In vivo imaging of glucose uptake and metabolism in tumors

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1 In vivo imging of glucose uptke nd metolism in tumors Simon Wlker-Smuel 1, Rjiv Rmswmy 1, Frncisco Torrelde 1,2, Mrilen Reg 2, Vineeth Rjkumr 3, S Peter Johnson 3, Simon Richrdson 1, Miguel Gonçlves 1, rold G Prkes 4, Erik Årstd 5, Dvid L Thoms 2, R Brr Pedley 3, Mrk F Lythgoe 1,6 & Xvier Goly 2,6 Tumors hve greter relince on neroic glycolysis for energy production thn norml tissues. We developed noninvsive method for imging glucose uptke in vivo tht is sed on mgnetic resonnce imging nd llows the uptke of unleled glucose to e mesured through the chemicl exchnge of protons etween hydroxyl groups nd wter. This method differs from existing moleculr imging methods ecuse it permits detection of the delivery nd uptke of metoliclly ctive compound in physiologicl quntities. We show tht our technique, nmed glucose chemicl exchnge sturtion trnsfer (glucocest), is sensitive to tumor glucose ccumultion in colorectl tumor models nd cn distinguish tumor types with differing metolic chrcteristics nd pthophysiologies. The results of this study suggest tht glucocest hs potentil s useful nd cost-effective method for chrcterizing disese nd ssessing response to therpy in the clinic. is the primry source of energy in most orgnisms, where it is used in oth eroic nd neroic respirtion. Impired or ltered glucose consumption is ssocited with rnge of pthologicl conditions, nd the ility to noninvsively ssess glucose uptke with [ 18 F]-fluorodeoxyglucose ([ 18 F]FDG) positron emission tomogrphy (FDG-PET) hs found wide clinicl utility over the lst 3 yers. ere we propose new wy of detecting glucose uptke nd metolism tht hs no relince on rdioleled glucose nlogs. Insted we use nturl, nonrdioctive glucose t physiologiclly resonle quntities, which we imge s it enters pthologicl tissues. ur technique is sed on mgnetic resonnce imging (MRI), which is stndrd imging modlity tht is ville in most lrge hospitls, nd it functions through mechnism known s chemicl exchnge sturtion trnsfer (CEST) 1. Tumors hve greter relince on neroic glycolysis for energy production thn norml tissues, phenomenon tht is known s the Wrurg effect. This key discrimintor of tumors from norml tissues hs een exploited s trget for nticncer therpy s well in the detection of metsttic disese y FDG-PET 2. The ility to proe tumor glucose uptke y MRI without the use of rdioctive trcers would offer sustntil cost reductions reltive to FDG-PET nd yet still provide importnt clinicl enefits. With this in mind, we imed to evlute the sensitivity of our technique (nmed glucocest 3,4 ) to detect glucose uptke in tumors nd compre it to stndrd mrkers of tumor metolism nd pthophysiology such s hypoxi nd lood flow. RESULTS Comprison of glucocest with [ 18 F]FDG utordiogrphy utilizes two properties of hydroxyl protons: first, when exposed to mgnetic field, the mgnetic moments of hydroxyl protons precess t different frequency s those of ulk tissue wter nd cn therefore e selectively leled using rdiofrequency pulses; second, hydroxyl nd wter protons undergo exchnge, therey llowing mgnetic leling to e trnsferred from glucose to wter nd for glucose to e detected from the chnge in wter signl in the MRI imges (Fig. 1) 1. The CEST technique thus provides n mplifiction of detection y using the very lrge wter signl rther thn relying on the much smller signl from glucose. ving determined in vitro tht glucose concentrtions of only few millimolr could e detected with glucocest (Supplementry Fig. 1), we imed to determine the potentil of glucocest in mesuring regionl glucose uptke in vivo. Thus we performed gluco- CEST imging experiment, the results of which we compred with those from [ 18 F]FDG utordiogrphy 24 h lter. We evluted two sucutneous humn colorectl tumor mouse xenogrft models, nd, which hve mrkedly different phenotypes 5. In CEST experiments, the effect of exchngele solute protons on the MRI wter signl is visulized using the symmetric mgnetiztion trnsfer rtio (MTR sym ) curve. We here define new prmeter, the glucocest enhncement (GCE), s the chnge in re under the MTR sym curve from the re under seline curve (Fig. 1). Bseline imges of the re under the MTR sym curve reflect the influence of endogenous exchngele protons 6, lipids 7 nd other exchnge processes on the wter signl. These contminting effects re removed y sutrcting the imges efore injection from those fter injection using the GCE prmeter. 1 University College London (UCL) Centre for Advnced Biomedicl Imging, Division of Medicine nd Institute of Child elth, London, UK. 2 UCL Institute of Neurology, London, UK. 3 UCL Cncer Institute, London, UK. 4 Cncer Reserch UK nd Engineering nd Physicl Sciences Reserch Council (EPSRC) Cncer Imging Centre, The Institute of Cncer Reserch nd Royl Mrsden Ntionl elth Service Foundtion Trust, Sutton, Surrey, UK. 5 Deprtment of Chemistry, UCL, London, UK. 6 These uthors jointly directed this work. Correspondence should e ddressed to S.W.-S. Received 22 Ferury 212; ccepted 26 ctoer 212; pulished online 7 July 213; doi:1.138/nm.3252 nture medicine dvnce online puliction

