Journal of Cellular Biochemistry 90:502–508 (2003)

Tunable, Monochromatic X-Rays: An EnablingTechnology for Molecular/Cellular Imaging and Therapy

Frank Carroll*

Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37235-2675

Abstract Pulsed, tunable, monochromatic X-rays hold great potential as a cellular and molecular probe. Thesebeams can be tuned to the binding energy of orbital electrons in atoms, making them extremely useful in diagnostic k-edgeimaging and Auger cascade radiotherapy. Their wide tunability makes them ideal for the performance of varioustechniques as disparate as protein crystallography and three-dimensional, compressionless, monochromatic mammo-graphy. Since only the frequency best suited to the task at hand is used, radiation exposure to patients or animals is ex-ceedingly low when compared to standard X-ray techniques. J. Cell. Biochem. 90: 502–508, 2003. � 2003 Wiley-Liss, Inc.

Key words: monochromatic X-rays; k-edge; Auger cascade; crystallography; mammography

In the 108 years since Roentgen’s discovery ofX-rays, use of these beams in the diagnostic andtherapeutic arenas has developed into a fine art.One has only to think of multislice ComputedTomography (CT) with three-dimensional re-construction used everyday in most hospitals toconfirm this. However, such modalities still relyon ‘‘brute force’’ X-ray production in tubes thatrely on converting 99% of their energy into heatand the remaining 1% into braking radiation(Brehmstralung) to produce ‘‘white’’/polychro-matic X-rays.These,unfortunately,deliverhighradiation doses to the patient and create signi-ficant scatter as they penetrate the tissues.These ‘‘white X-rays’’ are similar, in many re-spects, to the admixture of many different visi-ble colors from a standard light bulb, perceivedas white light by the eye.

The invention of lasers with their intensenarrow bandwidth emissions has led to a re-volution in the ways that we use light in oureveryday lives to analyze and cut materials,

store and display data, transmit information,perform surgery, and so on.

In like manner, development of the methodol-ogy to produce intense beams of tunable, narrowbandwidth X-rays from a compact source couldact as an enabling force that would open newdoors in diagnostic imaging, therapeutics, andbiomedical research.

To that end, a development project begun in1987 at the Vanderbilt University Medical FreeElectron Laser (MFEL) Center sought to pro-duce such X-ray beams using the phenomenonof Inverse Compton Scattering (Fig. 1). Late in1998, our group was successful in producingpulsed, tunable, monochromatic X-rays usingthe free electron laser as a source of both high-energy electrons and intense infrared (IR) laserlight. Focusing these two beams to a diameter of100 microns and colliding them head-on yieldedtunable, monochromatic X-rays in the 14–18 keV range [Carroll et al., 1990, 1999].

However, for use in a clinical or research set-ting, even this technique left much to be desired.The FEL, for example, is approximately 30 mlong, and creates an exceptionally intenseradiation environment while running, necessi-tating its installation in a heavily shielded vaultconsisting of over 2 m of concrete. Since theoriginal monochromatic X-ray beamline yieldedonly about 176 X-ray photons/3 ps micropulseof electrons, creation of a useful beam for imag-ing required millions of electron pulses. Inaddition, this technique mandated deflection

� 2003 Wiley-Liss, Inc.

*Correspondence to: Frank Carroll, MD, Department ofRadiology and Radiological Sciences, Vanderbilt UniversityMedical Center, 1221 21st Avenue South, Nashville, TN37232-2675. E-mail: frank.carroll@vanderbilt.edu

Received 24 June 2003; Accepted 25 June 2003

DOI 10.1002/jcb.10632

of the X-rays off of mosaic pyrolytic graphitecrystals at a large angle to bring them to ashirtsleeves environment where they could beused on a patient, animal, or sample. Over 95%of the X-ray flux produced was lost in thisfashion. As the electron beam was optimized formaximal X-ray production, IR photon outputspiraled downward hampering FEL perfor-mance. It was obvious that a new design wasneeded.

