Radiochemical and biological e alua ion
o no el
153
Sm/
166
Ho-amino acid–chi osan
complexes
F. Ma ques,
a
L. Gano,
a
M. K. S. Ba is a,
b,c
C. A. R. Gomes,
c
P. Gomes,
b
and I. San os
a
153
Sm/
166
Ho-chi osan complexes ha e been conside ed p omising agen s o in e nal adia ion he apy. By di ec
adminis a ion, complexes solu ion con e s in o a gel, a physiological pH, allowing i s e en ion o a long ime. He ein,
we epo on he syn hesis o
153
Sm/
166
Ho complexes wi h he no el amino acid–chi osan polyme s, N-(c-p opanoyl-
alin)–chi osan (CHICO- al) and N-(c-p opanoyl-aspa ic acid)–chi osan (CHICO-asp). The main goal o his s udy was o
ob ain da a on he adiochemical and biological beha iou o hese complexes and in o ma ion ega ding hei he apeu ic
po en ial when compa ed o
153
Sm/
166
Ho-chi osan. Radiolabelling yield o
153
Sm/
166
Ho-amino acid–chi osan complexes was
dependen on polyme concen a ion bu less dependen on pH. Radiochemical s abili y was shown o be highe o amino
acid–chi osans han o chi osan, wi h
153
Sm/
166
Ho-CHICO- al being s able up o 3 h, while
153
Sm/
166
Ho-CHICO-asp is s able
up o 24 h. In he p esence o asco bic acid adiochemical s abili y o
153
Sm/
166
Ho-CHICO- al and
153
Sm/
166
Ho-CHICO was
imp o ed, dec easing o
153
Sm/
166
Ho-CHICO-asp. In i o beha iou o
153
Sm complexes was s udied in mice. The
adioac i e amino acid–chi osans can be di ec ly injec ed in o blood s eam wi hou signi ican e en ion on injec ion si e,
being apped by li e . Biodis ibu ion s udies sugges ha he adioac i e amino acid–chi osans, due o i s wa e solubili y
and s abili y may be conside ed po en ial candida es o be u he explo ed o li e a ge ed nuclea he apy.
Keywo ds: adiolan hanides; chi osan de i a i es; amino acid; polyme s; in e nal adia ion he apy
In oduc ion
In e nal adia ion he apy (IRT) wi h unsealed b-emi ing adio-
nuclides has eme ged o he ea men o cance as an
al e na i e o ex e nal adio he apy. b-emi e s ha e ad an ages
o he ea men o umou s owing o hei physical cha ac e -
is ics, in pa icula hei sho so issue pene a ion ange,
deli e ing high adia ion dose o umou wi hou ad e se
adia ion e ec s on he su ounding no mal issues.
1
Among he
b-emi e s,
166
Ho (
1/2
26.8 h, b
max
1.85 MeV (51%), g0.081 MeV
(7.5%) and
153
Sm (
1/2
46.8 h, b
max
0.81 MeV (21%), g0.103 MeV
(38%) appea o be good candida es o IRT.
2
Chi osan, a polyme o 2-deoxy-2-amino-D-glucose ob ained
by N-deace yla ion o chi in has unique p ope ies o a b oad
a ie y o applica ions.
3–5
I s chemical s uc u e is cha ac e ized
by he deg ee o ace yla ion (DA), which also de e mines i s
abili y o chela e me al ions.
3
Chemical modi ica ions o
enhance chela ing p ope ies, selec i i y and me al ion capaci y
o chi osan ha e been p oposed and a ious chi osan de i a-
i es ha e been designed o imp o e hese ea u es.
6
Keeping
his in mind, N-(2-ca boxye hyl)–chi osans ha e been p epa ed
and hei me al complexa ion p ope ies and po en ial applica-
ions ha e been s udied.
7–9
Owing o i s capaci y o complex b-emi e me al ions
h ough i s amino g oups, chi osan appea s o be a p omising
he apeu ic al e na i e o local ea men o umou s.
10
The
main ea u es o hese complexes a e hei solubili y unde
acidic condi ions and he easy con e sion o gel a he local o
adminis a ion (physiological pH), wi h he co esponding
e en ion o he adionuclide. Based on his p inciple,
153
Sm/
166
Ho-chi osan complexes ha e been p epa ed wi h
ela i ely high adiochemical pu i y (490%) and hei biological
beha iou has been conside ed p omising o local he apy o
p os a e and skin cance ,
11–13
b ain glioma,
14
enal cys s
15
and
heuma oid a h i is.