2 Figure 1 Schemtic digrm illustrting the principles underlying glucocest. () A simulted mgnetic resonnce frequency spectr with single glucose (hydroxyl group) nd wter pek (not to scle). nd wter pools with full equilirium mgnetiztion re irrdited with nrrow-ndwidth rdiofrequency pulse centered t the hydroxyl group resonnt frequency, which sturtes their mgnetiztion. Protons in hydroxyl groups then exchnge with wter protons, trnsferring their mgnetiztion nd reducing the signl tht cn e mesured. By continuously sturting the signl from wter through this exchnge process, therey further reducing the lrge wter signl, glucocest provides n mplifiction process for the glucose signl. () In CEST experiment, the wter signl is usully mesured s function of sturtion pulse frequency, which is known s the z spectrum. Simulted z spectr re shown here, with three hydroxyl group resonnces longside the symmetric mgnetiztion trnsfer rtio (MTR sym, which is the difference in signl on either side of the wter pek centered t p.p.m.). After glucose injection, the concentrtion of hydroxyl groups resonting t 1.2, 2.1 nd hydroxyl groups Wter We used grdient-echo CEST (GE-CEST) sequence to cquire imges from slice through the lrgest xil extent of ech tumor t seline nd t 6 min fter intrperitonel (i.p.) olus injection C 2 MTR sym Bseline z spectrum C Sturtion frequency (p.p.m.) Sturtion Nrrow ndwidth sturtion pulse hydroxyl groups Wter After glucose injection MTR sym z spectrum Sturtion frequency (p.p.m.) GCE of glucose. A comprison of lood glucose mesurements fter i.p. nd intrvenous (i.v.) injections, nd the susequent glucocest response, suggested tht the slow glucose kinetics fter i.p. injection re preferle to the rpid chnges fter i.v. injection, with n increse in lood glucose concentrtion of pproximtely 5 mm (Supplementry Fig. 2). Imges of glucose uptke from crosssection through mouse xenogrft reveled significntly greter GCE in tumors compred to muscle (.16 ±.4 (men ± s.e.m.) nd.4 ±.2%, respectively; P <.1) (Fig. 2). We returned the mice to their cges nd llowed them to recover for 24 h, fter which we dministered etween 1 nd 15 MBq of [ 18 F]FDG (Fig. 3). The medin ctivity t 6 min fter dministrtion ws significntly higher in thn tumors (P <.1). Similrly, we mesured significnt difference in the medin GCE etween the two tumor types nd sttisticlly significnt correltion etween the medin [ 18 F]FDG nd glucocest mesurements (r 2 =.7, P <.1). [ 18 F]FDG nd GCE imges, oth cquired t 6 min fter injection, lso showed similr regionl uptke (Fig. 4). C 2 hydroxyl groups Chemicl exchnge verly Wter Sturtion frequency (p.p.m.) 2.9 p.p.m. from wter increses, cusing n increse in the size of the hydroxyl peks in the MTR sym spectrum. The GCE is defined s the chnge in the re under the MTR sym curve from seline (for simplicity, only the effect of glucose nd not those of the metolic products of glycolysis re shown). Are under MTR sym Bseline 6 min enhncement (AU) cm M T 1 cm M T enhncement.8.4 Figure 2 In vivo glucocest dt from sucutneous tumor xenogrft models. () Exmple glucocest imge dt from four tumors showing the rw re under the MTR sym imges efore nd 6 min fter injection of 1.1 mmol per kg ody weight glucose solution. Imges from two types of humn colorectl tumor xenogrft models with differing vsculr nd cellulr phenotypes ( nd ) re shown. The seline imge contrst reflects vritions in wter content, endogenous exchngele protons, lipid signl nd conventionl mgnetiztion trnsfer effects. Also shown re the corresponding GCE imges, which show the chnge in MTR sym t 6 min fter glucose injection. AU, ritrry units. () GCE mps from cross-section through two mouse xenogrfts (), with rrows pointing to the tumor (T) nd prspinl muscle (M) regions. The color scle represents the mount of GCE, nd the underlying gryscle imges re for ntomicl reference; regions suject to motion during the cquisition (for exmple, the gut) hve een removed from the glucose imges for clrity. uptke in the tumor is visily higher thn in the muscle. All dt were cquired using the GE-CEST sequence. dvnce online puliction nture medicine