In April 2001, after 2 years of design andengineering, a new prototype device was com-pleted and commissioned at the MFEL Centerbut used a configuration that was not that of anFEL. This machine uses a linear acceleratoroperating in what we call the ‘‘single pulse’’mode and a tabletop terawatt IR laser to providethe counter propagated beams. It delivers 1010

X-ray photons/8 ps pulse throughout its tunable12–50 keV range at anywhere from a 1–10%bandwidth in a conebeam area geometry. Asingle electron pulse is accelerated when theterawatt laser fires, allowing operation of theentire machine in a shirtsleeves environmentcontaining unbadged personnel. This machinehas been operational for 1½ years and is used formonochromatic imaging of phantoms and mice,and for feasibility studies and applicationsresearch [Carroll et al., 2003]. The versatilityof the monochromatic X-rays produced hasunlocked a treasure chest of possibilities inmolecular imaging and cellular manipulation.Among these are k-edge imaging, Auger cascade

radiotherapy, and monochromatic 3-D compres-sionless mammography to name a few.

k-EDGE IMAGING

The manner in which an X-ray beam interactswith matter, of course, depends upon thechemical composition of the matter. In complextissues, such interactions are weighted propor-tionally toward heavier or lighter elements.Although the body is predominantly made up ofhydrogen, oxygen, carbon, and nitrogen, thepresence of tightly packed nuclear chromatin inhighly cellular tumors, for example, would shifta tissues’ composition away from just water,and therefore change it’s mass attenuation (i.e.,the less hydrogen and oxygen present and themore phosphorous, nitrogen, and carbon thatreplace them in the more plentiful nuclei, thegreater the stopping power of the tissue). Theseeffects have been seen in breast malignancieswithout the addition of any contrast agents, andcan be seen in normal organs such as the thyroid[Johns and Yaffe, 1987].

Transgenic mouse models expressing eitherthe neu proto-oncogene or transforming growthfactor (TGF-a) in the mammary epithelium de-velop spontaneous focal mammary tumors thatoccur over long latency. These models offer atest bed in which to follow changes in linearattenuation of the tissues as the epithelialalterations occur over 6 months from glandularand ductal tissues that are normal, to those withclearly defined macroscopic hyperplasias ortumors. Tyrosine kinase inhibitors are beingtested to halt or reverse these effects in themammary tissues. These transgenic mice can befollowed longitudinally over time with a mono-chromatic X-ray beam without the exceedinglyhigh radiation doses now delivered in even onemicroCT exam [Arteaga et al., 2001].

The addition of other atomic species can signi-ficantly enhance k-edge effects, particularly asone tunes the incident radiation beam to targetthe k-edge of the element given. k-edge refers tothe specific binding energy of the innermost ork-shell electron in the atom of interest. If, forexample, iodine were introduced into a tissue bymeans of an iodine tagged tumor affinitive drug,one could detect its presence in rather smallconcentrations given a monochromatic beamtuned to 33.2 keV (the binding energy of itsk-shell electron) and a good imaging detector(Fig. 2). The X-ray photon, in this case, matches

Fig. 1. Inverse Compton Scattering entails the head-on colli-sion of an energetic packet of electrons and an intense laser pulse(in this case infrared light reflected off of a beryllium mirror) at apoint called the interaction zone (IZ). The light photons arescattered off of the electrons gaining energy and shortening theirwavelength to the X-ray region of the spectrum. Since theelectron energy is tunable, the X-rays are tunable. Since the lightwaves were almost all at the same frequency, the X-rays comingout are almost all at the same wavelength. The X-rays arescattered in the same direction as the electrons were traveling,and exit the beamline through the beryllium mirror and aberyllium window.

Tunable, Monochromatic X-Rays for Imaging 503

the binding energy of that electron, and ‘‘knocksit’’ out of its orbit. The X-ray, having transferredits energy to the electron, is extinguished fromthe beam, thus revealing the presence of theiodine along the X-ray’s original path.

