clinical translationrdquo TranslCancer Res 2(4) 256ndash268 (2013)

2W Ngwa H Korideck A I Kassis R Kumar S Sridhar G M Makrigior-gos and R A Cormack ldquoIn vitro radiosensitization by gold nanoparticlesduring continuous low-dose-rate gamma irradiation with I-125 brachyther-apy seedsrdquo Nanomed Nanotechnol Biol Med 9(1) 25ndash27 (2013)

3M Garcia-Barros F Paris C Cordon-Cardo D Lyden S Rafii AHaimovitz-Friedman Z Fuks and R Kolesnick ldquoTumor response toradiotherapy regulated by endothelial cell apoptosisrdquo Science 300(5622)1155ndash1159 (2003)

4H J Park R J Griffin S Hui S H Levitt and C W Song ldquoRadiation-induced vascular damage in tumors Implications of vascular damage inablative hypofractionated radiotherapy (SBRT and SRS)rdquo Radiat Res177(3) 311ndash327 (2012)

5D W Siemann ldquoThe unique characteristics of tumor vasculature andpreclinical evidence for its selective disruption by tumor-vascular disruptingagentsrdquo Cancer Treat Rev 37(1) 63ndash74 (2011)

6P Carmeliet and R K Jain ldquoMolecular mechanisms and clinical applica-tions of angiogenesisrdquo Nature 473(7347) 298ndash307 (2011)

7J N Rich ldquoCancer stem cells in radiation resistancerdquo Cancer Res 67(19)8980ndash8984 (2007)

8T Reya S J Morrison M F Clarke and I L Weissman ldquoStem cellscancer and cancer stem cellsrdquo Nature 414(6859) 105ndash111 (2001)

9L E Ailles and I L Weissman ldquoCancer stem cells in solid tumorsrdquo CurrOpin Biotechnol 18(5) 460ndash466 (2007)

10H J Mauceri N N Hanna M A Beckett D H Gorski M J StabaK A Stellato K Bigelow R Heimann S Gately M Dhanabal G A SoffV P Sukhatme D W Kufe and R R Weichselbaum ldquoCombined effects ofangiostatin and ionizing radiation in antitumour therapyrdquo Nature 394(6690)287ndash291 (1998)

11D W Siemann D J Chaplin and M R Horsman ldquoVascular-targetingtherapies for treatment of malignant diseaserdquo Cancer 100(12) 2491ndash2499(2004)

12E A Murphy B K Majeti L A Barnes M Makale S M Weis KLutu-Fuga W Wrasidlo and D A Cheresh ldquoNanoparticle-mediated drugdelivery to tumor vasculature suppresses metastasisrdquo Proc Natl Acad SciU S A 105(27) 9343ndash9348 (2008)

13R I Berbeco W Ngwa and G M Makrigiorgos ldquoLocalized dose enhance-ment to tumor blood vessel endothelial cells via megavoltage x-rays andtargeted gold nanoparticles New potential for external beam radiotherapyrdquoInt J Radiat Oncol Biol Phys 81(1) 270ndash276 (2011)

14S D Perrault C Walkey T Jennings H C Fischer and W C W ChanldquoMediating tumor targeting efficiency of nanoparticles through designrdquoNano Lett 9(5) 1909ndash1915 (2009)

15F Van den Heuvel J P Locquet and S Nuyts ldquoBeam energy considerationsfor gold nano-particle enhanced radiation treatmentrdquo Phys Med Biol55(16) 4509ndash4520 (2010)

16S J McMahon W B Hyland M F Muir J A Coulter S Jain K TButterworth G Schettino G R Dickson A R Hounsell J M OrsquoSullivanK M Prise D G Hirst and F J Currell ldquoBiological consequences ofnanoscale energy deposition near irradiated heavy atom nanoparticlesrdquoSci Rep 1 18 (2011)

17M Douglass E Bezak and S Penfold ldquoMonte Carlo investigation of theincreased radiation deposition due to gold nanoparticles using kilovoltageand megavoltage photons in a 3D randomized cell modelrdquo Med Phys 40(7)071710 (9pp) (2013)

18P Tsiamas B Liu F Cifter W F Ngwa R I Berbeco C Kappas KTheodorou K Marcus M G Makrigiorgos E Sajo and P ZygmanskildquoImpact of beam quality on megavoltage radiotherapy treatment techniquesutilizing gold nanoparticles for dose enhancementrdquo Phys Med Biol 58(3)451ndash464 (2013)

19B L Jones S Krishnan and S H Cho ldquoEstimation of microscopic doseenhancement factor around gold nanoparticles by Monte Carlo calcula-tionsrdquo Med Phys 37(7) 3809ndash3816 (2010)

20S H Cho ldquoEstimation of tumour dose enhancement due to gold nanoparti-cles during typical radiation treatments A preliminary Monte Carlo studyrdquoPhys Med Biol 50(15) N163ndashN173 (2005)

21R Murata D W Siemann J Overgaard and M R Horsman ldquoImprovedtumor response by combining radiation and the vascular-damaging drug56-dimethylxanthenone-4-acetic acidrdquo Radiat Res 156(5) 503ndash509(2001)

22D W Siemann and A M Rojiani ldquoThe vascular disrupting agent ZD6126shows increased antitumor efficacy and enhanced radiation response inlarge advanced tumorsrdquo Int J Radiat Oncol Biol Phys 62(3) 846ndash853(2005)

23W R Wilson A E Li D S M Cowan and B G Siim ldquoEnhancement oftumor radiation response by the antivascular agent 56-dimethylxanthenone-4-acetic acidrdquo Int J Radiat Oncol Biol Phys 42(4) 905ndash908 (1998)

24D W Siemann and M R Horsman ldquoVascular targeted therapies inoncologyrdquo Cell Tissue Res 335(1) 241ndash248 (2009)