3 Medin GCE (%) c (medin GCE) * [ 18 F]FDG utordiogrphy (medin percentge of dose) Reltionship etween glucose uptke, perfusion nd hypoxi Composite fluorescence microscopy imges of perfusion nd hypoxi (using oechst nd pimonidzole stining, respectively) reveled tumors to e more uniformly perfused nd less hypoxic thn tumors (with 5% ± 3% (men ± s.d) nd 35% ± 12% hypoxi, respectively) (Fig. 4). We found no correltion etween the sptil distriutions of pimonidzole nd oechst stining (P >.5). A pixel-y-pixel comprison of [ 18 F]FDG nd pimonidzole uptke fter imge registrtion nd regridding reveled significnt correltion in tumors (P <.1) ut not in tumors. We found no correltion on pixel-y-pixel sis etween oechst nd FDG concentrtion for either of the two tumor types. Generlly, pixel-y-pixel comprisons of GCE nd histologicl imges were chllenging ecuse of nonliner deformtions occurring during tissue processing, so we insted compred the verges from whole-tumor sections. From this nlysis we found tht GCE nd pimonidzole uptke were correlted in tumors, lthough t lower level of sttisticl significnce (P <.5), nd we found no correltion in the verged signl from tumors. We found no correltion etween GCE nd oechst uptke in either tumor type. Comprtmentliztion of tumor glucocest mesurements To investigte the reltionship etween the delivery of glucose to tumor tissue nd its metolism y tumor cells, we performed glucocest experiment, which we followed immeditely with dynmic contrst-enhnced (DCE) MRI cquisition in which we monitored the uptke of olus of gdolinium-diethylenetrimine pentcette (Gd-DTPA, commonly used MRI contrst gent) with time s it ws delivered to the tumor (n = 4 tumors nd n = 4 tumors). Gd-DTPA is useful mrker of delivery, s fter systemic injection it extrvstes into tissue through gps in lood vessel wlls ut cnnot trverse cell memrnes. Thus, mesurement of the uptke of Gd-DTPA in tumor reflects the locl lood flow, vsculr permeility nd volume of the extrcellulr spce 8. Eqully, the mesured enhncement in glucocest experiment could reflect ech of these tissue properties, in ddition to n intrcellulr glucose frction, potentilly in metolized form (for exmple, s hexoses nd pentoses of the glycolytic pthwy). Comprison of DCE MRI re under the curve (AUC) imges with GCE imges showed some similrities etween the regionl uptke of Medin dose (%) d (medin GCE) [ 18 F]FDG utordiogrphy Gd-DTPA enhncement (medin re under enhncement curve, AU) * Figure 3 Comprison of glucocest with ex vivo [ 18 F]FDG utordiogrphy nd in vivo Gd-DTPA uptke. (,) Tumor glucose uptke mesured using glucocest () nd [ 18 F]FDG utordiogrphy () in two humn colorectl tumor xenogrft models ( nd ). The uptke of oth glucose nd FDG ws significntly different etween the two tumor types (*P <.1, Mnn-Whitney U test). The centrl rs in nd show the men vlue, the edges of the oxes represent the qurtile vlues, nd the whiskers show the upper nd lower rnges. (c) Sctter plot of medin tumor [ 18 F]FDG nd GCE showing significnt correltion (P <.1, Spermn s ρ). (d) Sctter plot of medin Gd-DTPA nd GCE, which re not significntly correlted (P >.5, Spermn s ρ). All CEST dt were cquired using the GE-CEST sequence. Gd-DTPA nd glucose (Supplementry Fig. 3), lthough the differences etween the two mesurements were rguly more pprent thn the similrities, nd we found no significnt correltion etween them (Fig. 3d; P >.5). In further group of tumors (n = 5 tumors nd n = 5 tumors), we dministered [U- 13 C]glucose i.p. t the sme dose s tht used in the glucocest experiments. At 6 min fter injection, we freeze clmped nd resected the tumors. We cquired 1 -decoupled 13 C nucler mgnetic resonnce (NMR) spectr of the queous phse seprted from ech tumor frgment (Fig. 5). We detected glucose nd glucose-6-phosphte from doulets in the C1α region of the 13 C spectr, with reltive chemicl shift of.13 p.p.m The reltive re of these peks gve rtio of leled glucose-6-phosphte to glucose of 42% ± 18% (men ± s.e.m.) nd 38% ± 21% in nd tumors, respectively. In phntoms, glucose nd glucose-6-phosphte produced similr z spectr, wheres fructose-6-phosphte nd fructose-6-iphosphte produced smller signls (Fig. 5 nd Supplementry Fig. 4). Also evident in the 13 C spectr were lctte nd mino cids, such s glutmine, glutmte, turine nd lnine, resulting from the glutmine synthesis pthwy. Notly, ech of these mino cids contins mide groups tht hve strong CEST effect in vitro from the exchnge etween mide protons nd wter (Fig. 5c). Conversely, lctte, which ws evident in the 13 C spectr, hs negligile CEST effect compred with tht of glucose, with in vitro mesurements reveling lctte re under the MTR sym curve of 4% tht of glucose. Similrly, in phntom experiments, the verge CEST effect from glutmine, glutmte, turine nd lnine ws 83% ± 5% tht found in glucose ut ws centered on single resonnce t 3.5 p.p.m., s compred with the three glucose resonnces, which were situted etween 1 p.p.m. nd 4 p.p.m. [ 18 F]FDG utordiogrphy Fluorescence microscopy 1 cm GCE Frction of dose (%) Blue: perfusion Green: hypoxi Figure 4 Exmple glucocest, [ 18 F]FDG utordiogrphy nd fluorescence microscopy imges otined from the sme tumor section (two nd two humn colorectl xenogrft models). The fluorescence microscopy imges show perfused (lue) nd hypoxic (green) regions corresponding to oechst nd pimonidzole stining, respectively. All CEST dt in this figure were cquired using the GE-CEST sequence. nture medicine dvnce online puliction