A number of drugs are already under inves-tigation for diagnostic use as molecular orcellular tags, and as contrast agents. Early ex-periments with new ideas for diagnostic agentshave already begun in our laboratory. These arebeing performed with iodine containing COX-2agents, Gd containing immunoliposomes, andPV-10 (iodinated rose Bengal)1 (Provectus,Inc.). COX-2 protein is not expressed exten-sively in normal cells, but is expressed signifi-cantly in stomach, colon, pancreas, liver, lung,breast, and prostate malignancies [DuBoiset al., 1996]. This makes COX-2 an attractivemolecular target in research animals andpotentially humans. Researchers at other insti-tutions have done preliminary work on manyother diagnostic drugs such as: hepatocyteselective iodinated triglycerides, which act asa negative contrast agent [Lee et al., 1997];AgTPPS4, which is a porphyrin derivative thataccumulates in vasculature around tumors[Young et al., 1998]; iodine containing micellesmade from polymers [Torchilin et al., 1999]; Gdcompound P 760, which slowly diffuses into theinterstitium [Kroft et al., 1999]; gases such asXe for airways and alveoli [Rubenstein et al.,1995]; perfluorocarbons which can be used asboth liquids and gases; dextran-coated Fe oxidenanoparticles [Moore et al., 2000]; and hexa-nuclear transition metal cluster compounds[Mullan et al., 2000], to name a few. Certainlythe currently available iodinated contrastagents used intravenously, intra-arterially andeven intrathecally can be used at extremely

low doses using monochromatic X-rays both atthe 33.2 keV k-edge and, to even better advan-tage in certain portions of the body, such as thebreast, in the 20–30 keV range. Marked reduc-tion in the concentrations of contrast that canbe visualized, opens the door to IV angiographyusing small intravenous injections, reducingthe need for catheterization of the arterialsystem, thus improving safety, and patientacceptance [Ohtsuka et al., 1994; Dix, 1995;Dix et al., 2003].

Gadolinium containing MRI contrast agentsare currently used in the angiography setting asa substitute for iodine in allergic individuals,but there is some controversy that it is lesstoxic than iodine in equally attenuating doses(0.5 mol/L Gd attenuates the same as 60–80 mgI/cc). This is partly due to the polychromaticbeam that is used (70–90 KVP), which is nottuned to the k-edge of the gadolinium, markedlyreducing its visibility. By tuning to the k-edge ofthe gadolinium atom (50.2 keV), one can usemuch less contrast, maintaining the k-edgeeffect, but the body is much more transparentto the X-ray beam than it would be at the k-edgeof iodine, thereby also reducing the radiationdose to the patient.

Heavy elements do not necessarily need to beintroduced exogenously into the body to takeadvantage of this k-edge effect. Some elementsconcentrate in tissues in certain diseases (e.g.,in Wilson’s disease, there is an abnormal overaccumulation of Cu; in hemochromatosis, ironbuilds up in tissues, such as liver and lung; leadpoisoning affects calcium deposition and resorp-tion in the regions of rapid bone growth atepiphyses, etc.). These elements can be easilydetected using tuned monochromatic X-raybeams.

Fig. 2. A test tube containing an iodine solution with approximately 37.5 mg I/cc, was imaged with amonochromatic X-ray beam at progressively higher energies (1 keV steps). Absorption of the X-rays by theiodine initially decreases with increasing energy, as expected, until the k-edge of iodine (33.2 keV) isreached. Above that energy absorption increases markedly causing the iodine within the tube to ‘‘light up’’revealing its presence.

504 Carroll

Osteoporosis screening as currently practic-ed, is an example of chemical probing using dif-ferent frequencies of X-rays. Few people think ofthis as X-ray probing of molecular compositionof bone, but that is precisely what it is.

One need not be exactly tuned to the k-edgeof an element to see a detectable effect. In fact,at low concentrations of heavy elements (e.g.,iodine), one can discern tissue concentrations atand beyond micromolar levels within laboratoryanimals such as mice, when imaged far belowthe k-edge, due to the increased likelihood thatlower energy X-ray photons will interact withheavier elements (more so than water) due tothe photoelectric effect that is dominant in the20–30 keV energy range.