25D W Siemann E Mercer S Lepler and A M Rojiani ldquoVascular targetingagents enhance chemotherapeutic agent activities in solid tumor therapyrdquoInt J Cancer 99(1) 1ndash6 (2002)

26D B Chithrani S Jelveh F Jalali M van Prooijen C Allen R G BristowR P Hill and D A Jaffray ldquoGold nanoparticles as radiation sensitizers incancer therapyrdquo Radiat Res 173(6) 719ndash728 (2010)

27R I Berbeco H Korideck W Ngwa R Kumar J Patel S Sridhar SJohnson B Price A Kimmelman and G M Makrigiorgos ldquoDNA dam-age enhancement from gold nanoparticles for clinical MV photon beamsrdquoRadiat Res 178(6) 604ndash608 (2012)

Medical Physics Vol 43 No 1 January 2016

439 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 439

F 3 Photon energy spectra at depth= 2 10 and 20 cm for 6 MV deliverywith a standard flat beam (CuW target) a FFF (CuW target) beam and acarbon target beam Note the substantial increase in low energy photons at alldepths for the carbon target relative to the CuW target

of the relative improvement in EDEF is EDEFnew targetEDEFstandard flat(CuW)

3 RESULTS

The photon energy spectra calculated with the Monte Carlofor 6 MV standard (CuW) 6 MV FFF (CuW) and 6 MV(carbon) are shown in Fig 3 These spectra are generatedfor depths of 2 10 and 20 cm in tissue Figure 4 showsthe percentage of low energy photons (25ndash150 keV) for eachtarget and depth combination Relative to the 6 MV standard(CuW) beam the 6 MV FFF beam shows a substantialincrease in low energy photons for all depths At 10 cmdepth the 6 MV standard beam is composed of 8 lowenergy photons compared to 11 for the FFF beam The6 MV carbon target beam has a much larger proportion of lowenergy photons at all depths than either of the CuW beams(standard or FFF) At 10 cm depth the 6 MV carbon targetbeam is composed of 28 low energy photons This is nearlyfour times the low energy photon content of the standard 6MV beam and more than two and a half times that of the 6 MVFFF beam Of note the 6 MV carbon target beam becomesharder at greater depths whereas both 6 MV standard and FFFbeams become softer at greater depths in tissue

F 4 The percentage of low energy photons (25ndash150 keV) for a standard(CuW target) beam a FFF (CuW target) beam and a carbon target beam

F 5 The expected increase in the EDEF for 6 MV FFF (CuW) and 6 MV(carbon) respectively Results are shown relative to a 6 MV standard (CuW)beam At 10 cm depth the carbon target provides 77 times the EDEF

As expected from the Monte Carlo photon energy spectrumresults the relative improvement in EDEF for the carbon targetbeam is substantial at all depths The calculation of relativeincrease in EDEF is made independently for each depthcondition using the entire photon energy spectrum Figure 5shows the relative EDEF for the carbon target beam comparedto the 6 MV FFF beam At 2 cm depth the carbon target beamprovides 186 times the endothelial dose enhancement as a 6MV standard beam This reduces to 77 times at 10 cm depthand 40 times at 20 cm depth as the relative difference in theproportion of low energy photons decreases at the deepestdepths The 6 MV FFF beam would supply more than twiceas much endothelial dose at 2 cm decreasing to 15 times at20 cm depth

Due to the relative nature of the calculation in this paper thesize and concentration of the nanoparticles do not influencethe results In addition no assumptions have been made aboutcoating (eg PEG) or targeting (eg RGD)

The Monte Carlo data were also used to investigate theincrease in surface dose and loss of penetration depth forstandard and proposed beams The percent depth dose (PDD)curves for the 6 MV standard (CuW) 6 MV FFF (CuW)6 MV (carbon) normalized to deliver 100 dose at 10 cm

F 6 PDD for 6 MV standard (CuW) 6 MV FFF (CuW target) 6 MV(carbon) 25 MV (C) normalized to 100 at 10 cm depth

Medical Physics Vol 43 No 1 January 2016

440 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 440

F 7 Normalized percent skin dose as a function of number of parallelopposed treatment beams from different gantry angles A 25 MV (carbon)beam requires eight beam angles to limit the surface dose to the same levelas four beam angles of a 6 MV standard (CuW) beam (296) while stilldelivering 100 dose to the tumor

depth are shown in Fig 6 We define the surface dose as thecentral axis dose at 1 mm as a percentage of dmax

The loss of penetration depth and reduced skin sparingeffects of beams with more low energy photons contributeto higher entrance dose Beams of 6 MV FFF (CuW) and6 MV (carbon) contribute 21 and 52 more surface dosethan a standard flat 6 MV beam respectively HoweverFig 7 shows the reduction in surface dose by the use oftreatment plans consisting of multiple angles as are mostcommonly used clinically We simulated parallel opposedbeams to include both entrance and exit doses representinga worst-case scenario Cylindrical symmetry is assumed witha separation of 20 cm The normalization is 100 to apoint on the central axis at 10 cm depth To achieve thesame or less surface dose (296) as a 4-field standard flat6 MV delivery a 6 MV (carbon) beam requires five beams toreach the same level of skin sparing as a 4-field 6 MV standard

(CuW) delivery while still delivering 100 dose to the tumorat 10 cm depth In these figures we also show the results fora 25 MV (carbon) beam Currently used for imaging onlythis beam could have therapeutic use in the future

4 DISCUSSION

In this study it has been demonstrated that a 6 MV photonbeam generated using a clinical linear accelerator with acarbon target will provide a substantial increase in low energyphotons compared to conventional beams with a CuW targetThese additional low energy photons will translate into amultifold increase in endothelial dose enhancement whenincident upon gold nanoparticles in close proximity A fullstudy of 3D treatment planning with a 6 MV carbon targetbeam will be the subject of a future study