4 Figure 5 Results of [U- 13 C] NMR of tumor frgments nd in vitro z spectr of the sugrs nd mino cids identified from them. () Exmple 1 -decoupled 13 C NMR spectr from nd tumors tht were dministered [U- 13 C]glucose following the protocol used in the glucocest experiments. The pek ssignments re s follows: 1, lctte C2; 2, glutmte C2; 3, glutmine C2; 4, lnine C2; 5, turine C1; 6, turine C2; 7, glutmte C4; 8, lctte C3; nd 9, lnine C3. An expnsion of the C1α multiplet is shown tht corresponds to doulets from glucose nd glucose-6-phosphte (chemiclly shifted y.13 p.p.m. from the glucose doulet). Fitted Lorentzin peks re overlid. () z nd MTR sym spectr from glucose, glucose 6-phosphte, fructose 6-phosphte nd fructose 6,1-iphosphte. In vitro, glucose nd glucose-6-phosphte show similr CEST effects, wheres fructose-6-phosphte nd fructose 6,1-iphosphte show smller effect (Supplementry Fig. 4). Units on the verticl xis re signl intensity, S, normlized DISCUSSIN We present new technique nmed glucocest, which we used to detect the uptke of exogenously dministered, unleled glucose in tumors. Rised glucose uptke is hllmrk of solid tumors, nd its noninvsive ssessment would e of key importnce in the clinic, with potentil pplictions tht include tumor detection, monitoring tumor progression nd evluting response to therpy. Although we focused on tumors in this study, it is nticipted tht glucocest could find utility in other conditions, such s Alzheimer s disese or stroke. ur experiments reveled tht glucocest ws sufficiently sensitive to llow the detection of millimolr chnges in tumor hydroxyl group concentrtions fter injection. As glucocest mesures the chnge in signl from seline fter glucose injection, endogenous mounts of molecules with exchngele protons (of either mide or hydroxyl groups) do not contriute to the glucocest effect nd re ssumed to not ctlyze glucose-sed hydroxyl proton exchnge. owever, yproducts of glucose metolism fter intrcellulr uptke of the dministered glucose could contriute to the glucocest signl. We compred glucocest with [ 18 F]FDG utordiogrphy, which provides highly sensitive nd specific mesure of FDG uptke. Although FDG is n nlog of glucose with slightly differing phrmcokinetics 12, it provides the closest gold-stndrd technique for comprison. In ccordnce with the result from the glucocest experiments, [ 18 F]FDG utordiogrphy reveled significntly lower uptke of glucose in thn tumors, nd we oserved mrked sptil ccordnce etween the FDG nd glucose concentrtion mps. Moreover, the medin tumor GCE nd FDG uptke vlues were significntly correlted, therey providing vlidtion of the glucocest technique. These results lso help inform on the comprtmentliztion of the signl mesured using glucocest, s FDG cn only e metolized into its primry phosphorylted stte, t which point it ecomes trpped in the cell. Becuse of the vid ccumultion of glucose y tumor cells 13, mesurement t 6 min fter dministrtion proly contins sustntil proportion of FDG tht hs ccumulted in the intrcellulr comprtment 14, G6P Frequency (p.p.m.) Reltive intensity S/S (%) MTR sym (%) c Reltive intensity S/S (%) MTR sym (%) 13 C NMR spectroscopy of tumor frgments dministered [U- 13 C]glucose reveled the presence of leled glucose in oth tumor types, which could e either intrcellulr or extrcellulr in origin, longside mesurle quntities of glucose-6-phosphte. ur in vitro mesurements of the CEST effect cused y the first four moleculr species in the glycolytic pthwy show tht intrcellulr stges of glycolysis cn e detected with glucocest, with glucose-6-phosphte giving n pproximtely equl enhncement s glucose. The concentrtion of intrcellulr glucose hs een found previously to depend strongly on the concentrtion of extrcellulr glucose, with one study estimting the intrcellulr glucose concentrtion to e hlf of tht outside the cell 16. Similrly, reserchers from nother study 17 showed tht the concentrtion of intrcellulr glucose depends on the rte of glucose uptke nd metolism, which in turn depends on cell type, with intrcellulr glucose concentrtions rnging from very low (<.7 mm) to s high s those of extrcellulr glucose (>5 mm). Thus, lthough neither 13 C NMR nor glucocest cn distinguish etween intrcellulr nd extrcellulr free glucose, contriution y intrcellulr glucose to the glucocest signl is possile, nd n ttenution of the signl from extrcellulr glucose could occur s result of the lower p of the extrcellulr fluid. Indeed, from phntom mesurements (Supplementry Fig. 5), intrcellulr nd extrcellulr p vlues of 7.2 nd 6.9, respectively, could result in 16% lower signl from the extrcellulr comprtment per mole of glucose. These dt, together with the lck of sptil concordnce with Gd-DTPA enhnced mps, suggest tht glucocest does not simply report on vsculr delivery of glucose ut lso on cellulr uptke nd metolic ctivity. [U- 13 C]glucose NMR lso reveled the incorportion of