The effect of inherent tissue changes withvarious pathological states and the addition ofexogenous heavy elements into those tissues arenot necessarily additive. Going to a higher X-rayenergy to interact with the more tightly boundk-shell electron of a heavier atomic element willtend to obliterate the underlying effects seeninherently in tumors that are best imaged withlower energies and hence higher soft tissuecontrast.

THERAPY

When the k-shell electron of iodine is knockedout of its orbit by tuning monochromatic X-raysto 33.2 keV, the ejected electron is replaced inthe K orbit by an electron from the L orbit. Asthis electron drops from the L to the k-shell,it gives off a 28.3 keV characteristic photon.Likewise, the L-shell electron is then replacedby an electron from the M-shell. This in turngives off a 4.3 keV photon. The N-shell followsthe lead of the other shells and contributes anelectron to the M giving off a 0.6 keV photon.As one could expect, adding up the energies ofthese various photons comes to 33.2 keV. Thesecharacteristic photons interact with the matterin their surrounding medium, traveling lessthen a few microns at most for the softer X-rays,but penetrating some distances for the moreenergetic ones. This entire process is known asan Auger cascade (Fig. 3).

A unique approach to targeted therapy ispossible using an infusion of iodinated deoxyur-idine (IUdR) into a patient. This allows thereplacement of as much as 10% of the thymidinein the nuclear DNA of rapidly dividing cells.An external monochromatic beam may then

be used to displace the k-shell electron in thecontained iodine, thereby creating an Augercascade within the DNA, creating double-stranded breaks. One Auger event in the DNAof a cell is the equivalent of delivering 0.05 Gy(5R) to the cell [Kassis et al., 1987]. Significantreductions in the doses needed for radiotherapycould be achieved in this way. Monte Carlocalculations show a 25–50% reduction in doseneeded, depending on depth of tumor andstarting energy of the monochromatic beam.The inner shell (k-shell) ionization events are4–8 times less frequent if one uses BUdRinstead of IUdR. Pignol et al. [2003] have shownthat the k-shell events are strongly tied to thephoton spectrum of the beam or radionuclideused to knock the k-shell electron from its orbitand that the lower one can go in beam energytoward the k-shell binding energy the better itgets [Karnas et al., 1999].

It would seem intuitive that by using aslightly more energetic beam, more of thephotons in that beam would survive passagethrough the overlying tissues to make it to atumor at a given depth. It would then seem bestto place heavier atomic species in the cell thathave k-shell binding energies that would con-form to these more energetic photons. Giventhis logic, gadolinium with a k-shell bindingenergy of 50.2 keV and now present in somecurrent chemotherapeutic agents would seem

Fig. 3. Auger cascade. A 33.2 keV monochromatic X-rayknocks the K-shell electron out of its orbit around the nucleusextinguishing the X-ray photon. The ejected photoelectroninteracts with surrounding tissues. Meanwhile, the L-shell andM-shell electrons fall into the next lowest orbit emitting softX-rays in the process. These interact with the surrounding softtissues as well. Cascades such as this can be quite damaging ifthey occur in very close proximity to DNA in the cell nucleus.

Tunable, Monochromatic X-Rays for Imaging 505

ideal. Unfortunately, the doses at which it isused clinically are not relevant for the Augercascade phenomenon. One of the problems withusing Gd-Tex, for example, as a radiosensitizeris that it winds up mainly in the mitochondriarather than in the DNA in the nucleus [Milleret al., 1999]. If one is given the choice of eithercreating free radicals randomly within a cellhoping to incapacitate various intracellularmechanisms or, alternatively, to create a dou-ble-stranded break in the DNA that will halt cellreplication in its tracks, the choice requireslittle profound cogitation.

It would appear then that it is more advan-tageous to improve the effectiveness of radio-sensitizers through optimizing irradiationdepth and photon energy than to attempt forc-ing more of the drug into the cell throughpharmacological manipulation.

