Rational Design of Sequestering Agents for Plutonium and Other Actinides

76 Pages·2005·1.56 MB·English

Chem.Rev.2003,103,4207−4282 4207
Rational Design of Sequestering Agents for Plutonium and Other Actinides
Anne E. V. Gorden, Jide Xu, and Kenneth N. Raymond*
DepartmentofChemistry,UniversityofCalifornia,Berkeley,California94720
Patricia Durbin
ChemicalSciencesDivision,ErnestOrlandoLawrenceBerkeleyNationalLaboratory,UniversityofCalifornia,Berkeley,California94720
Received December23,2002
Contents 6.6. Hydroxypyridinone (HOPO)-Based 4246
Plutonium-Sequestering Agents
1. Introduction 4208
6.7. Mixed Ligands 4249
2. Background 4209
6.8. Orally Effective HOPO Ligands 4251
2.1. Actinides in Applications 4209
6.9. Ligand Toxicity 4252
2.2. Behavior of Plutonium in Biological Systems 4209
6.10. Comparison of Efficacy for Pu Sequestration 4254
2.3. Chelation Therapy 4211
6.11. Ligands for Plutonium Removal from Bone 4255
2.4. Current Chelation Methods Using DTPA 4212
7. Thorium-Sequestering Agents 4256
3. Designing a Model System 4213 7.1. Thorium Coordination ChemistrysSimilarities 4256
3.1. Actinide Coordination Chemistry 4213 to Pu(IV)
3.1.1. Characteristic Features 4213 7.2. Structural Characterization as Model for the 4256
3.1.2. Lanthanides as Models for Actinides 4215 Pu(IV) System
3.2. Requirements for an Effective Sequestering 4216 7.3. Decorporation of Thorium 4259
Agent 8. Americium-Sequestering Agents 4260
3.3. Biological Means for Evaluation 4216 8.1. Americium Coordination Chemistry 4260
3.3.1. Initial Assessment 4216 8.2. Lanthanides(III) as Models for Am(III): Eu(III) 4261
3.3.2. Collaborative Studies 4218 and Lu(III)
4. A Biomimetic Approach toward 4219 8.3. Gd(III) Complexes as Models for Am(III) 4262
Actinide-Sequestering Agents 8.4. Multidentate Amino Acetic Acids for Am(III) 4262
4.1. Similarities between Fe(III) and Pu(IV) 4219 Chelation Therapy
4.2. Complexes with Naturally Occurring 4220 8.5. Multidentate CAM Ligands for Am(III) 4264
LigandssSiderophores Chelation Therapy
4.3. Design of Ligand Scaffolds 4221 8.6. Multidentate HOPO Ligands for Am(III) 4265
4.3.1. Chelating Groups in Siderophores 4221 Chelation Therapy
4.3.2. Multidentate Coordination Systems 4221 8.7. Ligands for Americium Removal from Bone 4265
4.3.3. Ligand Geometry and Denticity 4223 9. Uranyl Ion-Sequestering Agents 4266
5. Ligand Synthesis 4224 9.1. Uranium and Uranyl Coordination Chemistry 4266
5.1. Ligand Systems 4224 9.2. Uranium in Biological Systems 4268
5.2. Catecholamide (CAM) Ligands 4224 9.3. Depleted Uranium 4269
5.3. Terephthalamide (TAM) Ligands 4232 9.4. Uranyl Complexes with Multidentate CAM 4270
Ligands
5.4. Hydroxypyridinone (HOPO) Ligands 4234
9.5. Uranyl Complexes with Multidentate TAM 4270
5.5. Mixed Ligands 4236
Ligands
5.6. Sulfonamide Ligands 4237
9.6. Uranyl Complexes with Multidentate HOPO 4270
6. Plutonium-Sequestering Agents 4238
Ligands
6.1. Plutonium Coordination Chemistry 4238
9.7. Ligand Cocktails for Multiple Actinides 4271
6.2. Ce(IV) and Hf(IV) as Models for Pu(IV) 4239
10. Neptunium-Sequestering Agents 4273
6.3. Catecholamide (CAM)-Based 4241
10.1. Neptunium Coordination Chemistry 4273
Plutonium-Sequestering Agents
10.2. Neptunium under Physiological Conditions 4273
6.3.1. Cyclic Systems 4241
10.3. Neptunium Decorporation Using Multidentate 4274
6.3.2. Multidentate Linear Systems 4242
CAM Ligands
6.4. Biological Evaluation Leads to Improved 4242
10.4. Neptunium Decorporation Using Multidentate 4274
Ligand Systems
HOPO Ligands
6.5. Terephthalamide (TAM)-Based Ligands 4246
11. Conclusions 4275
12. Acknowledgments 4276
13. Abbreviations 4276
*Towhomcorrespondenceshouldbeaddressed.Phone: (510)642-
7219.Fax: [phone].E-mail: [email protected]. 14. References 4277
10.1021/cr990114xCCC:$44.00 ©2003AmericanChemicalSociety
PublishedonWeb10/28/2003
4208 ChemicalReviews,2003,Vol.103,No.11 Gordenetal.
Anne E. V. Gorden was born in Kansas City, Missouri, and grew up in ProfessorKennethN.Raymondwasbornin1942inAstoria,Oregon.He
the north Dallas area in Texas. A National Merit Scholar (1992) and attended Reed College, where he received a B.A. in 1964. His Ph.D.
recipientoftwoGeneralElectricFacultyfortheFutureFellowships(1995, research at Northwestern University, under the direction of Professors
1996),shegraduatedfromEmoryUniversityinAtlanta,Georgia,in1996, FredBasoloandJamesA.Ibers,concernedthesynthesisandstructure
earning a B.S. in chemistry as well as completing a second major in offive-coordinatemetalcomplexes.UponcompletinghisPh.D.,hebegan
literature.ShethenreturnedtoTexas,attendinggraduateschoolatthe hisfacultyappointmentattheUniversityofCaliforniaatBerkeleyin1967,
UniversityofTexasatAustin,whereherthesiswork,underthedirection becomingAssociateProfessorin1974andProfessorin1978.Hiswork
ofProfessorJonathanL.Sessler,concernedthedesignandsynthesisof has been recognized with several awards, including the Ernest O.