16–17
Following hese esul s,
166
Ho-chi osan
(DW-166HC) has been app o ed in Ko ea as a adiopha maceu-
ical o he ea men o small hepa ocellula ca cinoma
(HCC).
18,19
Howe e , DW-166HC is sensi i e o deg ada ion
induced by adia ion and i s use immedia ely a e syn hesis is
highly equi ed.
We ha e been wo king on he chemical modi ica ion o
chi osan amino g oups in o de o imp o e bo h he polyme
wa e solubili y o e a b oade pH ange and i s chela ing
79
Resea ch A icle
Recei ed 24 Janua y 2008, Re ised 28 Oc obe 2008, Accep ed 1 No embe 2008 Published online 16 Decembe 2008 in Wiley In e science
(www.in e science.wiley.com) DOI: 10.1002/jlc .1571
J. Label Compd. Radiopha m 2009, 52 79–83 Copy igh 2008 John Wiley & Sons, L d.
a
Ins i u o Tecnolo
´gico e Nuclea , Es ada Nacional 10, 2686-953 Saca e
´m,
Po ugal
b
CIQUP, Depa amen o de Quı
´
mica, Faculdade de Cie
ˆncias, Uni e sidade do
Po o, Rua do Campo Aleg e 687, P-4169-007 Po o, Po ugal
c
LAQUIPAI, Depa amen o de Quı
´
mica, Faculdade de Cie
ˆncias, Uni e sidade do
Po o, Rua do Campo Aleg e 687, P-4169-007 Po o, Po ugal
*Co espondence o: F. Ma ques, Ins i u o Tecnolo
´gico e Nuclea , Es ada
Nacional 10, 2686-953 Saca e
´m, Po ugal.
E-mail: [email p o ec ed]
p ope ies, o po en ial biomedical applica ions.
7–9
Recen ly,
we ha e p epa ed wo no el amino acid–chi osan polyme s,
N-(g-p opanoyl- alin)–chi osan and N-(g-p opanoyl-aspa ic
acid)–chi osan, om low molecula weigh chi osan and
N
a
-(3-b omop opanoyl)– aline o N
a
-(3-b omop opanoyl)–aspa ic
acid, espec i ely.
20
S uc u es o chi osan (CHICO, 1),
N-(g-p opanoyl- alin)–chi osan (CHICO- al, 2a)andN-(g-p opanoyl-
aspa ic acid)–chi osan (CHICO-asp, 2b) a e p esen ed in Figu e
1. In iew o he in e es ing p ope ies o ou no el amino
acid–chi osan de i a i es,
21
we decided o explo e he
coo dina ion capabili y o hese modi ied chi osan owa ds
153
Sm/
166
Ho, wo he apeu ically ele an adionuclides. He ein,
we desc ibe he syn hesis o
153
Sm/
166
Ho-N-(g-p opanoyl-
alin)–chi osan and
153
Sm/
166
Ho-N-(g-p opanoyl-aspa ic acid)–
chi osan as well as ou da a on hei adiochemical and
biological beha iou as compa ed wi h he espec i e chi osan
analogous.
Resul s and discussion
Syn hesis and s abili y o he adiolabelled complexes
I adia ion o
152
Sm/Ho-ni a es yielded 140 MBq/mg (
153
Sm)
and 190 MBq/mg (
166
Ho) wi h high adionuclidic pu i y as
con i med by he ypical g- ay spec um.
22
The complexa ion
eac ion condi ions we e op imized in o de o ob ain
153
Sm/
166
Ho-complexes wi h high adiochemical pu i y. The
labelling yield o
153
Sm/
166
Ho-CHICO–amino acid complexes
was no highly dependen on he pH, bu depends on he
polyme concen a ion. Complexes we e ob ained wi h yields
highe han 98% a pH 3–7 wi h 1% (w/ ) polyme solu ion,
while he complexa ion yield d as ically dec eases a lowe
concen a ion (Table 1). In con as , he labelling yield o
153
Sm/
166
Ho-CHICO complexes was highly dependen on bo h
pa ame e s, eaching only 98% a pHC3 and using a 1% CHICO
solu ion.