In a similar vein, the combination of anadenovirus, a symporter gene, and prostatespecific compounds can also be used therapeu-tically. While not containing the target atomitself, this combination, when given to mice, in-fects the prostate cells, altering cellular geneticmakeup, imparting new capabilities to the cellenabling it to transport and concentrate sodiumiodide, much like thyroid cells [Spitzweg et al.,2001; Cho et al., 2002]. While current experi-ments use radioactive iodine uptake and itsdisintegrations to then both diagnose and treattumors, collateral damage may be expected botharound the prostate cells themselves, but also inthe thyroid gland, salivary glands, stomach andso forth where iodine may also accumulate. Useof non-radioactive iodine with an external beamtuned to the k-edge of the iodine could poten-tially spare these other organs, while still creat-ing Auger cascades within the transformed cellsto help in killing them.

A newer and somewhat elegant method oftesting distribution of dose in tissues to learnmore about the k-edge enhancements withAuger cascades is the use of aqueous polymergels. These consist of tissue equivalent materi-als with radiosensitive monomers dispersedthroughout the gel. The products of radiolysis(production of free radicals) cause the mono-mers to polymerize. The degree of polymeriza-tion depends directly upon radiation dose.When these gels are studied in a magneticresonance imaging unit, the water relaxationtimes are shorter in the presence of polymers ormacromolecules. These in essence act like self-

developing three-dimensional photographicemulsions. If one were to seed ‘‘tumors’’ contain-ing k-edge drugs into these gels, one coulddirectly test the effectiveness and build up ofradiation dose equivalency using IUdR andmonochromatic radiation.

Where does molecular/cellular imaging even-tually take one? While it is unlikely or evenunnecessary that we will ever need to see onlyone cell or one metabolic event, imaging down tothe cellular level is possible but the radiationburden is so high that it is impractical even withmonochromatic X-rays. Fortunately, people areconglomerations of many cells. If we wish touse molecular or cellular imaging in every dayclinical practice, we must not only explore theeffectiveness of monochromatic X-rays in cellcultures or single cells but also determinewhether or not we can see these effects at depthwithin the patient. This is going to requirepenetrating radiation of some sort, whether it ismonochromatic X-rays, radio waves, gammarays, or ultrasound. There are, of course, manytrade offs in spatial resolution, detector effi-ciency, and the concentrations of materials thatneed to be present in the tissues for detectabilityby different modalities. Needless to say, onetechnique will not suffice for all situations.Multimodality approaches to understandingthe molecular events at depth within a patientcertainly need to be available to clinicians.

Any techniques that translate into the clinicalarena must gain patient acceptance. Patientswill not accept invasive or painful techniques.An example of this is the compression usedin current day mammography. Compression-less examinations, use of oral drugs rather thanintravenous drugs, and low radiation doseswill all be high on the list of ‘‘musts.’’ In three-dimensional, compressionless, monochromaticmammography, inherent differences in thelinear attenuation of the cells in cancers[Carroll et al., 1994] will be much easier todetect without the overlap of structures withinthe breast that is currently problematic with 2-D images [Gordon and Sivaramakrishna, 1999].This technique will produce an examinationthat is much more reproducible from year toyear making better use of computer assisteddiagnosis (CAD) techniques now showing pro-mise. This could all be accomplished with amuch lower radiation dose than that currentlydelivered [Boone, 1999; Kimme-Smith, 1999;Boone et al., 2001]. High spatial and contrast

506 Carroll

resolution are needed if we are to use this type ofmolecular/cellular imaging to best advantage.

The pulsed, tunable, monochromatic X-raymachine currently used to perform applicationsresearch in phantoms and animals is capable offorming an image in 8 ps, but can do so only onceevery 300 s. Needless to say, if this paradigm isto be used in the clinical setting, a higher re-petition rate machine will be needed to makethese studies practical. Developments in lasertechnology are being incorporated into themachine design allowing it to be useful clinicallyin cancer diagnosis and treatment, calciumscreening, coronary and lung perfusion studieswith intravenous injections, and a whole host ofother scenarios.