glucose cron molecules into mino cids such s glycine, glutmine, turine nd lnine. Under the ssumption tht the presence of dditionl glucose cuses n increse in the concentrtion of these molecules, the lrge CEST effect ssocited with these molecules from mide proton exchnge (rther thn hydroxyl proton exchnge) 18,19 could provide phosphte Fructose 6-phosphte Fructose 6,1-iphosphte Frequency (p.p.m.) Alnine Glutmine Turine Glutmte Lctte Frequency (p.p.m.) to reference mesurement, S, t 2 p.p.m. from the pek of the wter resonnce. (c) z nd MTR sym spectr from glucose, lctte, glutmine, glutmte, lnine nd turine. shows strong CEST effect from hydroxyl proton exchnge, wheres the mino cids show CEST effect through mide proton exchnge. Lctte shows miniml effect. dvnce online puliction nture medicine

5 n lterntive intrcellulr contriution to the glucocest signl. It is conceivle tht the differing shpes of the z spectr ssocited with hydroxyl nd mide proton exchnge my llow these two phenomen to e modeled nd seprted in vivo, which would potentilly llow glycolysis nd glutmine synthesis nd metolism to e seprtely proed. Thus, the comined effects of (i) extended vsculr delivery of glucose, (ii) the presence of extrcellulr glucose, intrcellulr glucose nd phosphorylted sugrs in the glycolytic pthwy, (iii) increses in mino cid concentrtion from glutmine synthesis nd (iv) lower extrcellulr p led to the conclusion tht the source of the glucocest signl could e ttriuted to oth intrcellulr nd extrcellulr comprtments, which explins its ccordnce with [ 18 F]FDG utordiogrphy mesurements. We lso found correspondence with pimonidzole stining for hypoxi in tumors, which grees with previous mesurements in the sme model y uthors of previous study, who showed tht this correspondence ws due to the expression of the glucose trnsporters GLUT-1 nd GLUT-4 (ref. 2). We did not find this reltionship in tumors, which were much less hypoxic. It is lso importnt to note the lck of correltion etween either FDG or glucocest signl nd oechst stining ( mesure of perfusion), which would indicte tht the mesured glucocest signl is not limited y vsculr delivery, s lso rgued ove in reltion to Gd-DTPA uptke. This result is prticulrly relevnt, s the glucocest signl is potentilly sensitive to physiologicl chnges induced y hyperglycemi such s incresed lood flow nd decresed p. Additionl mesurements of oth properties fter glucose injection showed tht neither lood flow nor p chnged for the dose of glucose dministered (1.1 mmol per kg ody weight), therey confirming tht the oserved glucocest signl ws not cused y concomitnt effects due to hyperglycemi (defined s lood glucose concentrtion >2 mm (ref. 21)) (Supplementry Fig. 6). The mjor findings of this study re therefore tht glucocest hs the sensitivity to discriminte etween differing tumor phenotypes nd tht glucocest nd [ 18 F]FDG my e le to provide similr yet complimentry informtion. These conclusions hve strong implictions for the future utility of glucocest, s the ility to discriminte etween tumors of differing pthophysiologies would e of prticulr importnce for dignosis, prognosis nd potentilly ssessing response to therpy. Some chllenges ssocited with the clinicl trnsltion of glucocest remin to e overcome, such s the lower field strengths used in the clinic, which would reduce the chemicl shift etween glucose nd wter nd therey increse the colescence time, during which the chemicl exchnge rte would e fster thn the chemicl shift. owever, the effect of this difference on the glucocest signl is not strightforwrd to predict nd must e experimentlly evluted on clinicl systems. The potentil loss of contrst-to-noise rtio cused y lower field strengths my e compensted in prt y the dvnced, rpid imging technologies ville on clinicl scnners. Although no clinicl implementtions of ccelerted CEST cquisition schemes hve yet een reported, techniques such s echo-plnr imging, stedy-stte free precession nd fst-spin echo hve een used extensively in mgnetiztion trnsfer imging, which is closely relted technique, nd could e redily pplied to CEST mesurement Similrly, s glucocest relies on the mesurement of sufficient contrst etween signls from different selective sturtions, signl verging, in conjunction with rpid imging techniques, would enle such differences to e more esily discriminted within cliniclly cceptle exmintion time. If it is sufficiently sensitive, glucocest offers promising new tool for proing tumor glucose ccumultion nd metolism, which nturlly ligns with FDG-PET s n ovious cndidte for comprison. Although FDG-PET uses trce mounts of FDG, we hve shown tht the physiologicl concentrtions of glucose required for detection y glucocest re insufficient to produce ny mesurle chnges in p or lood flow. Scling the dose used in this study to 7-kg humn would correspond to 14 g of glucose, which is pproximtely the sme s found in hlf of stndrd-sized chocolte r. rl