11,16
The s abili y o he CHICO–amino acid complexes was
ollowed by ITLC, using he ch oma og aphic sys ems indica ed
in he expe imen al sec ion. Bo h complexes ha e in i o
adiochemical beha iou di e en han ha o hei CHICO
analogous. While he la e complex emains in he o igin, in
acco dance wi h i s colloidal na u e, he CHICO-asp and CHICO-
al complexes mig a e wi h R
alues o app oxima ely 0.4 and
0.6, espec i ely (Table 2). None heless, in bo h cases he
p esence o ee adiolan hanide was ne e de ec ed.
A e o ma ion,
153
Sm/
166
Ho-CHICO-asp/CHICO- al com-
plexes showed ela i ely high adiochemical pu i y wi hin a
su icien ime pe iod o e en ual clinical applica ions
(
153
Sm/
166
Ho-CHICO- al is s able up o 3 h and
153
Sm/
166
Ho-
CHICO-asp is s able up o 24 h), while
153
Sm/
166
Ho-CHICO
appea ed o be mo e sensi i e and deg ading wi h s o ing.
23
As
an example, we show in Figu e 2 how as
153
Sm-CHICO
deg ades leading o new adiochemical species wi h ime. As
shown in Figu e 2,
153
Sm-CHICO leads o a new species wi h
R
E0.22, 30 min a e o ma ion, and wi h ime new species a e
o med p og essi ely wi h highe R
alues. The amino acid
de i a i es a e s able o a longe pe iod o ime and he
decomposi ion co esponds o he o ma ion o a new adio-
chemical species along wi h he o iginal ones. The di e en
beha iou ound o ou complexes may be due o he p esence
o one o wo ca boxyla e g oups in he chi osan backbone,
which may con ibu e o s uc u al s abiliza ion o he adio-
ac i e complexes.
Conside ing ha asco bic acid (AA), an an ioxidan adical
sca enge , is o en used as a ood addi i e o as a s abilize in
adiopha maceu ical composi ions,
24,25
we ha e decided o
e alua e he e ec o his compound on he adiochemical
s abili y o
153
Sm/
166
Ho-chi osan de i a i es and a he same
ime on
153
Sm/
166
Ho-chi osan. As can be seen in Figu e 2,
80
Table 1. Labelling yield s polyme concen a ion a he
pH ange 3–7
Polyme Conc. (% w/ ) Labelling yield (%)
CHICO- al 0.5 0
1100
CHICO-asp 0.5 0
1100
Table 2. Radiochemical beha iou o
153
Sm/
166
Ho-amino acid–CHICO complexes
R
153
Sm/
166
Ho-CHICO
153
Sm/
166
Ho-CHICO- al
153
Sm/
166
Ho-CHICO-asp
153
Sm/
166
Ho(NO
3
)
3
00.6 0.4 0.9–1.0
Figu e 1. Molecula s uc u es o chi osan (1), N-(g-p opanoyl- alin)–chi osan (2a)
and N-(g-p opanoyl-aspa ic acid)–chi osan (2b).
F. Ma ques e al.
www.jlc .o g Copy igh 2008 John Wiley & Sons, L d. J. Label Compd. Radiopha m 2009, 52 79–83
he adical sca enge has sligh ly imp o ed he s abili y o
153
Sm-CHICO, in ag eemen wi h he esul s p e iously de-
sc ibed by Zoldne s e al.
24
The s abili y o his compound seems
o be ela i ely dependen on he na u e o he solu ion
componen s. In ace ic acid solu ions, o example, Zoldne s e al.
desc ibed ha chi osan deg ades wi h he o ma ion o mo e
wa e -soluble agmen s along he ime, as a esul o oxida i e
and hyd oly ic spli ing o he polyme chains. Mo eo e , i has
also been e e ed ha
166
Ho-chi osan is adia ion sensi i e,
heading o dec easing in he complex iscosi y.
23
The inc ease
s abili y o
153
Sm-CHICO in he p esence o AA may be due o
he e ec o AA as a sca enge o possible adicala species and/
o o he addi ional coo dina ion capabili y o AA.
23,24
Rega ding
he
153
Sm/
166
Ho-CHICO–amino acid complexes, he addi ion o
AA (2% AA solu ion) has signi ican ly a ec ed i s adiochemical
beha iou . Fo compound
153
Sm/
166
Ho-CHICO- al i s s abili y
enhanced signi ican ly up o 24 h. In con as , he addi ion o AA
o
153
Sm/
166
Ho-CHICO-asp esul ed in a high deg ee o
deg ada ion o he ini ial complexes, wi h o ma ion o
se e al species. Based on he he mo-s abili y and s uc u al
s udies p e iously pe o med o CHICO and o CHICO-amino
acid polyme s, by di e en ial scanning calo ime y and
scanning elec on mic oscopy, he CHICO-asp has a loose
mac omolecula s uc u e han i s CHICO- al coun e pa and a
highes he mo-sensi i i y and wa e -holding capaci y, which
implies ha i s sup amolecula s uc u e is weake han ha o
i s coun e pa (Figu e 3).