One potential application of this work is the use of afast-switching target (FST) to generate custom photon energyspectra Different clinical scenarios of gold nanoparticle-aidedradiation therapy will call for different mixes of lowhighenergy photon spectra This will depend on beam anglefield size patient thickness and proximity of normal tissuesdose fractionation and other clinical parameters Togglingbetween different targets during beam delivery will generate acustomized photon energy spectrum (Fig 8) The optimalspectrum can be determined prior to treatment deliverysimilar to the modulation of multileaf collimators in intensity-modulated radiation therapy

This study is focused on photon beams with a peak energyof 6 MV Lower energy beams with alternative targets couldoffer similar advantages in increased proportion of low energyphotons Some currently available linear accelerators are ableto deliver imaging beams of 25 MV using a low Z targetPreviously published studies have shown that 40ndash50 ofthe primary photons from a 25 MV (carbon) beam are inthe diagnostic range33 However these beam lines are notapproved for human radiation therapy and will also likely

F 8 Conventional delivery (left) is contrasted with FST delivery (middle and right) These drawings depict incoming 65 MeV electrons colliding with thelinear accelerator target generating photons for radiation therapy The resultant photon energy spectra for 10 cm depth in tissue are shown for each deliverymode respectively These spectra are shown in greater detail in Fig 3 (Left) Conventional (conv-CuW) delivery is shown with the standard CuW target anda flattening filter (Middle) FST delivery with only the high Z (FFF-CuW) target the flattening filter is removed (Right) FST delivery with only the low Z

(FFF-C) target the flattening filter is removed

Medical Physics Vol 43 No 1 January 2016

441 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 441

suffer from a low dose-rate An additional challenge willbe the balance of tumor coverage and skin sparing fordeep-seated tumors Simulated PDD and surface dosecalculations are shown in Figs 6 and 7 for comparisonwith the 6 MV beams

Collateral advantages of the fast-switching target researchinclude novel clinical imaging concepts We anticipate thatboth volumetric and planar imaging with the therapy beamwill be greatly improved by the target modifications presentedhere resulting in improved patient setup and beamrsquos-eye-viewin-treatment imaging3443ndash45 For example fast and periodicimaging of a lung tumor with a low Z target could be usedto update predictive models of respiratory motion withoutinterruption of the treatment delivery Previously publishedimaging work with low Z targets demonstrated a markedimprovement in image contrast using a 235 MV beam with acarbon target33

5 CONCLUSION

Our results indicate that replacing the CuW target witha carbon target in a clinical linear accelerator should resultin a multifold increase in the radiation dose enhancement totumor blood vessel endothelial cells when GNP is in closeproximity The resulting disruption of tumor vasculature canprovide a new therapeutic tool for clinical situations wherethe deliverable radiation dose is limited by adjacent normaltissue The concept of customizing photon spectra via a fast-switching target is a novel concept which could offer a furtherpersonalized solution for each unique clinical scenario

ACKNOWLEDGMENTS

This project was supported in part by a grant fromVarian Medical Systems Inc (JR) and the National CancerInstitute of the National Institutes of Health under AwardNos R03CA164645 and R21CA188833 (RIB) The contentis solely the responsibility of the authors and does notnecessarily represent the official views of the National CancerInstitute or the National Institutes of Health

a)Author to whom correspondence should be addressed Electronic mailrberbecopartnersorg

1D K Chatterjee T Wolfe J Lee A P Brown P K Singh S R BhattaraiP Diagaradjane and S Krishnan ldquoConvergence of nanotechnology withradiation therapy-insights and implications for clinical translationrdquo TranslCancer Res 2(4) 256ndash268 (2013)

2W Ngwa H Korideck A I Kassis R Kumar S Sridhar G M Makrigior-gos and R A Cormack ldquoIn vitro radiosensitization by gold nanoparticlesduring continuous low-dose-rate gamma irradiation with I-125 brachyther-apy seedsrdquo Nanomed Nanotechnol Biol Med 9(1) 25ndash27 (2013)

3M Garcia-Barros F Paris C Cordon-Cardo D Lyden S Rafii AHaimovitz-Friedman Z Fuks and R Kolesnick ldquoTumor response toradiotherapy regulated by endothelial cell apoptosisrdquo Science 300(5622)1155ndash1159 (2003)

4H J Park R J Griffin S Hui S H Levitt and C W Song ldquoRadiation-induced vascular damage in tumors Implications of vascular damage inablative hypofractionated radiotherapy (SBRT and SRS)rdquo Radiat Res177(3) 311ndash327 (2012)

5D W Siemann ldquoThe unique characteristics of tumor vasculature andpreclinical evidence for its selective disruption by tumor-vascular disruptingagentsrdquo Cancer Treat Rev 37(1) 63ndash74 (2011)

6P Carmeliet and R K Jain ldquoMolecular mechanisms and clinical applica-tions of angiogenesisrdquo Nature 473(7347) 298ndash307 (2011)

7J N Rich ldquoCancer stem cells in radiation resistancerdquo Cancer Res 67(19)8980ndash8984 (2007)

8T Reya S J Morrison M F Clarke and I L Weissman ldquoStem cellscancer and cancer stem cellsrdquo Nature 414(6859) 105ndash111 (2001)

9L E Ailles and I L Weissman ldquoCancer stem cells in solid tumorsrdquo CurrOpin Biotechnol 18(5) 460ndash466 (2007)

10H J Mauceri N N Hanna M A Beckett D H Gorski M J StabaK A Stellato K Bigelow R Heimann S Gately M Dhanabal G A SoffV P Sukhatme D W Kufe and R R Weichselbaum ldquoCombined effects ofangiostatin and ionizing radiation in antitumour therapyrdquo Nature 394(6690)287ndash291 (1998)