novelexpandedporphyrinsandoligopyrrolesforselectiveioncoordination, Lawrence Award of the Department of Energy (1984), a Humboldt
in a collaborative project with Los Alamos and Argonne National Research Award for Senior U.S. Scientists (1991), and the American
Laboratories as a Seaborg Research Fellow (1999) and as a Seaborg Chemical Society Alfred Bader Award in Bioinorganic or Bioorganic
Institute Research Fellow (2000−2002). In 1999 and 2000, she was Chemistry(1994).HehasbeenanAlfredP.Sloanresearchfellow(1971−
awardedtwoDeltaGammaFoundationFellowshipsforWomeninScience. 1973),aMillerresearchprofessorattheUniversityofCalifornia(1977−
Aftercompletingherdissertationin2002,Dr.Gordenbeganapostdoctoral 1978, 1996) and Guggenheim fellow (1980−1981). He was elected to
appointment at the University of California at Berkeley with Professor theNationalAcademyofSciencesin1997,andtheAmericanAcademy
KennethN.Raymond,investigatingthestructuralandsolutionproperties ofArtsandSciencesin2001.Inadditiontohisacademicappointmentat
ofsiderophore-basedactinide-sequesteringagents. the University of California, he is a cofounder of Lumiphore Inc., which
utilizesnewluminescentagentsdevelopedinhislaboratory,andFaculty
SeniorScientistandInterimDirectoroftheSeaborgCenteratLawrence
Berkeley National Laboratory. He is the author of 12 patents and
approaching400researchpublications.
shown to reduce acute radiation damage, chemical
toxicity,andlateradiationeffects.Therecentdevel-
opmentofimprovedactinide-sequesteringagentsfor
potentialuseinchelationtherapyhasbeenbasedon
a body of work in several areas of coordination
chemistry. Key among these is the expansion of our
fundamental understanding of the structural and
solution (thermodynamics) coordination of the ac-
tinides.Thisunderstandingallowslanthanidemetal
ions to be used as suitable models for the actinides.
Describedinthisworkisanoverviewofanapproach
JideXuwasborninChina.HeearnedtheequivalentofaB.S.inchemistry
in1964atWannanUniversity.AfterabriefperiodinagricultureinAnhui, toward the design and optimization of actinide-
China (1964−1967), he worked for Anhui Chizhou Chemical Fertilizer sequestering agents.
FactoryinAnhui,China(1967−1980).Afterthistimeawayfromacademics,
hereturnedtoAnhuiUniversityasastudentandlecturer(1980−1986), This rational approach for the design of preorga-
completing the equivalent of a Ph.D. in 1986. At that time, he was nizedmultidentatesequesteringagentsforactinides
appointedanAssociateProfessorandAdvisortoGraduateStudentsat wasinspiredbysiderophores,thenaturallyoccurring
Anhui University, and for his work there he was recognized with an
microbial iron(III)-sequestering agents. Biological
OutstandingTeacherCollectiveAward(1989)andaSignificantAchieve-
evaluationoftheefficacyandtoxicityoftheseligands
ment Award of Anhui Science and Technology Commision (1989). He
cametoBerkeleyfirstasaVisitingScholar(1989−1992)andpostdoctoral has provided comprehensive data for the ongoing
research fellow (1990−1992), and is currently serving as Staff Scientist ligand optimization process. This has enabled the
workingwithProfessorKennethN.Raymond,involvedinallaspectsof development of a class of promising highly selective
researchandprojectdevelopmentinhislaboratories.
agents for in vivo chelation of Pu(IV). In addition,
severallow-toxicitytetradentatelinearligandswith
a pentylene or diethyl ether backbones containing
1. Introduction catecholate or hydroxypyridinonate binding groups
havebeenfoundtochelateotheractinidesandhave
Providing effective chelation therapy in response beenidentifiedassuitableagentsforinvivochelation
to internal human actinide contamination has been of Am(III), Np(IV/V), or U(VI).
RationalDesignofSequesteringAgentsforActinides ChemicalReviews,2003,Vol.103,No.11 4209
to actinides. Of these, plutonium (Pu) and uranium
(U) are the elements most likely to be encountered.
Plutonium has been manufactured through the ir-
radiation of nuclear fuel to be isolated for material
of a grade suitable for military use in weapons and
spaceexplorationapplications,butincivilianenergy
production applications, plutonium is generated as
a byproduct of systems that are based primarily on
uranium fission.4 Today, with close to one-third of
the world’s electrical power supply produced using
nuclearsources,5theoverallamountofspentnuclear
fuels generated each year is in the range of 9000-
10000 tons.4 This yearly quantity of spent fuel
contains about 75 tons of Pu.4 The total amounts of
plutonium produced from power reactors accumu-
Patricia W. Durbin was born in Oakland, California. She received both lated globally is an estimated 7000 metric tons
herB.S.inchemistry(1948)andherPh.D.inbiophysics(1953)fromthe
worldwide, most of which is dilute and contained in
University of California at Berkeley. Dr. Durbin began her distinguished
this spent reactor fuel.4,6 In addition, it has been
career in biophysics and actinide biology as a laboratory assistant and
technicianatCrockerLaboratoryattheUniversityofCaliforniaatBerkeley estimated that, after 50 years of production, 100
in 1946 while still a student. Upon completing her Ph.D., she was an metrictonsofpurifiedplutoniumhasbeenproduced
instructor in medical physics from 1953 to 1957 at the University of in the United States and presumably a similar
CaliforniaatBerkeley.Concurrently,shebeganworkasaphysiologistat amountinRussia.4,6Thesequantitiesareincreasing
LawrenceBerkeleyNationalLaboratory(LBNL),apositionshehelduntil
daily, and thus the challenge of managing, safely
beingpromotedtoStaffSeniorScientistatLBNLin1978.Shehasserved
storing,andlimitingthepotentialenvironmentalor
onnumerouscommitteesfortheNationalCouncilonRadiationProtection
(NCRP) (1956−1991), including serving as a NCRP Councilor (1975− injurious effects is constantly on the rise.7
1991), and has been on advisory panels for the National Academy of While plutonium has been introduced into the
SciencesNationalResearchPanel(NAS−NRP)CommitteeonRadioactive environmentviaatomicweaponstestsandaccidents
WasteManagement(CRWM)onHanfordWastes(1976−1978),Savannah atnuclearfacilities,theneedfortherapiestoisolate
RiverWastes(1978−1981),andOakRidgeNationalLaboratoryWastes
ingestedand/orinhaledactinidematerialswasprevi-
(1982−1985). She has been honored with the Distinguished Scientific
ouslyconsideredanissuesolelyofconcernfortrained
Achievement Award from the Health Physics Society (1984), to which
shewaselectedaFellowin1985.Sinceretiringin1991,shehascontinued radiationworkersworkingwithsizablequantitiesof
studiesasaParticipatingGuestandSeniorScientistatLBNL. actinides.8Unfortunately,recenteventshavebrought