20,21
Thus, while CHICO- al has a
compac and con inuous ilm-like s uc u e, CHICO-asp has a
highly po ous mo phology, p obably due o elec os a ic
epulsions be ween i s highe numbe o ca boxyla e g oups.
The po ous mo phology o CHICO-asp may allow AA, a well-
known chela ing agen ,
26,27
o e icien ly pene a e in o he
polyme ic ma ix and compe e o me al complexa ion wi h
he polyme chela ing g oups. In CHICO- al he s uc u e is
mo e compac and s able so ano he oxygen dono co-ligand
may lead o a mixed-ligand complex, which will be ancho ed on
he dono g oups o he amino acids as well as on he AA,
leading o he s abiliza ion o he adiome al by a syne gic
e ec .
24,26
Biodis ibu ion o he
153
Sm-labelled complexes in mice
P elimina y biodis ibu ion s udies we e only pe o med
o
153
Sm-complexes. Fo compa ison,
153
Sm-CHICO was also
s udied in he same animal model. As expec ed, he
153
Sm-CHICO was almos comple ely e ained a he si e o
adminis a ion and no adioac i i y exc e ion was ound up o
24 h. On he con a y, he CHICO-amino acid complexes could
be injec ed di ec ly in o he blood s eam by he ail ein. Fo
bo h complexes a high li e up ake was ound, despi e i. .
injec ion and he exc e ion was e y slow o negligible.
Howe e , he wo complexes ha e shown sligh ly di e en
biodis ibu ion pa e ns (Figu e 4). While
153
Sm-CHICO- al was
associa ed o high hepa ic adioac i i y e en ion ha enhanced
o e ime, he
153
Sm-CHICO-asp was slowly clea ed om he
li e in o he in es ine, which is a disad an age i one wan s o
ea li e cance . Addi ionally, he up ake by he li e should be
speed up in o de o educe he adia ion dose o he blood
cells. The signi ican e en ion o ac i i y in he li e ound o
153
Sm-CHICO- al can p obably be due o he in i o o ma ion o
adiochemical species o colloidal/polyme ic na u e.
Expe imen al
Chemicals: En iched sama ium oxide (Sm
2
O
3
, 98.4% as
152
Sm)
was pu chased om Camp o Scien i ic and na u al Ho
2
O
3
(99.9%) om S em. Chi osan (abb e ia ed CHICO)
(MW150 000; DA = 0.10) was supplied by Sigma-Ald ich.
81
Figu e 2. Radioac i e dis ibu ion on he ITLC-SA s ips o
153
Sm-CHICO complex
ob ained in he absence and p esence o asco bic acid o e ime.
Figu e 3. SEM mic og aphs (100 magni ica ion) o CHICO (A), CHICO- al (B) and CHICO-asp (C).
F. Ma ques e al.
J. Label Compd. Radiopha m 2009, 52 79–83 Copy igh 2008 John Wiley & Sons, L d. www.jlc .o g
Ins an hin laye ch oma og aphy (ITLC) s ips we e supplied
by Polyg am, Mache ey-Nagel. N-(g-p opanoyl- alin)–chi osan
(abb e ia ed CHICO- al) and N-(g-p opanoyl-aspa ic acid)–chi-
osan (abb e ia ed CHICO-asp) we e syn hesized and pu i ied
acco ding o me hods p e iously epo ed.
21
All ma e ials we e
eagen g ade unless o he wise speci ied.
Syn hesis o he pep ide chi osan polyme s: The syn hesis o he
wo no el CHICO-based polyme s was epo ed in de ail
elsewhe e.