11D W Siemann D J Chaplin and M R Horsman ldquoVascular-targetingtherapies for treatment of malignant diseaserdquo Cancer 100(12) 2491ndash2499(2004)

12E A Murphy B K Majeti L A Barnes M Makale S M Weis KLutu-Fuga W Wrasidlo and D A Cheresh ldquoNanoparticle-mediated drugdelivery to tumor vasculature suppresses metastasisrdquo Proc Natl Acad SciU S A 105(27) 9343ndash9348 (2008)

13R I Berbeco W Ngwa and G M Makrigiorgos ldquoLocalized dose enhance-ment to tumor blood vessel endothelial cells via megavoltage x-rays andtargeted gold nanoparticles New potential for external beam radiotherapyrdquoInt J Radiat Oncol Biol Phys 81(1) 270ndash276 (2011)

14S D Perrault C Walkey T Jennings H C Fischer and W C W ChanldquoMediating tumor targeting efficiency of nanoparticles through designrdquoNano Lett 9(5) 1909ndash1915 (2009)

15F Van den Heuvel J P Locquet and S Nuyts ldquoBeam energy considerationsfor gold nano-particle enhanced radiation treatmentrdquo Phys Med Biol55(16) 4509ndash4520 (2010)

16S J McMahon W B Hyland M F Muir J A Coulter S Jain K TButterworth G Schettino G R Dickson A R Hounsell J M OrsquoSullivanK M Prise D G Hirst and F J Currell ldquoBiological consequences ofnanoscale energy deposition near irradiated heavy atom nanoparticlesrdquoSci Rep 1 18 (2011)

17M Douglass E Bezak and S Penfold ldquoMonte Carlo investigation of theincreased radiation deposition due to gold nanoparticles using kilovoltageand megavoltage photons in a 3D randomized cell modelrdquo Med Phys 40(7)071710 (9pp) (2013)

18P Tsiamas B Liu F Cifter W F Ngwa R I Berbeco C Kappas KTheodorou K Marcus M G Makrigiorgos E Sajo and P ZygmanskildquoImpact of beam quality on megavoltage radiotherapy treatment techniquesutilizing gold nanoparticles for dose enhancementrdquo Phys Med Biol 58(3)451ndash464 (2013)

19B L Jones S Krishnan and S H Cho ldquoEstimation of microscopic doseenhancement factor around gold nanoparticles by Monte Carlo calcula-tionsrdquo Med Phys 37(7) 3809ndash3816 (2010)

20S H Cho ldquoEstimation of tumour dose enhancement due to gold nanoparti-cles during typical radiation treatments A preliminary Monte Carlo studyrdquoPhys Med Biol 50(15) N163ndashN173 (2005)

21R Murata D W Siemann J Overgaard and M R Horsman ldquoImprovedtumor response by combining radiation and the vascular-damaging drug56-dimethylxanthenone-4-acetic acidrdquo Radiat Res 156(5) 503ndash509(2001)

22D W Siemann and A M Rojiani ldquoThe vascular disrupting agent ZD6126shows increased antitumor efficacy and enhanced radiation response inlarge advanced tumorsrdquo Int J Radiat Oncol Biol Phys 62(3) 846ndash853(2005)

23W R Wilson A E Li D S M Cowan and B G Siim ldquoEnhancement oftumor radiation response by the antivascular agent 56-dimethylxanthenone-4-acetic acidrdquo Int J Radiat Oncol Biol Phys 42(4) 905ndash908 (1998)

24D W Siemann and M R Horsman ldquoVascular targeted therapies inoncologyrdquo Cell Tissue Res 335(1) 241ndash248 (2009)

25D W Siemann E Mercer S Lepler and A M Rojiani ldquoVascular targetingagents enhance chemotherapeutic agent activities in solid tumor therapyrdquoInt J Cancer 99(1) 1ndash6 (2002)

26D B Chithrani S Jelveh F Jalali M van Prooijen C Allen R G BristowR P Hill and D A Jaffray ldquoGold nanoparticles as radiation sensitizers incancer therapyrdquo Radiat Res 173(6) 719ndash728 (2010)

27R I Berbeco H Korideck W Ngwa R Kumar J Patel S Sridhar SJohnson B Price A Kimmelman and G M Makrigiorgos ldquoDNA dam-age enhancement from gold nanoparticles for clinical MV photon beamsrdquoRadiat Res 178(6) 604ndash608 (2012)

Medical Physics Vol 43 No 1 January 2016

440 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 440

F 7 Normalized percent skin dose as a function of number of parallelopposed treatment beams from different gantry angles A 25 MV (carbon)beam requires eight beam angles to limit the surface dose to the same levelas four beam angles of a 6 MV standard (CuW) beam (296) while stilldelivering 100 dose to the tumor

depth are shown in Fig 6 We define the surface dose as thecentral axis dose at 1 mm as a percentage of dmax

The loss of penetration depth and reduced skin sparingeffects of beams with more low energy photons contributeto higher entrance dose Beams of 6 MV FFF (CuW) and6 MV (carbon) contribute 21 and 52 more surface dosethan a standard flat 6 MV beam respectively HoweverFig 7 shows the reduction in surface dose by the use oftreatment plans consisting of multiple angles as are mostcommonly used clinically We simulated parallel opposedbeams to include both entrance and exit doses representinga worst-case scenario Cylindrical symmetry is assumed witha separation of 20 cm The normalization is 100 to apoint on the central axis at 10 cm depth To achieve thesame or less surface dose (296) as a 4-field standard flat6 MV delivery a 6 MV (carbon) beam requires five beams toreach the same level of skin sparing as a 4-field 6 MV standard

(CuW) delivery while still delivering 100 dose to the tumorat 10 cm depth In these figures we also show the results fora 25 MV (carbon) beam Currently used for imaging onlythis beam could have therapeutic use in the future