Of interest, is the fact that monochromaticX-ray beams produced by inverse Compton scat-tering are ideal for the performance of proteincrystallography [Harteman et al., 2001]. Withaddition of a high repetition rate laser to one ofthese machines, crystallography in all of itsforms can be performed outside of the synchro-tron setting speeding up the determination ofthe three-dimensional structure of a subjectprotein. If one need not wait for months or weeksto get time on a synchrotron beamline to ascer-tain whether or not a protein crystal is useful forcrystallography and will give a good diffractionpattern and yield the 3-D information needed,the tempo of drug discovery and structuralproteomics could be significantly enhanced.

Pulsed, tunable, monochromatic X-rays havegreat potential as an enabling technology fordiagnostic and therapeutic techniques that willbe quite useful in the arenas of patient care,small animal research, and drug development[Carroll, 2002]. In these formative years, therationale for how they are best used must relyon understanding the cellular and molecularmechanisms that they can easily probe. Merelyseeing internal anatomy is not enough; we needto be able to remotely feel its texture, probe itschemistry, or delete it entirely if it is an un-wanted intruder. First, we need to do no harm,so we must peek at the microscopic innards ofour patients painlessly and as unobtrusively aspossible. This type of X-ray probe holds promisethat we must carefully nurture.

ACKNOWLEDGMENTS

The author thanks Virginia Adcox for herexcellent secretarial, administrative, and tech-

nical assistance in the preparation of thismanuscript.

REFERENCES

Arteaga CL, Chinratanalab W, Carter MB. 2001. Inhibitorsof HER2/neu (erbB-2) signal transduction. Semin Oncol28(Suppl 18):30–35.

Boone JM. 1999. Glandular breast dose for monoenergeticand high energy X-ray beams: Monte Carlo assessment.Radiology 213:23–37.

Boone JM, Nelson TR, Lindfors KK, Seibert JA. 2001.Dedicated breast CT: Radiation dose and image qualityevaluation. Radiology 221:657–667.

Carroll FE. 2002. Perspectives. Tunable, monochromaticX-rays: A new paradigm in medicine. AJR 179:583–590.

Carroll FE, Waters JW, Price RR, Brau CA, Roos CF, TolkNH, Pickens DR, Stephens WH. 1990. Near-monochro-matic X-ray beams produced by the free electron laserand compton backscatter. Invest Radiol 25:465–471.

Carroll FE, Waters JW, Andrews WW, Price RR, PickensDR, Willcott R, Tompkins P, Roos C, Page D, Reed G,Ueda A, Bain R, Wang P, Bassinger M. 1994. Attenuationof monochromatic X-rays by normal and abnormal breasttissues. Invest Radiol 29:266–272.

Carroll FE, Waters JW, Traeger RH, Mendenhall MH,Clark WW, Brau DA. 1999. Production of tunable,monochromatic X-rays by the Vanderbilt free-electronlaser. Proceedings SPIE. Free Electron Laser ChallengesII 3614:139–146.

Carroll FE, Mendenhall MH, Traeger RH, Brau C, WatersJW. 2003. Pulsed, tunable, monochromatic X-rays from acompact source: New opportunities. AJR (in press).

Cho JY, Shen DHY, Yang W, Williams B, Buckwalter TLF,La Perle KMD, Hinkle G, Pozderac R, Kloos R, NagarajaHN, Barth RF, Jhiang SM. 2002. In vivo imaging andradioiodine therapy following sodium iodide symportergene transfer in animal model of intracerebral gliomas.Gene Ther 9:1139–1145.

Dix WR. 1995. Intravenous coronary angiography withsynchrotron radiation. Prog Biophys Mol Biol 63:159–191.

Dix WR, Kupper W, Dill T, Hamm CW, Job H, Lohmann M,Reime B, Ventura R. 2003. Comparison of intravenouscoronary Angiography using synchrotron radiatiobn withselective coronary Angiography. J Synchrotron Rad 10:219–227.

DuBois RN, Radhika A, Reddy BS, Entingh AJ. 1996.Increased cyclooxygenase-2 levels in carcinogen-inducedrat colonic tumors. Am J Gastroenterol 110:1259–1262.