to light the potential for exposure to actinides to
2. Background members of the population at large as the result of
anaccidentalreleaseoranintentionaldissemination
2.1. Actinides in Applications caused by sabotage or a so-called “dirty” bomb.
Although the likelihood of the contamination of a
If the development of the energy potential of the
largegrouporareausingthismethodmightbesmall
actinides ceased today, the use of actinides in both
becauseofthelimitsontheavailabilityofradioactive
civilian energy generation and space exploration
materials and the technical knowledge required to
wouldstillrequirefurtherresearchdirectedtoward
effectively carry out such an attack,9 the possibility
avarietyofenvironmentalandhealthissuesresult-
exists, and there is a high potential for panic by
ingfromtheseapplications.1Complicatingtheprob-
peopleintheareaofsuchareleaseandalimitedtime
lem is the fact that, in comparison to that of the
periodinwhichtodeterminepreciselywhoreceived
d-transition metals, our fundamental knowledge of
asufficientdosetobeharmfulinwhichtoadminister
theactinides,theirbasicchemistry,andcoordination
treatment.10Currently,wehavelimitedcapabilities
systems is still relatively early in its development.2
toaddresssuchascenario;therefore,itisimportant
The energy potential of the actinides first impacted
tohavethemeansofmakingavailablesafe,nontoxic,
the world with the invention of the atomic bomb in
effective (preferably orally bioavailable) chelating
1945, at the time overshadowing the scientific im-
agents for decontamination or easily synthesized,
plications of their groundbreaking discovery. Since
inexpensive chelating agents for new separations
thatfirstisolationofplutoniumandthesubsequent
technologies.1,10
inception of the Atomic Age, the civilian use of
actinides has primarily been to provide a large
2.2. Behavior of Plutonium in Biological Systems
fractionofthedevelopedworld’selectricity;however,
thisandweaponsprogramshavegeneratedalegacy The rationale for actinide removal therapy is the
of environmental wastes and a large worldwide premise that reducing the amounts of the tissue
inventory of actinide elements.3,4 burdensandcumulativeradiationdosessignificantly
All isotopes of the actinide elements are radio- diminishes radiation-induced tissue damage and
active.Thelengthsofthehalf-livesofthemoststable carcinogenesis,andreduceschemicaldamagetothe
isotopes of these elements decrease across the ac- kidneys and liver. The high specific activity alpha
tinide series, with the heaviest members being so emissionsofthecommonisotopesofthetransuranic
unstabletheycanonlybecreatedandisolatedafew actinidesmaketheseelementspotentcarcinogens.11-17
atomsatatime.2Becauseofthewideruseofnuclear Unlike organic poisons, which the body is able to
fuel sources, there is an increased risk of exposure metabolize,thesetoxicmetalsareeitherexcretedor
4210 ChemicalReviews,2003,Vol.103,No.11 Gordenetal.
Figure1. (a)Clearanceofintravenouslyinjectedsolubleactinidesfromtheplasmavolumeofmice(3ngof238Pu,1558ng
of241Am,3263.6µgof232+235U,121and44µgof237Np122).(b)Distributionofsolubleactinidesinthetisuesofmice1dayafter
intravenousinjection(3ngof238Pu,1558ngof241Am,1563.6µgof232+235U,121and44µgof237Np122).
immobilized.Inthecaseoftheactinides,immobiliza- inthebombingofHiroshima),butthechemicaland
tion in the body presents the problem of localized radioactive properties of plutonium are such that it
sites of intense radiation and increasing absorbed alsocauseslong-termdamageandinducescancerin
radiationdosesastheemittedalphaparticlesrepeat- thetissuesinwhichitisdeposited.12,14-17Somewhat
edly affect limited groups of cells.11-17 Prompt ag- fortuitously,theviableroutesofinternalplutonium
gressive chelation therapy limits the retention of contamination are in large part limited to direct
these toxic metals by preventing their coordination physicaltransportsuchasthroughingestion,inhala-
with and immobilization by tissue constituents and tion, or wound contamination.
by promoting their excretion from the body. These Plutonium is immobilized readily in sediments in
processes serve to lessen or eliminate both acute naturalwaters,inpartduetopoorsolubilityandthe
radiationtoxicityand/orchemicaldamageintissues formation of polymers.9,23 Plutonium has, however,
caused by the intake of actinides.8,10,16,18,19 We have been found to migrate in nonhumic, carbonate-rich
chosen to focus on plutonium as the most likely soils,presumablybecausethesesoilslackthehumic
hazard presenting the greatest potential threat, as materials left by the decomposition of plant matter
Puhasbyfarthegreatestretentioninthebodyafter thatretardthemigrationofplutonium.23Thesesame
contaminationbyactinides.14,16-22Thosesubstantial humic materials also increase the solubility of plu-
differencesinactinidetransportandretentioninthe tonium in seawater. Increasing the solubility of
bodyaredemonstratedinFigure1a,whichdisplays plutoniumincreasesthepotentialforenvironmental
the plasma clearances in mice of intravenously (iv) migration, thus increasing the bioavailability of the
injected Pu(IV), Np(V), Am(III), and U(VI), and in metal.24
Figure1b,whichdisplaysthetissuedistributionsin Itwaslongheldthattheinabilityofuncomplexed
mice one day after (iv) injection of Pu(IV), Np(V), plutonium to cross physiological barriers greatly
Am(III), and U(VI).19 hinders its concentration in the food chain.21,25,26
The hazards one typically associates with pluto- Nonetheless, there continues to be concern that
nium and other radionuclides are acute radiation naturally occurring chelating agents, in particular
damage and sickness caused by exposure to large thosethatcoordinateiron,mightcomplexsufficient
quantitiesofradiation(asinthecaseofthoseinjured Putoalterthatsituation.21,23,27Consequently,inves-
RationalDesignofSequesteringAgentsforActinides ChemicalReviews,2003,Vol.103,No.11 4211
tigations using siderophores, naturally occurring endosteal bone surfaces, the most important long-
iron-chelatingligands,wereconductedtoincreasethe term consequence of a systemic actinide intake is
rateofdissolutionofplutonium(IV)hydroxides.28One inductionofbonetumors.Theproximityoftrabecular
siderophore,desferrioxamine-B(DFOB),wasshown bonetowell-nourishederythropoieticmarrowandits
to facilitate the uptake of Pu(IV) into bacteria; inherently more rapid growth and maintenance
however,inthiscase,uptakeofFe(III)wasinhibited, remodeling make reduction by chelating agents of
and cell reproduction ceased.29 actinide deposits on these most sensitive bone sur-
faces particularly desirable.52-55 Studies using min-
The ability of a complexing agent to transport
eralized bone or uncalcified matrix models for bone
actinide(IV) ions depends on many factors. These
havedemonstratedthatactinideshaveaffinitiesfor
include the rate of dissolution from solid hydrolysis
bone mineral and also for bone proteins, such as
and polymeric products formed by the metal, the
stabilityofthemetal-ligandcomplex,andtheability sialoproteins,chondroitinsulfate-proteincomplexes,
andglycoproteins,andthatPubindsatthemineral-
of the complex to compete with other substrates to
organicinterfacesofbonesurfacesindependentlyof
retain the metal. The effects of ethylenediaminetet-
thepresenceoffunctionalboneormarrowcells.56-58
raaceticacid(EDTA),diethylenetriaminepentaacetic
It is still unclear whether either one alone or a
acid(DTPA),citrate,humicacid,fulvicacid,nitrilo-
combinationofbothligandtypes(mineralorprotein)
triacetic acid (NTA), and siderophores (naturally
constitutethelong-termbindingsitesinintactbone;
occurringiron-coordinatingspecies)onthemigration
of Pu(IV) and Th(IV) have been studied.30-36 Both however,thecentralpurposeofchelationtherapyfor
internally deposited actinides must be reduction of
EDTA and DTPA have been shown to increase the
thebonesurfacedeposittolessenthelocalradiation
uptake of plutonium and americium into certain
dose, which in turn should reduce bone tumor risk,
plants, with major implications for the introduction
of actinides into the food chain.37-41 The circum- prolong tumor latency, and increase tumor-free life
expectancy.