4 DISCUSSION

In this study it has been demonstrated that a 6 MV photonbeam generated using a clinical linear accelerator with acarbon target will provide a substantial increase in low energyphotons compared to conventional beams with a CuW targetThese additional low energy photons will translate into amultifold increase in endothelial dose enhancement whenincident upon gold nanoparticles in close proximity A fullstudy of 3D treatment planning with a 6 MV carbon targetbeam will be the subject of a future study

One potential application of this work is the use of afast-switching target (FST) to generate custom photon energyspectra Different clinical scenarios of gold nanoparticle-aidedradiation therapy will call for different mixes of lowhighenergy photon spectra This will depend on beam anglefield size patient thickness and proximity of normal tissuesdose fractionation and other clinical parameters Togglingbetween different targets during beam delivery will generate acustomized photon energy spectrum (Fig 8) The optimalspectrum can be determined prior to treatment deliverysimilar to the modulation of multileaf collimators in intensity-modulated radiation therapy

This study is focused on photon beams with a peak energyof 6 MV Lower energy beams with alternative targets couldoffer similar advantages in increased proportion of low energyphotons Some currently available linear accelerators are ableto deliver imaging beams of 25 MV using a low Z targetPreviously published studies have shown that 40ndash50 ofthe primary photons from a 25 MV (carbon) beam are inthe diagnostic range33 However these beam lines are notapproved for human radiation therapy and will also likely

F 8 Conventional delivery (left) is contrasted with FST delivery (middle and right) These drawings depict incoming 65 MeV electrons colliding with thelinear accelerator target generating photons for radiation therapy The resultant photon energy spectra for 10 cm depth in tissue are shown for each deliverymode respectively These spectra are shown in greater detail in Fig 3 (Left) Conventional (conv-CuW) delivery is shown with the standard CuW target anda flattening filter (Middle) FST delivery with only the high Z (FFF-CuW) target the flattening filter is removed (Right) FST delivery with only the low Z

(FFF-C) target the flattening filter is removed

Medical Physics Vol 43 No 1 January 2016

441 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 441

suffer from a low dose-rate An additional challenge willbe the balance of tumor coverage and skin sparing fordeep-seated tumors Simulated PDD and surface dosecalculations are shown in Figs 6 and 7 for comparisonwith the 6 MV beams

Collateral advantages of the fast-switching target researchinclude novel clinical imaging concepts We anticipate thatboth volumetric and planar imaging with the therapy beamwill be greatly improved by the target modifications presentedhere resulting in improved patient setup and beamrsquos-eye-viewin-treatment imaging3443ndash45 For example fast and periodicimaging of a lung tumor with a low Z target could be usedto update predictive models of respiratory motion withoutinterruption of the treatment delivery Previously publishedimaging work with low Z targets demonstrated a markedimprovement in image contrast using a 235 MV beam with acarbon target33

5 CONCLUSION

Our results indicate that replacing the CuW target witha carbon target in a clinical linear accelerator should resultin a multifold increase in the radiation dose enhancement totumor blood vessel endothelial cells when GNP is in closeproximity The resulting disruption of tumor vasculature canprovide a new therapeutic tool for clinical situations wherethe deliverable radiation dose is limited by adjacent normaltissue The concept of customizing photon spectra via a fast-switching target is a novel concept which could offer a furtherpersonalized solution for each unique clinical scenario

ACKNOWLEDGMENTS

This project was supported in part by a grant fromVarian Medical Systems Inc (JR) and the National CancerInstitute of the National Institutes of Health under AwardNos R03CA164645 and R21CA188833 (RIB) The contentis solely the responsibility of the authors and does notnecessarily represent the official views of the National CancerInstitute or the National Institutes of Health

a)Author to whom correspondence should be addressed Electronic mailrberbecopartnersorg

1D K Chatterjee T Wolfe J Lee A P Brown P K Singh S R BhattaraiP Diagaradjane and S Krishnan ldquoConvergence of nanotechnology withradiation therapy-insights and implications for clinical translationrdquo TranslCancer Res 2(4) 256ndash268 (2013)

2W Ngwa H Korideck A I Kassis R Kumar S Sridhar G M Makrigior-gos and R A Cormack ldquoIn vitro radiosensitization by gold nanoparticlesduring continuous low-dose-rate gamma irradiation with I-125 brachyther-apy seedsrdquo Nanomed Nanotechnol Biol Med 9(1) 25ndash27 (2013)

3M Garcia-Barros F Paris C Cordon-Cardo D Lyden S Rafii AHaimovitz-Friedman Z Fuks and R Kolesnick ldquoTumor response toradiotherapy regulated by endothelial cell apoptosisrdquo Science 300(5622)1155ndash1159 (2003)

4H J Park R J Griffin S Hui S H Levitt and C W Song ldquoRadiation-induced vascular damage in tumors Implications of vascular damage inablative hypofractionated radiotherapy (SBRT and SRS)rdquo Radiat Res177(3) 311ndash327 (2012)

5D W Siemann ldquoThe unique characteristics of tumor vasculature andpreclinical evidence for its selective disruption by tumor-vascular disruptingagentsrdquo Cancer Treat Rev 37(1) 63ndash74 (2011)

6P Carmeliet and R K Jain ldquoMolecular mechanisms and clinical applica-tions of angiogenesisrdquo Nature 473(7347) 298ndash307 (2011)

7J N Rich ldquoCancer stem cells in radiation resistancerdquo Cancer Res 67(19)8980ndash8984 (2007)

8T Reya S J Morrison M F Clarke and I L Weissman ldquoStem cellscancer and cancer stem cellsrdquo Nature 414(6859) 105ndash111 (2001)

9L E Ailles and I L Weissman ldquoCancer stem cells in solid tumorsrdquo CurrOpin Biotechnol 18(5) 460ndash466 (2007)