Gordon R, Sivaramakrishna R. 1999. Mammograms arewaldograms: Why we need 3-D longitudinal breastscreening. Appl Radiol 28:12–25.

Harteman FV, Baldis HA, Kerman AK, Le Foll A,Luhmann NC, Rupp B. 2001. Three-dimensional theoryof emittance in Compton scattering and X-ray proteincrystallography. Phys Rev E 64:016501-1–016501-26.

Johns PC, Yaffe MJ. 1987. X-ray characterization or normaland neoplastic breast tissues. Phys Med Biol 32:675–695.

Karnas SJ, Edward Y, McGarry RC, Battista JJ. 1999.Optimal photon energies for IUdR k-edge radiosensitiza-tion with filtered X-ray and radioisotope sources. PhysMed Biol 44:2537–2549.

Kassis AI, Sastry KSR, Adelstein SJ. 1987. Kinetics ofuptake, retention and raeiotoxicity of 125 IUDR in

Tunable, Monochromatic X-Rays for Imaging 507

mammalian cells: Implications of localized energy deposi-tion by Auger processes. Rad Res 109:78–89.

Kimme-Smith C. 1999. New digital mammography systemsmay require different X-ray spectra and therefore, moregeneral normalized glandular dose values. Radiology213:7–10.

Kroft LJ, Doornbos J, van der Geest RJ, Benderbous S,de Roos A. 1999. Infarcted myocardium in pigs: MRimaging enhanced with slow-interstitial-diffusion gado-linium compound P760. Radiololgy 212:467–473.

Lee FT, Chosy SF, Naidu SF, Goldfarb S, Weichert JP,Bakan DA, Kuhlman JE, Tambeaux RH, Sproat IA. 1997.CT depiction of experimental liver tumors: Contrastenhancement with hepatocyte-selective iodinated trigly-cerides versus conventional techniques. Radiology 203:465–470.

Miller RA, Woodburn K, Fan Q, Renschler MF, Sessler JL,Koutcher JA. 1999. In vivo animal studies with gadoli-nium (III) texaphyrin as a radiatioin enhancer. Int JRadiat Oncol Biol Phys 45:981–989.

Moore A, Marecos E, Bogdanov A, Weissleder R. 2000.Tumoral distribution of long-circulating dextran-coatediron oxide nanoparticles in a rodent model. Radiology214:568–574.

Mullan BF, Madsen MT, Messerle L, Kolesnichenko V,Kruger J. 2000. X-ray attenuation coefficients of high-

atomic-number, hexanuclear transition metal clustercompounds: A new paradigm for radiographic contrastagents. Acad Radiol 7(4):254–259.

Ohtsuka S, Sugishita Y, Hyodo K. 1994. Intravenouscoronary angiography using a two dimensional imagingsystem. Synchrotron Radiat News 7:21–22.

Pignol JP, Rakovitch E, Beachey D, Sech CL. 2003.Clinical significance of atomic inner shell ionization(ISI) and Auger cascade for radiosensitization usingIUdR, BUdR, platinum salts, or gadolinium porphyrincompounds. Int J Radiat Oncol Biol Phys 55(4):1082–1091.

Rubenstein E, Giacomini JC, Gordon HJ, Rubenstein JAL,Brown G. 1995. Xenon k-edge dicromographic broncho-graphy: synchrotron radiation based medical imaging.Nucl Instrum Methods A 364:360–361.

Spitzweg C, Dietz AB, O’Connor MK, Bergert ER, TindallDJ, Young CYF, Morris JC. 2001. In vivo sodium iodidesymporter gene therapy of prostate cancer. Gene Ther8:1524–1531.

Torchilin VP, Frank-Kamenetsky MD, Wolf GL. 1999. CTvisualization of blood pool in rats by using long-circulat-ing, iodine-containing micelles. Acad Radiol 6(1):61–65.

Young LA, Kalet IJ, Rasey JS, Nelson JA. 1998. 125Ibrachytherapy k-edge dose enhancement with AgTPPS4.Med Phys 25(5):709–718.

508 Carroll