stances in which introduction of actinides into the
foodchaincouldoccurrequireadditionalstudyofthe Bydivertingcirculatingactinidetoexcretion,prompt
formationconstantsoftheactinidecomplexesofthe chelation therapy can prevent deposition on bone
substratesofconcernaswellasthepotentialforthe surfaces and remove some loosely bound actinide
substratesthemselvestobepresentinhighenviron- already deposited. Protracted therapy can prevent
mental concentrations.27 bonesurfacedepositionofactinidethatisrecirculated
fromothertissuesandreservoirs(lungsorcontami-
Plutonium is a potent carcinogen in mammals
natedwounds)andredepositiononnewbonesurfaces
because of its alpha radioactivity and long-term
ofactinidereleasedfrombone.19,42,55,59Amongthefew
retention of the complexes it forms with bone and
investigationsoftheefficacyofchelationtherapyfor
tissue constituents once it is ingested, inhaled, or
suppressing the carcinogenic effect of deposited ac-
introduced into the blood through a wound or
tinides,theexperimentalconditionsvarywidelysthe
abrasion.14-17,42-44 The retention of Pu in soft tissue
injected nuclide, dose, mode of exposure, animal
canbeattributedtothesimilarityofPu(IV)andFe-
species, and chelation treatment protocol.19,52,53,60-69
(III).21 Pu can maintain up to four oxidation states
Theoutcomesofthestudiesusinginjectedactinides
in aqueous solutions, and the most likely at physi-
range from encouraging to quite favorable, because
ologicalpHisPu(IV).Inmammals,Pu(IV)isassoci-
chelationtherapygenerallyreducedbonetumorrisk
ated to a high degree with Fe(III) transport and
(inproportionto,orinsomecasestoagreaterdegree
storage systems.21,26 In mammalian liver, Pu(IV)
than the reduction of skeletal radiation dose), re-
becomes associated with the iron-storage protein
ducedradiationdamagetosofttissues,andincreased
ferritin.45,46Inbloodplasma,thesmall,highlycharged
bonetumorlatencyandsurvival.Treatmentefficacy
Pu(IV)ioncirculatesboundtotheprotein,transfer-
appearedtobegreatestwhentreatmentwasinitiated
rin,whichnormallytransportsFe(III),occupyingone
within hours of exposure and then was continued
or both of the Fe-binding sites therein.47-49 While
over a significant fraction of the life span. Early
largequantitiesofcitricacidcandisplacethepluto-
treatment is particularly important, because it re-
nium once it is coordinated to transferrin, these
duces both initial skeletal radiation dose rate and
quantities are so large as to induce toxic calcium
cumulative skeletal dose.70
depletioninvivo.50Asaconsequence,onceboundas
atransferrincomplex,Pu(IV)isnotefficientlyfiltered
2.3. Chelation Therapy
by the kidneys, inhibiting renal excretion.14-17 The
Pu-transferrin complex circulating in the blood Thepotentialhealthhazardsofplutoniumandthe
graduallydissociates,toformmorestablelong-lived actinides were recognized early in the development
Pu complexes with bioligands in the skeleton and ofnuclearmaterials,andsoonafterthefirstreactor-
liver. Plutonium accumulates in parenchymal cells generated plutonium was produced, the search for
of the liver, in reticuloendothelial cells in many effectivemeansofdecorporationbegan.71,72TheHealth
tissues, on mineralized surfaces of bone, and in GroupoftheManhattanProjectassignedtothistask
some cases it is bound by connective tissue pursuedthreegeneralresearchgoals: toquantifythe
proteins.15,43,46,51-55 metabolism of the fission products and heaviest
The endosteal bone surfaces, particularly in the elements,toquantifytheacuteandlong-termtoxicity
axialskeleton,areconsideredthemostsensitivesites of ionizing radiation from external and internal
for radiation-induced bone tumors.44 Because the sources, and to find ways to remove internally
actinides preferentially deposit on those sensitive deposited radioelements from the body.71,73 Great
4212 ChemicalReviews,2003,Vol.103,No.11 Gordenetal.
progresshasbeenmadeintheensuingyearstoward using yttrium (in the form of 91Y) and later cerium
accomplishmentofthefirsttworesearchtasks,44,74,75 (using 144Ce) as models for Pu. The 91Y-EDTA
buttheremovalofradioelementsfromthebodyhas chelate injected intravenously (iv) in rats proved to
proved to be more difficult. The earliest efforts to be sufficiently stable that 70% of the 91Y was recov-
removeactinidesbymeansofdietarymanipulation, eredinurinein24h.Atthetime,thiswasanotable
supplements of hormones, common carboxylic acids achievement.91
or complexing agents, or colloidal zirconium citrate The acute toxicity of Na -EDTA was detected
4
werediscouraging,asthesemeasureshadlittleeffect almostimmediately,andCaNa -EDTAwasusedin
2
ontherateorquantityofplutoniumexcreted.72,76-78 the demonstration of enhanced excretion and some
From this work, it was determined that the only mobilization of injected 91Y, 144Ce, and 239Pu in
practicaltherapytoreducethehealthconsequences rats.92-94Simultaneously,inaseparatestudy,Catsch
of internal actinide contamination was aggressive, obtained similar results.95 While CaNa2-EDTA pro-
andoftenprotracted,treatmentwithchemicalagents motedsomeexcretion,itsshortcomingsasanactinide
that would form excretable low-molecular-weight decorporation agent were soon recognized.57 When
chelates.19,21,42,76 Ideally, such agents should have administered over prolonged periods, it is renally
greateraffinityatphysiologicalpHforactinideions toxic (500 µmol kg-1 d-1 for 16 days in rats).85
thanthecomplexingspeciesthatbindthemintissues CaNa2-EDTA depletes vital divalent trace metals
and body fluids; they should have low affinities for (e.g.,zinc)withgreaterchelatestabilities.85Finally,
essential divalent metal ions; they must be of low and most importantly, the efficacy of the chelate is
chronic toxicity at effective dose.21,59,79,80 It is also only improved by increasing dose, due to the limits
highly desirable, especially in cases requiring long- ofactinidechelationimposedbytheneedtousethe
term treatment, to have a decorporation agent that Ca salt.76
is orally effective.81,82
2.4. Current Chelation Methods Using DTPA
Progressindevelopingimprovedagentsthatmeet
therequirementsforthisapplicationhasbeenslow, Itbecameapparentthatnewligandswithgreater
sporadicallymarkedbyserendipitous“discoveries”of affinitiesthanEDTAformultivalentcationsandwith
industrially prepared chemicals and natural iron atleastthesameorpreferablysmalleraffinitiesfor