10H J Mauceri N N Hanna M A Beckett D H Gorski M J StabaK A Stellato K Bigelow R Heimann S Gately M Dhanabal G A SoffV P Sukhatme D W Kufe and R R Weichselbaum ldquoCombined effects ofangiostatin and ionizing radiation in antitumour therapyrdquo Nature 394(6690)287ndash291 (1998)

11D W Siemann D J Chaplin and M R Horsman ldquoVascular-targetingtherapies for treatment of malignant diseaserdquo Cancer 100(12) 2491ndash2499(2004)

12E A Murphy B K Majeti L A Barnes M Makale S M Weis KLutu-Fuga W Wrasidlo and D A Cheresh ldquoNanoparticle-mediated drugdelivery to tumor vasculature suppresses metastasisrdquo Proc Natl Acad SciU S A 105(27) 9343ndash9348 (2008)

13R I Berbeco W Ngwa and G M Makrigiorgos ldquoLocalized dose enhance-ment to tumor blood vessel endothelial cells via megavoltage x-rays andtargeted gold nanoparticles New potential for external beam radiotherapyrdquoInt J Radiat Oncol Biol Phys 81(1) 270ndash276 (2011)

14S D Perrault C Walkey T Jennings H C Fischer and W C W ChanldquoMediating tumor targeting efficiency of nanoparticles through designrdquoNano Lett 9(5) 1909ndash1915 (2009)

15F Van den Heuvel J P Locquet and S Nuyts ldquoBeam energy considerationsfor gold nano-particle enhanced radiation treatmentrdquo Phys Med Biol55(16) 4509ndash4520 (2010)

16S J McMahon W B Hyland M F Muir J A Coulter S Jain K TButterworth G Schettino G R Dickson A R Hounsell J M OrsquoSullivanK M Prise D G Hirst and F J Currell ldquoBiological consequences ofnanoscale energy deposition near irradiated heavy atom nanoparticlesrdquoSci Rep 1 18 (2011)

17M Douglass E Bezak and S Penfold ldquoMonte Carlo investigation of theincreased radiation deposition due to gold nanoparticles using kilovoltageand megavoltage photons in a 3D randomized cell modelrdquo Med Phys 40(7)071710 (9pp) (2013)

18P Tsiamas B Liu F Cifter W F Ngwa R I Berbeco C Kappas KTheodorou K Marcus M G Makrigiorgos E Sajo and P ZygmanskildquoImpact of beam quality on megavoltage radiotherapy treatment techniquesutilizing gold nanoparticles for dose enhancementrdquo Phys Med Biol 58(3)451ndash464 (2013)

19B L Jones S Krishnan and S H Cho ldquoEstimation of microscopic doseenhancement factor around gold nanoparticles by Monte Carlo calcula-tionsrdquo Med Phys 37(7) 3809ndash3816 (2010)

20S H Cho ldquoEstimation of tumour dose enhancement due to gold nanoparti-cles during typical radiation treatments A preliminary Monte Carlo studyrdquoPhys Med Biol 50(15) N163ndashN173 (2005)

21R Murata D W Siemann J Overgaard and M R Horsman ldquoImprovedtumor response by combining radiation and the vascular-damaging drug56-dimethylxanthenone-4-acetic acidrdquo Radiat Res 156(5) 503ndash509(2001)

22D W Siemann and A M Rojiani ldquoThe vascular disrupting agent ZD6126shows increased antitumor efficacy and enhanced radiation response inlarge advanced tumorsrdquo Int J Radiat Oncol Biol Phys 62(3) 846ndash853(2005)

23W R Wilson A E Li D S M Cowan and B G Siim ldquoEnhancement oftumor radiation response by the antivascular agent 56-dimethylxanthenone-4-acetic acidrdquo Int J Radiat Oncol Biol Phys 42(4) 905ndash908 (1998)

24D W Siemann and M R Horsman ldquoVascular targeted therapies inoncologyrdquo Cell Tissue Res 335(1) 241ndash248 (2009)

25D W Siemann E Mercer S Lepler and A M Rojiani ldquoVascular targetingagents enhance chemotherapeutic agent activities in solid tumor therapyrdquoInt J Cancer 99(1) 1ndash6 (2002)

26D B Chithrani S Jelveh F Jalali M van Prooijen C Allen R G BristowR P Hill and D A Jaffray ldquoGold nanoparticles as radiation sensitizers incancer therapyrdquo Radiat Res 173(6) 719ndash728 (2010)

27R I Berbeco H Korideck W Ngwa R Kumar J Patel S Sridhar SJohnson B Price A Kimmelman and G M Makrigiorgos ldquoDNA dam-age enhancement from gold nanoparticles for clinical MV photon beamsrdquoRadiat Res 178(6) 604ndash608 (2012)

Medical Physics Vol 43 No 1 January 2016

441 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 441

suffer from a low dose-rate An additional challenge willbe the balance of tumor coverage and skin sparing fordeep-seated tumors Simulated PDD and surface dosecalculations are shown in Figs 6 and 7 for comparisonwith the 6 MV beams

Collateral advantages of the fast-switching target researchinclude novel clinical imaging concepts We anticipate thatboth volumetric and planar imaging with the therapy beamwill be greatly improved by the target modifications presentedhere resulting in improved patient setup and beamrsquos-eye-viewin-treatment imaging3443ndash45 For example fast and periodicimaging of a lung tumor with a low Z target could be usedto update predictive models of respiratory motion withoutinterruption of the treatment delivery Previously publishedimaging work with low Z targets demonstrated a markedimprovement in image contrast using a 235 MV beam with acarbon target33