21
B ie ly, N
a
-(3-b omop opanoyl)- aline and N
a
-(3-
b omop opanoyl)-aspa ic acid we e p epa ed by eac ing he
ele an L-amino acid e -bu yl es e s wi h 3-b omop opanoic
acid in he p esence o dicyclohexylca bodiimide (DCCI) as
coupling eagen . A e being isola ed by column ch oma o-
g aphy on silica, he e -bu yl es e s we e success ully iden i ied
by
1
H and
13
C NMR. These es e s we e hen clea ed by acidolysis
wi h nea TFA, wi h quan i a i e o ma ion o he co esponding
ee ca boxylic acids N
a
-(3-b omop opanoyl)- aline and N
a
-(3-
b omop opanoyl)-aspa ic acid, whose s uc u es we e also
con i med by NMR. The ca boxylic acids ob ained as abo e
desc ibed we e co alen ly a ached o chi osan as ollows:
chi osan was dissol ed in wa e con aining 4 M equi alen s o
N
a
-(3-b omop opanoyl)- aline o N
a
-(3-b omop opanoyl)-aspa -
ic acid. The eac ions we e allowed o p oceed a 601C unde
magne ic s i ing and wi h daily addi ions o NaHCO
3
o keep pH
wi hin he 6–8 ange. The pep ide–chi osans we e pu i ied by
dialysis agains deionized wa e o 5–7 days, and hen
eeze-d ied.
P oduc ion o
153
Sm and
166
Ho:
153
Sm and
166
Ho we e
p oduced by
152
Sm(n,g)
153
Sm and
165
Ho(n,g)
166
Ho eac ion,
espec i ely, in he ITN Nuclea Resea ch Po uguese Reac o
(1 MW). I adia ion was pe o med using ni a e a ge s (Sm/Ho,
10 mg) p epa ed om he co esponden iso opically en iched
152
Sm
2
O
3
o na u al Ho
2
O
3
unde a he mal neu on lux
o 1.5 10
13
n/cm
2
s and epi he mal neu on lux o
3.1 10
11
n/cm
2
s o 1–2 h. Following i adia ion, he a ge s
we e econs i u ed in H
2
O o yield 1% (w/ )
153
Sm/
166
Ho-ni a e
solu ion o complex p epa a ion. The adionuclide pu i y was
assessed by gspec ome y wi h a Ge(Li)-de ec o (Canbe a)
and ac i i ies we e measu ed by a adioiso ope calib a o (Aloka,
Cu ieme e IGC-3, Tokyo, Japan).
Radiolabelling p ocedu e: The p epa a ion o
153
Sm/
166
Ho-
complexes wi h a high labelling yield (498%) was op imized.
Typically, 40 mLo 1%
153
Sm(NO
3
)
3
solu ion o 20 mLo 1%
166
Ho(NO
3
)
3
solu ion was added o 700 mL o CHICO o CHICO-
based polyme solu ion in 1% ( / ) ace ic acid, ollowed by
ho ough s i ing o 20 min a oom empe a u e. The
adiolabelling pH o he esul ing solu ions was 3.0 o
153
Sm/
166
Ho-CHICO complex and 7.0 (by adding an app op ia e
olume o 1 N NaOH solu ion) o
153
Sm/
166
Ho-pep ide-chi osan
based complexes. The labelling e iciency was accomplished by
ITLC, using ITLC-SA s ips de eloped wi h MeOH:H
2
O:ace ic acid
(50:50:0.5) as he mobile phase. In his sys em, he adiochemical
species mig a e wi h he R
p esen ed in Table 2. Radioac i e
dis ibu ion on he ITLC-SA s ips was de ec ed by using a
Be hold LB 505 de ec o coupled o a adioch oma og am
scanne . The s abili y o he
153
Sm/
166
Ho-CHICO o
153
Sm/
166
Ho-
CHICO-based complexes was assessed by measu ing he adio-
chemical pu i y by ITLC o e ime, up o 24 h. The e ec o he
adical sca enge AA (2% AA solu ion) on he s abili y o he
complexes was also s udied.
In i o s udies: Biodis ibu ion s udies we e ca ied ou using
no mal CD-1 mice om Cha les Ri e , Spain, acco ding o
p e iously epo ed p ocedu es.
22
Animals we e in a enously
injec ed, ia he ail ein, o in ape i oneally injec ed wi h 100 ml
(3.7 MBq) o he adiolan hanide complexes. A e 1 and 24 h
animals we e killed by ce ical disloca ion, he main o gans we e
dissec ed and he adioac i i y coun ed in a gcoun e (Be hold
LB 2111, Ge many). Biodis ibu ion esul s we e exp essed as
pe cen o injec ed dose pe o al o gan (% I.D./o gan).
Concluding ema ks
Conce ning he bes s a egy o deal wi h inope able HCC, he e
is a gene al lack o consensus. Classical app oaches include
ans-a e ial chemo-emboliza ion (TACE) o IRT h ough admin-
is a ion o adionuclide–lipiodol complexes ha ha e he
ad an age o being highly e ained by hepa ic umou s.