dministrtion could induce greter insulin response thn i.p. injection 25 ut would e esier to implement in the clinic thn i.v. injection nd would more closely mimic the slow enhncement protocol investigted in this study. A drinkle sugr solution could conceivly e ingested while person is in the scnner, which is similr to the technique used in stndrd glucose tolernce testing in ptients with dietes 26. This would enhnce ptient cceptnce, lthough period of fsting efore the scn my lso e required to stilize seline lood glucose concentrtions, s is commonly performed with rnge of medicl exmintions 27,28. could thus offer vile lterntive to FDG-PET, prticulrly s [ 18 F]FDG is expensive to mnufcture nd necessrily hs n ssocited rdition dose, which limits the ility to perform repeted, longitudinl mesurements nd cn prohiit exmintion of certin ptient popultions (such s young children or pregnnt women 27,28 ). Eqully, s glucocest uses unleled glucose to provide imge contrst, the logistics nd infrstructure necessry for the production nd delivery of [ 18 F]FDG re removed, therey simplifying the imging procedure. FDG-PET is generlly considered to e more expensive thn MRI 29,3, so glucocest could lso offer considerle finncil svings (lthough the estimted costs for the two modlities cn vry sustntilly from country to country 31 ). Furthermore, s the resolution of modern PET systems (typiclly of the order of mm 3 (ref. 32)) is much lower thn the resolution fforded y clinicl MRI scnners (typiclly round mm 3, which is fctor of 4 decrese in voxel size), glucocest could offer considerle improvements in sptil resolution over FDG-PET. Such improvements would llow for intrtumor heterogeneity to e more effectively proed nd smller tumor msses to e evluted, therey llowing erlier chrcteriztion of disese nd ssessment of response to therpy. Methods Methods nd ny ssocited references re ville in the online version of the pper. Note: Supplementry informtion is ville in the online version of the pper. Acknowledgments This work ws funded y King s College London nd UCL Comprehensive Cncer Imging Centre, nd The Institute of Cncer Reserch Cncer Imging Centre, Cncer Reserch UK nd EPSRC in ssocition with the Medicl Reserch Council (MRC), the Deprtment of elth (Englnd) (C16/A1334, C1519/A1331, C16412/A6269 nd C39/A8274) nd the British ert Foundtion nd ws supported y reserchers t the Ntionl Institute for elth Reserch UCL ospitl Biomedicl Reserch Centre. AUTR CNTRIBUTINS S.W.-S. designed nd performed experiments, nlyzed dt, developed the methodology nd wrote the pper. R.R. performed glucose til-vein mesurements, ssisted with in vivo experiments nd developed the rteril spin leling (ASL) post-processing softwre. F.T. nd M.R. performed most phntom experiments nd nlyzed dt. S.P.J. nd R.B.P. developed nd set up tumor xenogrft models. V.R. performed histology nd utordiogrphy mesurements nd nlyzed dt..g.p. performed 13 C NMR experiments. S.R. designed the espoke pprtus for in vivo imging. M.G. ssisted with in vivo experiments. D.L.T., E.A., R.B.P., nture medicine dvnce online puliction

6 X.G. nd M.F.L. gve conceptul dvice nd ssisted in the design of experiments. X.G. devised the initil glucocest concept nd experiment. X.G. nd M.F.L. jointly directed this reserch, helped perform experiments nd contriuted to the writing nd editing of this mnuscript. CMPETING FINANCIAL INTERESTS The uthors declre no competing finncil interests. Reprints nd permissions informtion is ville online t reprints/index.html. 1. Wrd, K.M. & Bln, R.S. Determintion of p using wter protons nd chemicl exchnge dependent sturtion trnsfer (CEST). Mgn. Reson. Med. 44, (2). 2. Kelloff, G.J. et l. Progress nd promise of FDG-PET imging for cncer ptient mngement nd oncologic drug development. Clin. Cncer Res. 11, (25). 3. Chn, K.W. et l. Imging of glucose uptke in rest tumors using non-leled d-glucose. Proceedings of the 19th Scientific Meeting, Interntionl Society for Mgnetic Resonnce in Medicine, 551 (Montrel, 211). 4. Wlker-Smuel, S., Johnson, S.P., Pedley, R.B., Lythgoe, M.F. & Goly, X. Assessment of tumour glucose uptke using gluco-cest. Proceedings of the 19th Scientific Meeting, Interntionl Society for Mgnetic Resonnce in Medicine, 182 (Montrel, 211). 5. El Emir, E. et l. Predicting response to rdioimmunotherpy from the tumor microenvironment of colorectl crcinoms. Cncer Res. 67, (27). 6. Zhou, J., Wilson, D.A., Sun, P.Z., Klus, J.A. & Vn Zijl, P.C. Quntittive description of proton exchnge processes etween wter nd endogenous nd exogenous gents for WEX, CEST, nd APT experiments. Mgn. Reson. Med. 51, (24). 7. Wlker-Smuel, S., Peter Johnson, S., Pedley, B., Lythgoe, M.F. & Goly, X. Extrcrnil mesurements of mide proton trnsfer using exchnge-modulted point-resolved spectroscopy (EXPRESS). NMR Biomed. 25, (212). 