5 CONCLUSION

Our results indicate that replacing the CuW target witha carbon target in a clinical linear accelerator should resultin a multifold increase in the radiation dose enhancement totumor blood vessel endothelial cells when GNP is in closeproximity The resulting disruption of tumor vasculature canprovide a new therapeutic tool for clinical situations wherethe deliverable radiation dose is limited by adjacent normaltissue The concept of customizing photon spectra via a fast-switching target is a novel concept which could offer a furtherpersonalized solution for each unique clinical scenario

ACKNOWLEDGMENTS

This project was supported in part by a grant fromVarian Medical Systems Inc (JR) and the National CancerInstitute of the National Institutes of Health under AwardNos R03CA164645 and R21CA188833 (RIB) The contentis solely the responsibility of the authors and does notnecessarily represent the official views of the National CancerInstitute or the National Institutes of Health

a)Author to whom correspondence should be addressed Electronic mailrberbecopartnersorg

1D K Chatterjee T Wolfe J Lee A P Brown P K Singh S R BhattaraiP Diagaradjane and S Krishnan ldquoConvergence of nanotechnology withradiation therapy-insights and implications for clinical translationrdquo TranslCancer Res 2(4) 256ndash268 (2013)

2W Ngwa H Korideck A I Kassis R Kumar S Sridhar G M Makrigior-gos and R A Cormack ldquoIn vitro radiosensitization by gold nanoparticlesduring continuous low-dose-rate gamma irradiation with I-125 brachyther-apy seedsrdquo Nanomed Nanotechnol Biol Med 9(1) 25ndash27 (2013)

3M Garcia-Barros F Paris C Cordon-Cardo D Lyden S Rafii AHaimovitz-Friedman Z Fuks and R Kolesnick ldquoTumor response toradiotherapy regulated by endothelial cell apoptosisrdquo Science 300(5622)1155ndash1159 (2003)

4H J Park R J Griffin S Hui S H Levitt and C W Song ldquoRadiation-induced vascular damage in tumors Implications of vascular damage inablative hypofractionated radiotherapy (SBRT and SRS)rdquo Radiat Res177(3) 311ndash327 (2012)

5D W Siemann ldquoThe unique characteristics of tumor vasculature andpreclinical evidence for its selective disruption by tumor-vascular disruptingagentsrdquo Cancer Treat Rev 37(1) 63ndash74 (2011)

6P Carmeliet and R K Jain ldquoMolecular mechanisms and clinical applica-tions of angiogenesisrdquo Nature 473(7347) 298ndash307 (2011)

7J N Rich ldquoCancer stem cells in radiation resistancerdquo Cancer Res 67(19)8980ndash8984 (2007)

8T Reya S J Morrison M F Clarke and I L Weissman ldquoStem cellscancer and cancer stem cellsrdquo Nature 414(6859) 105ndash111 (2001)

9L E Ailles and I L Weissman ldquoCancer stem cells in solid tumorsrdquo CurrOpin Biotechnol 18(5) 460ndash466 (2007)

10H J Mauceri N N Hanna M A Beckett D H Gorski M J StabaK A Stellato K Bigelow R Heimann S Gately M Dhanabal G A SoffV P Sukhatme D W Kufe and R R Weichselbaum ldquoCombined effects ofangiostatin and ionizing radiation in antitumour therapyrdquo Nature 394(6690)287ndash291 (1998)

11D W Siemann D J Chaplin and M R Horsman ldquoVascular-targetingtherapies for treatment of malignant diseaserdquo Cancer 100(12) 2491ndash2499(2004)

12E A Murphy B K Majeti L A Barnes M Makale S M Weis KLutu-Fuga W Wrasidlo and D A Cheresh ldquoNanoparticle-mediated drugdelivery to tumor vasculature suppresses metastasisrdquo Proc Natl Acad SciU S A 105(27) 9343ndash9348 (2008)

13R I Berbeco W Ngwa and G M Makrigiorgos ldquoLocalized dose enhance-ment to tumor blood vessel endothelial cells via megavoltage x-rays andtargeted gold nanoparticles New potential for external beam radiotherapyrdquoInt J Radiat Oncol Biol Phys 81(1) 270ndash276 (2011)

14S D Perrault C Walkey T Jennings H C Fischer and W C W ChanldquoMediating tumor targeting efficiency of nanoparticles through designrdquoNano Lett 9(5) 1909ndash1915 (2009)

15F Van den Heuvel J P Locquet and S Nuyts ldquoBeam energy considerationsfor gold nano-particle enhanced radiation treatmentrdquo Phys Med Biol55(16) 4509ndash4520 (2010)

16S J McMahon W B Hyland M F Muir J A Coulter S Jain K TButterworth G Schettino G R Dickson A R Hounsell J M OrsquoSullivanK M Prise D G Hirst and F J Currell ldquoBiological consequences ofnanoscale energy deposition near irradiated heavy atom nanoparticlesrdquoSci Rep 1 18 (2011)

17M Douglass E Bezak and S Penfold ldquoMonte Carlo investigation of theincreased radiation deposition due to gold nanoparticles using kilovoltageand megavoltage photons in a 3D randomized cell modelrdquo Med Phys 40(7)071710 (9pp) (2013)

18P Tsiamas B Liu F Cifter W F Ngwa R I Berbeco C Kappas KTheodorou K Marcus M G Makrigiorgos E Sajo and P ZygmanskildquoImpact of beam quality on megavoltage radiotherapy treatment techniquesutilizing gold nanoparticles for dose enhancementrdquo Phys Med Biol 58(3)451ndash464 (2013)

19B L Jones S Krishnan and S H Cho ldquoEstimation of microscopic doseenhancement factor around gold nanoparticles by Monte Carlo calcula-tionsrdquo Med Phys 37(7) 3809ndash3816 (2010)

20S H Cho ldquoEstimation of tumour dose enhancement due to gold nanoparti-cles during typical radiation treatments A preliminary Monte Carlo studyrdquoPhys Med Biol 50(15) N163ndashN173 (2005)