chelatorsandstudieswithderivatizedknownagents. divalent metals were needed. In 1954, octadentate
Comprehensive reviews and progress reports chart H -DTPAwaspatentedbytheGeigyChemicalCo.96
5
thehistoryandscopeofchelationtherapyforremov- Inlate1955,shortlyafterthedissociationconstants
ing internally deposited actinides: they cover vari- and log K values for its alkaline earth and lan-
ML
ouslythechemistryofmetalchelates,animalexperi- thanidechelatesweremeasured,90itspotentialasa
mentation to determine chelating agent efficacy for therapeutic agent for heavy metal poisoning was
reducing tissue actinide burdens and biological noted.77Theinvivostabilityof91Y-DTPAand140La-
effects, development of new agents and im- DTPA (urinary excretion nearly quantitative in 24
proved treatment protocols, and clinical applica- h) was reported by Kroll et al.,97 and the in vivo
tions.10,19,21,42,59,76-78,83-88 In recent years, steady chelationof144CeinratswasreportedbyCatschand
progresshasbeenmadethroughstrategiesfocusing Leˆ in 1957.98 The predicted efficacy of DTPA for in
ondesignofligandswithstructuralandcoordination vivochelationofPu(IV)wasverifiedbyV.H.Smith
propertiessuitableforactinidechelation.Thereviews the following year.99
cited above provide ample detail concerning the H -DTPAandNa -DTPAwerefoundtobeacutely
5 5
efficacy and clinical applications of the chelating
toxic,butthistoxicitycouldbesuppressedbyuseof
agents that have been used or proposed for actinide
the Ca chelate, which has a stability similar to that
decorporationaswellastheiruseandevaluation.A ofCaNa -EDTA.85,90CaNa -DTPAisalsoaboutas
2 3
brief mention of these should be made here for renally toxic as CaNa -EDTA, but because the log
2
general comparison and to highlight the areas in
K values for the DTPA chelates with lanthanide
ML
which there is need for improvement on current and actinide ions are 102-103 times greater than
techniques. those for EDTA, CaNa -DTPA is an effective re-
3
In 1947, a patent for hexadentate H -EDTA was moval agent at a much lower, clinically acceptable
4
issuedinSwitzerlandtoChemischeFabrikUetikon89 dose (30 µmol kg-1).42,85,90 In some species, CaNa -
3
foruseasananalyticalagentforcalciumandseveral DTPAistoxicifinjectedfrequently,duetodepletion
other metal ions. At that time, its dissociation ofessentialdivalentmetals.100SubstitutionofZnNa -
3
constants and log K values of its Ca, Mg, and Ba DTPA (log K 7 orders of magnitude greater than
ML ML
chelates were reported.90 Two years later, in late thatforCaNa -DTPA)90reducesoveralleffectiveness
3
1949,Foreman,whowasinvestigatingradioelement for Pu decorporation, but the lower toxicity allows
decontamination at the University of California dailytreatmentoveranextendedtime.52,101Polyami-
RadiationLaboratoryinBerkeley,learnedbychance nocarboxylicacids(PACAs)withlongercentralbridges
of this new complexing agent, then under the trade oradditionalcarboxylicacidgroupsweresynthesized
name Versene (Bersworth Chemical Co.). Foreman andtested.Theratiosoftheaffinitiesoftheseligands
postulated, if an aqueous solution of Versene dis- fortrivalentlanthanidesandCaarenotmorefavor-
solved lead phosphate at pH g 7, as claimed by the able than those of DTPA. None was more effective
distributor,itmightalsoformstablelanthanideand than CaNa -DTPA for in vivo chelation of Y or Ce;
3
actinidecomplexesthatcouldbeexcreted.Hesought infact,somewerelesseffective,andtheseinvestiga-
to examine this premise, beginning with studies tions were discontinued.42,85,102
RationalDesignofSequesteringAgentsforActinides ChemicalReviews,2003,Vol.103,No.11 4213
Other PACAs have been investigated for their it limits the frequency of doses that can safely be
ability to remove incorporated actinide deposits.103 administered.100
AnassortmentofPACAswithalkylchainsofvarious DerivatizationsandmodestmodificationsofDTPA
lengthswerefoundtoreduceAmdepositswhengiven were not found to sufficiently improve Pu chela-
orally.104Oneofthese,docosyl-triethylenetetramine- tion.42,85,117,118HydrophilicDTPAdoesnotpenetrate
pentaaceticacid(orC22TT),reducedplutoniumfrom cells and is therefore unable to act on aggregated
liver cytosol in vitro and was moderately effective actinides in phagocyctic cells60,94,119,120 and does not
whenaddedtothedietofrats14daysafterinjection compete for actinides already incorporated into
of 239Pu-citrate. The rats were fed 50 µmol per day bone.54,111Thesefactorsalsounderstandablylimitthe
for 10 days, resulting in 71% reduction in liver Pu efficacyofdecorporationifthechelatingagentisnot
andmodestreductionsinthespleenandkidneyPus administered immediately after the intake of radio-
16.7% and 13.8%, respectively. The differences in nuclides. The current FDA-approved drug, CaNa -
3
bone Pu, however, were negligible. This compound DTPA or ZnNa -DTPA, is also not orally effective
3
is still under study.104 attherecommendedclinicaldoseandisadministered
Hydrophilic CaNa -DTPA and ZnNa -DTPA, by injection or inhalation. Oral bioavailability is
3 3
which distribute only in extracellular water, cannot potentiallyamostdesirablepropertyofanactinide-
reactdirectlywithintracellularactinidedeposits.42,85 sequestering agent, especially if repeated doses are
AttemptsweremadetofacilitatetransportofCaNa - considered necessary or if a large number of people
3
DTPA across cell membranes to improve actinide requiretreatment.19Finally,DTPAisnotaneffective
removal of cellularly deposited actinides by encap- therapeutic agent for some other actinides, such as
sulation of CaNa -DTPA into liposomes,105 which Th(IV), Np(IV), or U(VI). This may be an issue if
3
accumulateintracellularlyinliver.Liposomalencap- more than one metal is present in an accident or if
sulationprolongedDTPAretentionintissuesinthe there are questions about the contaminant.59,121,122
body, mobilized somewhat more Pu (injected as a With these limits on the current treatment using
colloid) from liver, and prevented redistribution of DTPA, there remains a great deal of room for
liverPutobonemoreefficientlythaninjectedCaNa - improved decorporation methods, and there contin-
3
DTPA;however,dosage-dependentsplenichypertro- uestobeaneedformorepowerful,lesstoxic,orally
phy was an unacceptable side effect.42,105 activechelatingagentswithincreasedspecificityfor
A lipophilic derivative of H -DTPA incorporating actinide(IV) ions and U(VI).