8. Wlker-Smuel, S., Lech, M.. & Collins, D.J. Evlution of response to tretment using DCE-MRI: the reltionship etween initil re under the gdolinium curve (IAUGC) nd quntittive phrmcokinetic nlysis. Phys. Med. Biol. 51, (26). 9. Uguril, K., Brown, T.R., den ollnder, J.A., Glynn, P. & Shulmn, R.G. ighresolution 13C nucler mgnetic resonnce studies of glucose metolism in Escherichi coli. Proc. Ntl. Acd. Sci. USA 75, (1978). 1. Klderon, B., Kormn, S.., Gutmn, A. & Lpidot, A. Estimtion of glucose cron recycling in children with glycogen storge disese: A 13C NMR study using [U-13C]glucose. Proc. Ntl. Acd. Sci. USA 86, (1989). 11. Künnecke, B., Kustermnn, E. & Seelig, J. Simultneous in vivo monitoring of heptic glucose nd glucose-6-phosphte y (13)C-NMR spectroscopy. Mgn. Reson. Med. 44, (2). 12. rihrn, R. et l. Fundmentl limittions of [18F]2-deoxy-2-fluoro-D-glucose for ssessing myocrdil glucose uptke. Circultion 91, (1995). 13. nhn, D. & Weinerg, R.A. The hllmrks of cncer. Cell 1, 57 7 (2). 14. Ery, J.F. & Mnkoff, D.A. Tumor metolic rtes in srcom using FDG PET. J. Nucl. Med. 39, (1998). 15. Zidi,. Quntittive Anlysis in Nucler Medicine Imging (Springer, 25). 16. Fehr, M., Llonde, S., Lger, I., Wolff, M.W. & Frommer, W.B. In vivo imging of the dynmics of glucose uptke in the cytosol of CS-7 cells y fluorescent nnosensors. J. Biol. Chem. 278, (23). 17. John, S.A., ttoli, M., Weiss, J.N. & Rilet, B. Dynmic modultion of intrcellulr glucose imged in single cells using FRET-sed glucose nnosensor. Pflugers Arch. 456, (28). 18. Zhou, J., Ll, B., Wilson, D.A., Lterr, J. & vn Zijl, P.C. Amide proton trnsfer (APT) contrst for imging of rin tumors. Mgn. Reson. Med. 5, (23). 19. Zhou, J., Pyen, J.F., Wilson, D.A., Trystmn, R.J. & vn Zijl, P.C. Using the mide proton signls of intrcellulr proteins nd peptides to detect p effects in MRI. Nt. Med. 9, (23). 2. Derling, J.L. et l. Anlysis of the regionl uptke of rdioleled deoxyglucose nlogs in humn tumor xenogrfts. J. Nucl. Med. 45, (24). 21. Wlker-Smuel, S. et l. Improving pprent diffusion coefficient estimtes nd elucidting tumour heterogeneity using Byesin dptive smoothing. Mgn. Reson. Med. 65, (211). 22. Gloor, M., Scheffler, K. & Bieri,. Intrscnner nd interscnner vriility of mgnetiztion trnsfer-sensitized lnced stedy-stte free precession imging. Mgn. Reson. Med. 65, (211). 23. Rnjev, J.P., Frnconi, J.M., Mnelfe, C. & Berry, I. Mgnetiztion trnsfer with echo plnr imging. MAGMA 5, (1997). 24. Tyler, D.J. & Gowlnd, P.A. Rpid quntittion of mgnetiztion trnsfer using pulsed off-resonnce irrdition nd echo plnr imging. Mgn. Reson. Med. 53, (25). 25. Andrikopoulos, S., Blir, A.R., Deluc, N., Fm, B.C. & Proietto, J. Evluting the glucose tolernce test in mice. Am. J. Physiol. Endocrinol. Met. 295, E1323 E1332 (28). 26. Alerti, K.G. & Zimmet, P.Z. Definition, dignosis nd clssifiction of dietes mellitus nd its complictions. Prt 1: dignosis nd clssifiction of dietes mellitus provisionl report of W consulttion. Diet. Med. 15, (1998). 27. Deleke, D. et l. Procedure guideline for tumor imging with 18F-FDG PET/CT 1.. J. Nucl. Med. 47, (26). 28. Prker, J.A., Yester, M.V., Due-Witherspoon, E., Todd-Pokropek, A.E. & Royl,.J. Procedure guideline for generl imging: 1.. Society of Nucler Medicine. J. Nucl. Med. 37, (1996). 29. Shortt, C.P. et l. Whole-ody MRI versus PET in ssessment of multiple myelom disese ctivity. AJR Am. J. Roentgenol. 192, (29). 3. Plthow, C. et l. [Cost considertions for whole-ody MRI nd PET/CT s prt of oncologic stging] Rdiologe 48, (28). 31. Antoch, G. et l. Whole-ody dul-modlity PET/CT nd whole-ody MRI for tumor stging in oncology. J. Am. Med. Assoc. 29, (23). 32. Vllhjosul, S. Moleculr Imging: Rdiophrmceuticls for PET nd SPECT (Springer, London, 29). dvnce online puliction nture medicine

7 NLINE METDS Tumor models. All in vivo experiments were performed in ccordnce with the UK ome ffice Animls Scientific Procedures Act, 1986 nd United Kingdom Coordinting Committee on Cncer Reserch (UKCCCR) guidelines 33. Five-million or humn colorectl crcinom cells were injected sucutneously into the right flnk of femle MF1 nu/nu mice using 27G needle nd llowed to grow for 1 16 d. MRI experiments. We cquired ll MRI dt using horizontlore 9.4 T VNMRS system (Agilent, xford, UK). Before imging, mice were fsted for 24 h nd nesthetized in n induction ox using 3% isoflurne in oxygen followed y 1.5% oxygen through nose cone during MRI. Core ody temperture ws monitored nd mintined using physiologicl monitoring pprtus nd wrm ir lower. A solution of glucose ws prepred in sline t concentrtion of 14 mm, nd.2 ml ws dministered either s olus, i.v. through til vein or i.p. using nonmetllic peditric cnnul nd line running through the MRI scnner. Tumors were loclized using T2-weighted fst-spin echo sequence (Supplementry Methods), from which we defined slice through the lrgest extent of the tumor to use in susequent imging mesurements. dt were cquired using either GE-CEST imging sequence or n exchngemodulted point resolved