21R Murata D W Siemann J Overgaard and M R Horsman ldquoImprovedtumor response by combining radiation and the vascular-damaging drug56-dimethylxanthenone-4-acetic acidrdquo Radiat Res 156(5) 503ndash509(2001)

22D W Siemann and A M Rojiani ldquoThe vascular disrupting agent ZD6126shows increased antitumor efficacy and enhanced radiation response inlarge advanced tumorsrdquo Int J Radiat Oncol Biol Phys 62(3) 846ndash853(2005)

23W R Wilson A E Li D S M Cowan and B G Siim ldquoEnhancement oftumor radiation response by the antivascular agent 56-dimethylxanthenone-4-acetic acidrdquo Int J Radiat Oncol Biol Phys 42(4) 905ndash908 (1998)

24D W Siemann and M R Horsman ldquoVascular targeted therapies inoncologyrdquo Cell Tissue Res 335(1) 241ndash248 (2009)

25D W Siemann E Mercer S Lepler and A M Rojiani ldquoVascular targetingagents enhance chemotherapeutic agent activities in solid tumor therapyrdquoInt J Cancer 99(1) 1ndash6 (2002)

26D B Chithrani S Jelveh F Jalali M van Prooijen C Allen R G BristowR P Hill and D A Jaffray ldquoGold nanoparticles as radiation sensitizers incancer therapyrdquo Radiat Res 173(6) 719ndash728 (2010)

27R I Berbeco H Korideck W Ngwa R Kumar J Patel S Sridhar SJohnson B Price A Kimmelman and G M Makrigiorgos ldquoDNA dam-age enhancement from gold nanoparticles for clinical MV photon beamsrdquoRadiat Res 178(6) 604ndash608 (2012)

Medical Physics Vol 43 No 1 January 2016

442 Berbeco et al Low Z target tumor endothelial dose with gold nanoparticles 442

28S Jain J A Coulter A R Hounsell K T Butterworth S J McMahonW B Hyland M F Muir G R Dickson K M Prise F J CurrellJ M OrsquoSullivan and D G Hirst ldquoCell-specific radiosensitization by goldnanoparticles at megavoltage radiation energiesrdquo Int J Radiat OncolBiol Phys 79(2) 531ndash539 (2011)

29J F Hainfeld D N Slatkin and H M Smilowitz ldquoThe use of goldnanoparticles to enhance radiotherapy in micerdquo Phys Med Biol 49(18)N309ndashN315 (2004)

30D Y Joh L Sun M Stangl A Al Zaki S Murty P P SantoiemmaJ J Davis B C Baumann M Alonso-Basanta D Bhang G D KaoA Tsourkas and J F Dorsey ldquoSelective targeting of brain tumors withgold nanoparticle-induced radiosensitizationrdquo PLoS One 8(4) e62425(2013)

31S Kunjachan A Detappe R Kumar T Ireland L Cameron D E BiancurV Motto-Ros L Sancey S Sridhar G M Makrigiorgos and R I BerbecoldquoNanoparticle mediated tumor vascular disruption A novel strategy inradiation therapyrdquo Nano Lett 15(11) 7488ndash7496 (2015)

32D Parsons and J L Robar ldquoBeam generation and planar imaging at energiesbelow 240 MeV with carbon and aluminum linear accelerator targetsrdquo MedPhys 39(7) 4568ndash4578 (2012)

33D Parsons J L Robar and D Sawkey ldquoA Monte Carlo investigation oflow-Z target image quality generated in a linear accelerator using VarianrsquosVirtuaLinacrdquo Med Phys 41(2) 021719 (6pp) (2014)

34E J Orton and J Robar ldquoMegavoltage image contrast with low atomicnumber target materials and amorphous silicon electronic portal imagersrdquoPhys Med Biol 54 1275ndash1289 (2009)

35C Karzmark C Nunan and E Tanabe Medical Electron Accelerators(McGraw-Hill Inc Texas 1992)

36B Nordell and A Brahme ldquoAngular distribution and yield from brems-strahlung targets (for radiation therapy)rdquo Phys Med Biol 29(7) 797ndash810(1984)

37A Detappe P Tsiamas W Ngwa P Zygmanski M Makrigiorgos and RBerbeco ldquoThe effect of flattening filter free delivery on endothelial doseenhancement with gold nanoparticlesrdquo Med Phys 40(3) 031706 (4pp)(2013)

38NIST Database httpwwwnistgovsrdphysicshtml39A Cole ldquoAbsorption of 20-Ev to 50000-Ev electron beams in air and

plasticrdquo Radiat Res 38(1) 7ndash33 (1969)40P Tsiamas P Mishra F Cifter R I Berbeco K Marcus E Sajo and P

Zygmanski ldquoLow-Z linac targets for low-MV gold nanoparticle radiationtherapyrdquo Med Phys 41(2) 021701 (10pp) (2014)

41J L Robar S A Riccio and M A Martin ldquoTumour dose enhancementusing modified megavoltage photon beams and contrast mediardquo Phys MedBiol 47(14) 2433ndash2449 (2002)

42J Robar ldquoGeneration and modelling of megavoltage photon beams forcontrast-enhanced radiation therapyrdquo Phys Med Biol 51 5487ndash5504(2006)

43J Rottmann P Keall and R Berbeco ldquoReal-time soft tissue motion esti-mation for lung tumors during radiotherapy deliveryrdquo Med Phys 40(9)091713 (7pp) (2013)

44J Rottmann P J Keall and R I Berbeco ldquoMarkerless EPID image guideddynamic multileaf collimator tracking for lung tumorsrdquo Phys Med Biol58(12) 4195ndash4204 (2013)

45D Leary and J L Robar ldquoCBCT with specification of imaging dose andCNR by anatomical volume of interestrdquo Med Phys 41 011909 (7pp)(2014)

Medical Physics Vol 43 No 1 January 2016