5
two decane chains, colloquially called Puchel, was
3. Designing a Model System
synthesized at the National Radiation Protection
Board, UK, to produce a chelator that penetrated
cells.106 Injected Puchel reduced liver Pu as antici- 3.1. Actinide Coordination Chemistry
pated,andwheninhaled,itacceleratedPuclearance
3.1.1. Characteristic Features
fromthelungbutdidnotreducePuintheliver.26,107,108
Protracted weekly or monthly inhalations of Puchel Fifty years of investigations of actinide coordina-
causedlunginflammation,andwiththefindingthat tion chemistry make it possible to describe some
unacceptable liver damage occurred when it was general trends in their chemistry. Actinides form
given by injection, its further development was easilyhydrolyzedacidicmetalionsthatformstrong
abandoned.109 complexes with common chelating agents.3,7 These
Despite its ability to chelate soluble trivalent hard ions preferentially interact with hard acid
actinides and Pu(IV) in body fluids, conventional donors,suchasoxygenorcarboxylate,alkoxide,and
DTPA therapy has deficiencies.21,57,59,90,110,111 For fluorideanions,buthavebeenknowntodemonstrate
example, the log K of Pu(IV)-DTPA is not great some covalency in interactions with softer donor
ML
enoughtoaffectsolubilizationofplutoniumhydrox- atoms,suchaschloride,nitrogen,andsulfur.Unlike
ides at physiological pH.90 Thus, while DTPA can the elements of the lanthanide group (abbreviated
remove much of soluble actinide complexes in body Ln), which are primarily found in a characteristic
fluids, it is much less effective for removing lan- trivalentoxidationstate,thelighterweightactinides,
thanidesoractinidesaftermetalhydrolysisandthe those preceding americium in the periodic table,
subsequentformationofcolloidsorpolymers.60,86,102,112 exhibit a diverse redox chemistry.2
Once Pu is bound in tissues and bone, DTPA has While actinium (Ac) maintains a stable trivalent
little effect on its mobilization.42,111 Although octa- state in solution, the typical characteristic thorium
dentate, DTPA appears not to coordinate fully with (Th) oxidation state is tetravalent, that of protac-
tetravalent actinides, possibly not forming the opti- tinium (Pa) is pentavalent, and the most stable
mal 1:1 chelate with Pu(IV) because some of the oxidation state for uranium (U) is hexavalent. The
electron donor groups are sterically hindered from actinides between uranium and americium (Am)
proper orientation around the metal ion.21,90 DTPA possessfourprincipaloxidationstates,III,IV,V,and
isnotspecificformetalsofhighioniccharge,andthe VI,inadditiontoaheptavalentstateforneptunium
less potent Ca or Zn chelates must be used to avoid (Np)andpossiblyforplutonium(Pu).Thepenta-and
hypocalcemia and depletion of essential divalent hexavalent oxidation states exist as linear (“-yl”)
metalionssuchasZn,Co,Cu,andMn.42,57,110,113-116 dioxocations in most solutions and many solid me-
This effect was extreme enough to cause death in dia.2,123,124Commonmethodsforthechemicalsepara-
dogs due to Zn(II) depletion, in which high levels of tion of actinides from reactor fuels take advantage
DTPA were maintained by multiple injections, and of the unique differences in redox chemistry across
4214 ChemicalReviews,2003,Vol.103,No.11 Gordenetal.
Table1. BiteAngle,CoordinationNumber,andGeometryofActinide(IV)Complexes
coordination biteangles
metal complex number (deg) idealizedgeometry ref
Pu NH Pu(NO ) 12 50.9 icosohedron 307
4 36
Pu [Na Pu(CO ) ]‚2Na CO ‚33H O) 10 52.2 pseudohexagonalbipyramid 303
6 35 2 3 2
Pu Pu(DFOE)‚3H O 9 65.6 tricappedtrigonalprism 24
2
Pu Pu(thenoyltrifluoroacetylacetone) 8 trigonal-faceddodecahedron a
4
Th NH Th(NO ) 12 49.8 icosohedron 307
4 36
Th Th(N-isopropylpivalohydroxamate) 8 62.3 cube 80
4
Th Th(N-isopropyl-3,3-dimethylbutanohydroxamate) 8 63.0 trigonal-faceddodecahedron 80
4
Th Th(catechol) 8 66.8 trigonal-faceddodecahedron 310
4
Th Th(1,2-HOPO)‚H O 9 63.8 monocappedsquareantiprism 313
2
Th Th(PR-Me-3,2-HOPO) 9 63.4 monocappedsquareantiprism 322
4
Th Th(acac) 8 70.7 trigonal-faceddodecahedron b
4
Th Th(thenoyltrifluoroacetylacetone) 8 70.5 trigonal-faceddodecahedron c
4
Th Th(salicylaldehyde) 8 trigonal-faceddodecahedron d
4
Np Np(acac) 8 71.8 trigonal-faceddodecahedron e
4
U U(salicylaldehyde) 8 trigonal-faceddodecahedron d
4
U U(bipyridyl) 8 cube f
4
aBaskin,Y.;Prasad,N.S.K.J.Inorg.Nucl.Chem.1963,25,1011.bReeves,P.J.;Smith,A.J.Inorg.Chim.Acta1987,139,
51.cLenner,M.;Lindquist,O.ActaCrystallogr.1979,B35,600.dHill,R.J.;Rickard,C.E.F.J.Inorg.Nucl.Chem.1977,39,
1593.eAllard,B.J.Inorg.Nucl.Chem.1976,38,2109.fPiero,G.D.Cryst.Struct.Commun.1975,4,521.
thegroup.125-127Thetransamericiumactinideshave
feweroxidationstatesandbehavequitesimilarlyto
the trivalent lanthanides.128
Incomplexes,theactinide(III)andactinide(IV)ions
generally display variable and high (8, 9, 10, or
higher)coordinationnumbers.Theenergydifferences
between the various coordination geometries are
small;therefore,theyshowlowstereochemicalpref-
erences. Although the actinyl ions prefer to retain
their linear di-oxo structure, they also display vari-
ablecoordinationnumbers(6,7,8).Thiscombination
of factors serves to make the rational design of
specificactinide-sequesteringagentsquitechalleng-
ing. Better control of the coordination environment
can be imposed by using structurally predisposed
ligands. The large size and flexible coordination Figure2. Examplesofthethreeidealizedeight-coordinate
polyhedra geometries: trigonal dodecahedron (D ), bi-
geometryoftheactinideionsshouldprovidecluesto 2d
capped trigonal prism (C ), and square antiprism (D )
the design of actinide-specific chelating agents, and 2v 4d
withshapemeasureS(deg)andthedistancebetweenthe
twofundamentalquestionsinthedesigningarethe
shapesgivenforeachpair.Reprintedwithpermissionfrom
determination of which coordination number and ref130.Copyright2000AmericanChemicalSociety.