28–35
Howe e , TACE is no sui able o ad anced disease o pa ien s
wi h an obs uc ed ( h ombo ic) po al ein, whe eas adiola-
belled lipiodol (e.g.
131
I-lipiodol) is associa ed wi h pain on
injec ion and occasional induc ion o se e e pneumopa-
hies.
30,31
Radioimuno he apy can be a way o ci cum en
he abo e p oblems. Bu ea men s wi h he monoclonal
131
I-Hepama-1, hough associa ed wi h low oxici y, usually
equi es hepa ic a e y liga ion, whe eas polyclonal
131
I abbi
an i e i in IgG has been ela ed o h omobocy openia.
31
Al e na i ely, adiolabelled glass o esin mic osphe es ha e
been explo ed as po en ially sa e IRT agen s, bu hei clinical
e icacy has no been p o ed so a . Success ul ea men o li e
umou s in an animal model was achie ed wi h
166
Ho-labelled
poly-(L-lac ic acid) mic osphe es, which opens new possibili ies
owa ds he use o mic osphe es buil om biocompa ible
ma e ials.
31
In his con ex , adiolabelled chi osan-based poly-
me s appea as a mos a ac i e and cos -e ec i e choice, as
chi osan is cheap, biodeg adable, bioadhesi e and biocompa-
ible, and has low oxici y and low immunogenici y. Indeed, he
app o ed
166
Ho-chi osan complex (DW-166HC), was ound o be
a highly e ec i e and sa e new adiopha maceu ical agen o
IRT agains li e cance .
19
The CHICO-amino acid polyme s,
desc ibed he ein, we e ound o be sui able ligands o he
p epa a ion o s able
153
Sm/
166
Ho-complexes wi h high
labelling yields (498%) and high adiochemical pu i y o e
he ime. As compa ed wi h unmodi ied chi osan, he amino
82
Figu e 4. Whole body exc e ion and biodis ibu ion in he mos ele an o gans o
153
Sm-CHICO complexes a 1 and 24 h a e adminis a ion in mice.
F. Ma ques e al.
www.jlc .o g Copy igh 2008 John Wiley & Sons, L d. J. Label Compd. Radiopha m 2009, 52 79–83
acid de i a i es p esen se e al ad an ages o e en ual clinical
applica ions: wa e solubili y o e a wide pH ange and
quan i a i e o ma ion o non-colloidal adiolan hanide
complexes. Despi e hei highe luidi y, he adiolabelled
CHICO-amino acid complexes ha e highe s abili y han hei
CHICO coun e pa s and may be po en ially in e es ing o be
explo ed o he ea men o HCC and li e me as asis, when
ea ing he whole li e makes i mo e sui able as compa ed
wi h esec ion o li e ansplan a ion.
36
In addi ion, in a
clus e ed me as asis o p ima y umou , he c oss- i e e ec o
b

ene gy pa icles migh also be bene icial.
36,37
P elimina y
biological esul s ha e shown ha
153
Sm-CHICO-amino acid
complexes p esen high li e up ake specially CHICO- al. This
a ge ing o he li e may also be exploi ed o li e -speci ic
a ge ing and wi h he app op ia e adionuclide, o imaging.
38
Whe he he biodis ibu ion p o ile o his adioac i e amino
acid–chi osan could be imp o ed in o de o inc ease he blood
clea ance and hen minimize he adia ion dose o non- a ge
o gans he chance o adminis e i ia i. . injec ion may be a
signi ican ad an age ela i ely o he compounds ad oca ed o
he same pu pose, which equi e local adminis a ion. The
imp o ed adiochemical and biological cha ac e is ics o
153
Sm/
166
Ho-CHICO–amino acid complexes highligh he
in e es o u he explo e he chemical modi ica ion o chi osan
in o de o in oduce unc ional g oups o modula e i s
pha macokine ics, coo dina ion capabili y owa ds di e en
adionuclides and speci ici y o design speci ic adio ace s.
39
Acknowledgemen
The au ho s wish o hank he ITN Po uguese Resea ch Reac o
o he p oduc ion o
153
Sm and
166
Ho. P. Gomes and C. A. R.
Gomes hank FCT o unding o esea ch uni s CIQUP and
LAQUIPAI, espec i ely. M. K. S. Ba is a hanks FCT o he
doc o al g an ( e . SFRH/BD/13144/2003).
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