spectroscopy (EXPRESS) sequence for single-voxel (whole-tumor) mesurements 34. In the GE-CEST cquisition, lines from ech imge were cquired in liner order such tht for 128 phse-encoding steps, 1 sturtion pulses were pplied within the outer third of the k spce, enling stedy stte to e reched (Supplementry Fig. 7). Dt postprocessing involved the conversion of signl-intensity dt to the symmetric mgnetiztion trnsfer (MTR sym ) nd the GCE, which ws defined s the chnge in the re under the MTR sym curve etween.75 nd 4 p.p.m. ASL. We cquired ASL dt using FAIR Look-Locker sequence with singleslice spoiled grdient echo redout 35. Perfusion mps were clculted 36 y ssuming lood-prtition constnt of.9 nd longitudinl relxtion time of lood of 1,9 ms 37. Dynmic contrst-enhnced MRI. Mice were dministered 5 mm solution of Gd-DTPA (Mgnevist, Schering, Berlin) in sline s olus i.p. (.2 mmol per kg ody weight). Before injection, we estimted the seline longitudinl relxtion rte y fitting three-prmeter model to the multiple-inversion recovery Look-Locker dt. Grdient-echo imge dt were cquired for 5 min to mesure the seline signl intensity nd then for nother 6 min fter injection of the contrst gent. The AUC for gdolinium ws then clculted. [ 18 F]FDG utordiogrphy. Between 1 nd 15 MBq of [ 18 F]FDG ws dministered i.p. in.3 ml of sline. The [ 18 F]FDG ws llowed to circulte for 6 min to mirror the conditions in the glucocest experiments, t which point tumors were rpidly excised. We mintined the orienttion of the tumors, nd fter excision the tumors were snp frozen using liquid nitrogen cooled isopentne nd cut in hlf long the longest xil dimeter corresponding to the MRI imging slice. Stndrd curves for the quntifiction of [ 18 F]FDG ctivity were produced y spotting seril dilutions of the dministered dose (1%,.1%,.1% or.1%). [U- 13 C]glucose NMR spectroscopy of tumor frgments. [U- 13 C]glucose (Sigm-Aldrich, Gillinghm, UK) ws dministered i.p. to mice following the in vivo glucocest protocol on the enchtop. At 6 min fter injection, tumors were freeze clmped, resected nd stored t 8 C. Smples were seprted into the queous nd orgnic phses (Supplementry Methods) nd freeze dried, nd 1 -decoupled 13 C NMR spectr of the queous phse were cquired using 5 Mz Bruker DRX spectrometer (Bruker, Krlsruhe, Germny). 13 C free-induction decys were processed with 3-z line rodening efore Fourier trnsform. Spectr were nlyzed using MestReC (Mestrel, Sntigo de Compostel, Spin) nd in-house softwre written in the Interctive Dt Lnguge (IDL, Boulder, Cliforni) to fit multiple Lorentzin lineshpes. Immunofluorescence nd histochemicl nlyses. Pimonidzole ws dministered i.p. (6 mg per kg ody weight) nd llowed to circulte for 3 min efore the mice were euthnized to mesure tumor hypoxi with fluorescence microscopy. oechst ws dministered i.v. (1 mg per kg ody weight) nd llowed to circulte for 3 min efore tumors were rpidly resected nd cut in hlf. ne hlf ws snp frozen in isopentne cooled with liquid nitrogen, nd the other hlf ws fixed in formldehyde. Frozen tumor tissue ws sectioned t 1 µm with the tumor orienttion mintined for comprison with the MRI scns. Sections were viewed using n Axioimger microscope (Crl Zeiss, UK) t 1 mgnifiction. Perfusion ws viewed using ultrviolet filter (365-nm excittion), nd hypoxi ws viewed using FITC filter (45- to 49-nm excittion). The percentges of tumor hypoxi nd perfusion were quntified y defining the utofluoresence thresholds 38,39. Sttisticl nlyses. Mnn-Whitney U test ws used throughout to ssess differences in the mgnitudes of smples from two mesurements; Spermn s ρ ws used to ssess correltion. P <.5 ws tken to imply significnce. Additionl methods. Detiled methodology is descried in the Supplementry Methods. 33. Workmn, P. et l. Guidelines for the welfre nd use of nimls in cncer reserch. Br. J. Cncer 12, (21). 34. Wlker-Smuel, S., Johnson, S.P., Pedley, B., Lythgoe, M.F. & Goly, X. Extrcrnil mesurements of mide proton trnsfer using exchnge-modulted point-resolved spectroscopy (EXPRESS). NMR Biomed. 25, (212). 35. Cmpell-Wshurn, A.E. et l. Crdic rteril spin leling using segmented ECG-gted Look-Locker FAIR: vriility nd repetility in preclinicl studies. Mgn. Reson. Med. 69, (213). 36. Belle, V. et l. In vivo quntittive mpping of crdic perfusion in rts using noninvsive MR spin-leling method. J. Mgn. Reson. Imging 8, (1998). 37. Cmpell, A.E. et l. Equilirium contrst CMR for the detection of myloidosis in mice. J. Crdiovsc. Mgn. Reson. 13 (suppl. 1), 6 (211). 38. Wlker-Smuel, S. et l. Non-invsive in vivo imging of vessel clire in orthotopic prostte tumour xenogrfts. Int. J. Cncer 13, (212). 39. Burrell, J.S. et l. Investigting temporl fluctutions in tumor vsculture with comined crogen nd ultrsmll superprmgnetic iron oxide prticle (CUSPI) imging. Mgn. Reson. Med. 66, (211). doi:1.138/nm.3252 nture medicine

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