geometry are, indeed, preferred by a given actinide
metal ion with a given ligand. Because of the large of a closest idealized polyhedron is not straightfor-
ionic radii of actinides, the preferred coordination ward. An analysis of the shape is usually expressed
number is 8 for actinide complexes, with bidentate in terms of three high-symmetry polyhedra. These
chelatingagentsformingfive-orsix-memberedche- threeareshownFigure2: thetrigonaldodecahedron,
late rings. In general, the coordination number the bicapped trigonal prism, and the square anti-
dependsonthebiteanglesofthechelatingunits,as prism.131-133SubsequenttothatofPorai-Koshitsand
wellasthestericbulkoftheligands.Highercoordi- Aslanov,133anotherapproachwassuggestedbyMuet-
nation numbers are often encountered with ligands terties and Guggenberger134 for determining the
having small bite angles or by the incorporation of polyhedral shape by comparing chosen ideal and
solvent molecules, as shown in Table 1. observed pertinent dihedral angles and the nonpla-
narityofthetrapezoidal-typeatoms.Idealcoordina-
The most common coordination number encoun-
tion geometries were in turn proposed by Kep-
tered in actinide(III) and -(IV) complexes is 8. Cal-
culations of ligand-ligand repulsions indicate that ert,129,135takingintoaccountarepulsivepotentialof
the form of eq 1 to optimize the ideal coordination
either the square-antiprism (D ) or the trigonal-
4d
geometry of a given symmetry.
faced dodecahedron (D ) is the expected geometry
2d
for the coordination polyhedra of eight-coordinate
m
complexes.129 The Coulombic energy differences be- (∑R-n) (1)
tween these polyhedra are small, and the preferred ij
i*j
geometry is largely determined by steric require-
ments and small ligand field effects.130 WewillrefertothisastheKepertmodelandhave
Eight-coordinatecomplexesareknowninavariety chosenn)8.Dihedralanglesalongedgesaredefined
of coordination geometries in which the assignment as the angles between the normals to adjacent
RationalDesignofSequesteringAgentsforActinides ChemicalReviews,2003,Vol.103,No.11 4215
boundingfacesofthepolyhedron,wherethevertices producinglesshazardouswaste,aswellasproviding
ofthatpolyhedronaretheliganddonoratomsaround accesstoawiderrangeofavailableanalyticaltools.
themetal.This“shapeanalysis”isthenindependent The lanthanides have been found to be useful as
of the size of the polyhedron and allows for the actinide analogues for the purpose of structural
comparison of complexes formed by various metal investigationandmodelingstudies,becauseoftheir
ions and ligands. Recently, another approach to a chemicalsimilaritiesandreducedradioactivity.Itis
continuous symmetry measure was proposed by important to remember, as the capabilities of com-
Pinsky and Avnir, in which a least-squares method puter-generatedmodelingsystemsexpandandtheir
is used to fit all of the vertices of the observed makers promote said capabilities, that while com-
polyhedron to those of idealized values.136 puter modeling may be a useful tool, many systems
Inpreviousapproachestoshapeanalysis,129,131-136 still lack the capability to model actinide systems
only specific dihedral angles were used; however, if consistently and accurately, due in large part to
the symmetry of the complex deviates significantly limiteddata.Manyofthesesystemsuseothermetals
from an idealized geometry, it becomes difficult to to approximate parameters for actinide (and lan-
decide which dihedral angles to choose. In an alter- thanide!)systems.Thus,whilecomputermodelingis
native approach, one can compare the dihedral a useful tool, there is still no substitute for quality
angles, as these are intrinsically connected to the experimental data.
notionofshapeandarethebasisofsymmetry.From
Lanthanidesandactinideshaveseveralproperties
this, it can be suggested that the geometry of
in common. Both groups act as Lewis acids, have
complexesbeanalyzedusingallthedihedralangles
largeionicradii,possessflexiblecoordinationgeom-
(one for each pair of adjacent triangular planes) in
etries, and prefer high coordination numbers (espe-
the polyhedron. All observed dihedral angles in a
cially the coordination numbers 8 and 9), and both
given structure could then be compared with the
groups prefer interactions with hard acid donor
corresponding ideal values. To this end, following
atoms such as oxygen or carboxylate, alkoxide, and
general error theory, we suggest the use of S, the fluorideanions.3,124Althoughtransuraniumactinides
“shapemeasure”,toevaluatethedegreeofdistortion
have a wide variety of oxidation states available, in
from an ideal geometry; S is the minimal mean
their trivalent state they exhibit ionic radii similar
deviationofdihedralanglesalongalledges,defined
to those of the trivalent lanthanides in the same
as
column of the periodic table or one column to the
[ ]
left.137Adivisionexistswithintheactinidegroup,in
(cid:1)
which the early actinides have multiple oxidation
1 m
S(δ,θ))min ∑(δ -θ)2 (2) states and demonstrate some covalent character,
m i)1 i i while the late actinides (Am and beyond) are even
closer in their similarities to the chemistry of the
lanthanides and are found in the +3 oxidation
wheremisthenumberofallpossibleedges(herem
) 18), δ is the observed dihedral angle (angle state.123 While this has made the separation of
i
americiumfromlanthanidesanotherpressingnuclear
betweennormalsofadjacentfaces)alongtheithedge
of the experimental polyhedron, and θ is the same wastemanagementissue,oneofthemostchallenging
i
inseparationscience,126,128,138italsoservesasaprime
angleofthecorrespondingidealpolytopalshape(D ,
2d
D , or C structures shown in Figure 2).129 The exampleofhowlanthanidesfunctionasusefulmod-
4d 2v
els.
minimizationiscarriedoutbylookingatallpossible
orientationsoftheobservedstructure(δ)relativeto Theredoxpotentialsofthecatecholcomplexes(the
the reference polyhedron (θ). The value S(δ,θ) is a metal IV/III oxidation state couple), combined with
measure(ametricinthestrictmathematicalsense) the stability constants of the metal(III) complexes,
ofstructuralresemblancetoanidealpolytopalshape. allow indirect thermochemical determination of the
Based on this method, the shape analysis of a metal(IV)stabilityconstants.22Sincethestabilityand
coordinationpolyhedronisperformedinthreesteps. coordination chemistry of metal catecholate com-
The first step is the calculation of all the dihedral plexesarelargelydeterminedbythemetal’scharge-
anglesofeachpairofadjacentplanesinthepolyhe- to-ionic radius ratio,21,139,140 the lanthanide(III) cat-
dron.Thesecondstepinthisanalysisistofindwhich echolates are excellent models for corresponding
superpositionofthepolyhedrononthetargetedideal transuraniumcatecholatecomplexes.Thishasmade
polyhedron gives the smallest deviation for that themparticularlyusefulinmodelingthebehaviorof
idealized shape. Finally, eq 2 is used to compare S americium(III)catecholatesandinthedevelopment
for the different ideal coordination geometries. A ofamericiumdecorporationagents.22,87Europiumis
computer program that incorporates this algorithm in the same column of the periodic table as ameri-
hasbeendeveloped,andtheshapemeasuresforthe cium, and gadolinium is immediately to the right of
idealized polytopal shapes are given in Figure 2.130 europium.Theeight-coordinateionicradiiare1.066
Å for Eu, 1.053 Å for Gd, and 1.090 Å for Am.137
3.1.2. Lanthanides as Models for Actinides
Plutonium presents a more complex problem. Al-
Because of the hazards and expense associated though Pu has been found in each of the oxidation
withworkingwithactinidemetals,itisoftenconve- statesfromIIItoVIinaqueoussolution,thePu(IV)
nienttouseotherlesshazardousmetalsasanalogous stateispreferred.Biologicalevidenceindicatesthat
models.Thisenablesthedevelopmentofexperimen- most,ifnotallPuexistsasPu(IV)invivo.43Cerium
tal techniques while requiring less material and is the only lanthanide for which the +4 oxidation
4216 ChemicalReviews,2003,Vol.103,No.11 Gordenetal.
state is important and long-lived, stable for several possible to decrease the required drug dose. An
weeks, in aqueous solutions.124 For this reason, Ce- excellent selective coordinating ligand is of limited
(IV) has been chosen for studies in systems for use as a sequestering agent if it is not readily
investigating Pu coordination.141,142 The problem of absorbableintothebloodstream.However,predicting
selectivityforPuoverCeindecorporationorseques- whichcharacteristicsservetoimprovebioavailability
tering applications is limited; however, systems canbedifficult.146,147Althoughlipophiliccompounds
developed using lanthanides as models would have tendtobelargelyabsorbedwhenadministeredorally,
difficultiesforwastemanagementapplicationswhere the fraction of chelator orally absorbed for a range
quantities of Ce might become an issue.128 Further ofthebidentate3,4-HOPOsintherabbitwasfound
examplesofmodeledsystemswillbediscussedinthe to be insensitive to the lipophilicity of the iron-
contextoftheparticularactinidelaterinthisreview. sequestering agent.148
Lowtoxicityisanotheressentialrequirementofa
3.2. Requirements for an Effective Sequestering
metal-sequestering agent.149 Type of chelating unit,
Agent
ligand multidenticity, and topology are important
In general, the requirements for an effective se- influencing factors. In general, for the ligands with
questering agent are high selectivity toward metal the same chelating units, those of low denticity are
binding,lowtoxicity,andpreferablyhighoralactivity less toxic than those of high denticity, and linear
and low cost. There are several factors to be consid- ligandsarelesstoxicthanbranchedligands.Wehave
eredinthedesignofanactinide-sequesteringagent, alsoobservedthatthescaffoldstructurescouldbea
and key among these is designing a ligand that crucialfactor.Forexample,inthebis(bidentate)Me-
combines a high affinity for the target metal with a 3,2-HOPO ligands with different lengths of methyl-
low affinity for other biologically significant metal ene-linking bridges, the observed toxicity sequence
ions. Thus, the electronic properties of the target is C4 . C3 > C6 > C5, while that with a 5-LIO
metalandligandmustmatch.Thechelatemustalso scaffold (-CH CH OCH CH -) is the least toxic.150
2 2 2 2
beabletoassumetheappropriatecoordinationcavity Goodoraleffectivenessisaverydesirableproperty
size and geometry for the desired metal.143 As dis- of a sequestering agent. To have good oral activity,
cussed above, the actinide ions are “hard” cations, asequesteringagentshouldhaveareasonablyhigh
havelargecharge-to-radiusratios,andprefer“hard” lipophilicitytopenetratethebiomembrane,andthe
oxygen and negatively charged oxygen donors. Pre- resulting actinide complexes should be excreted via
ferring a coordination number of 8 or greater, ac- both urine and feces. Topology could also be an
tinideionshaveatendencytoformstablecomplexes important factor influencing oral activity; for ex-
withligandsofhighdenticity.2Foragivenchelating ample, linear octadentate HOPO ligands seem to
unit, the denticity and topology of a sequestering havemuchgreateroralactivitythantheirbranched
agentplayimportantrolesincomplexation,andthese analogues, such as those with N1-(2-aminoethyl)-
should be matched to the coordination number and N1-(2-[bis(2-aminoethyl)amino]ethyl)ethane-1,2-di-
the geometry requirements of the actinide ion, re- amine (PENTEN)-based backbones.150
spectively. A well-preorganized sequestering agent Good water solubility for both the sequestering
canachievemanyordersofmagnitudeofadditional agentanditsmetalcomplexisadesirableproperty;
stability (up to 6 in the case of iron-sequestering however, this is not always the case. The neutral
agents) upon metal complex formation.144,145 metalcomplexeswithmonoanionbindingunitligands,
Highselectivitytowardactinideionsiscritical.The such as hydroxamate or hydroxypyridinone, often
effectivebutnonselectiveamino-carboxylicacidligands have poor solubility in water and are most likely to
suchasDTPAcandepleteessentialbiologicalmetal be excreted via feces.150 Last, but not least, low cost
ions from patients, thus causing serious health is an important measure for practical application.
problems.42,57,90,110,113-116Selectingthecorrecttypeof
chelatingunitisthemostdecisivefactorinachieving 3.3. Biological Means for Evaluation
high selectivity toward the specific metal ion. The
bindingsubunitsfoundinsiderophoresscatecholates, 3.3.1. Initial Assessment
catecholamide, amino-carboxylic acids, hydroxam- Chemical properties, molecular modeling, and in
ates, or hydroxypyridinonates (HOPOs)stend to be vitro measurements may produce leads, but the
extremelyspecificforFe(III)aswellasPu(IV).Hence, efficacy and toxicity of a new drug must be estab-
sequestering agents bearing these binding units lished in living animals. From its beginnings, re-
usually form highly stable complexes with actinide searchanddevelopmentofsiderophore-basedactinide-
metal ions.21 Although the strongly basic catechola- sequesteringagentsincludedbiologicalevaluationas
mide ligands should exhibit high affinity toward a guide to ligand design. The stabilities of the
actinideions,theyalsoshowstrongaffinitytoprotons actinide chelates in the range of physiological pH
and are likely to be protonated under physiological would need to be great enough to displace the
conditions, which decreases their ability for metal actinidefromtheircomplexeswithbioligandsinthe
binding.Thefactthattheamino-carboxylicacids,1,2- blood,softtissues,andbone;anynewchelatingagent
HOPOs, and 3,2-HOPOs have pK values below or fortheactinides,particularlyforPu(IV),wouldalso
a
close to physiological pH, that is, they are deproto- needtobedemonstrablymoreeffectiveforpromoting
nated at pH 7.4, makes them very effective under actinide excretion than clinically accepted CaNa -
3
physiological conditions.19 DTPA or desferrioxamine (DFO).79
The bioavailability of a sequestering agent is also Good results from chemical in vitro studies of
important, as with increased bioavailability it is competitivebinding,forexampleremovalofactinides