IN. J. Nucl. Med. Biol. Vol. 12, No. 2, pp. 115-123, 1985 0047-0740/85 $3.00 + 0.00 Printed in Great Britain Pergamon Press Ltd

Relation between the Location of Elements in the Periodic Table

and Tumor-Uptake Rate

ATSUSHI ANDO’, ITSUKO ANDO’, TATSUNOSUKE HIRAKP and KINICHI HISADA’

‘The School of Allied Medical Professions and ‘School of Medicine, Kanazawa University, Kanazawa City, Japan

The bipositive ions and anions, with few exceptions, indicated a low tumor uptake rate. On the other hand, compounds of Hg, Au and Bi, which have a strong binding power to protein, showed a high tumor uptake rate. As Hg?+, Au+ and Bi’+are soft acids according to the classification of Lewis acids, it was thought that these ions would bind strongly to soft bases (R-SH, R-S-) present in tumor tissue. For many hard acids such as s5SZ+, 67Ga3+, ‘*‘HP+, and “Nb’+, tumor uptake rates are shown as a function of ionic potentials (valency/ionic radii) of the metal ions.

Considering the present data and previously reported results, it was presumed that hard acids of trivalence, quadrivalence and pentavalence would replace calcium in the calcium salts of hard bases (calcium salts of acid mucopolysaccharides, etc.).

Ionic potentials of alkaline metals and Tl were small, but the tumor-uptake rate of these elements indicated various values. As Ge and Sb are bound by covalent bonds to chloride, GeCl, and SbCl, behaved differently from many metallic compounds in tumor tissue.

Introduction A variety of’ radioisotopes injected intravenously produce a higher concentration in tumor than in normal tissues. Some of these isotopes have been used for detecting and locating tumors, using scintiscan- ning. For example, 67Ga-citrate, which was first used by Edwards and Hayes in 1969, has been extensively used for clinical tumor scanning. Since the discovery of tumor accumulation of radioactive bismuth by Kahn”’ in 1930, a number of radioactive inorganic compounds have been studied carefully by many investigators. These reports have been summarized by Paierson et al.,(*) by Larson,(3) and by Lopez- Majano and Alvarez-Cervera.(4) In 1968, we began to quantitatively determine the distribution of radio- active inorganic compounds in tumor bearing ani- mals. To date we have examined 55 elements and 122 compounds. In this study, metal organic compounds such as 67Ga-citrate are classified inorganic com- pounds, because 67Ga is dissociated from 67Ga-citrate in solution. We investigated the uptake rate in tumor tissues, and other properties of these inorganic com- pounds.

In the present paper, relations among uptake rate in tumor tissue, location of elements in the periodic

All correspondence should be addressed to: Atsushi Ando. Ph.D.. The School of Allied Medical Professions, Kanazawa University 5- 1 I-80. Kodatsuno, Kanazawa City, 920 Japan.

table, and some properties of these inorganic com- pounds are summarized and discussed. Binding sub- stances of these compounds are also discussed.

Materials and Methods

Animals

Donryu rats (body weight 150-200 g) underwent S.C. implantation of Yoshida sarcoma (2 x 10’ cells/O.5 mL) in the right thigh. Six to seven days later an appropriate amount of radioactive nuclide was administered, at which time the tumor had grown to 1.5-2.0 cm in diameter.

Radioactive inorganic compounds in solution

These labeled compounds were prepared as carrier free nuclides or as those containing little stable nuclide. Concentrated radioactive compounds were obtained commercially from The Radiochemical Centre (England), New England Nuclear (U.S.A.), Union Carbide Corporation (U.S.A.), Oak Ridge National Laboratory (U.S.A.), Commissariant A L’Energie Atomique (France), Philips-Duphar Cyclotron and Isotope Laboratories (Holland), Japan Atomic Energy Research Institute (Japan), and others. These nuclides were prepared in the appropriate chemical forms (chloride, nitrate, citrate, acetate, oxalate, etc.) and were adjusted to the pH and the osmotic pressure at which radioactive prepa-

115

116 Arsusl-n ANDo Cl al

rations can be injected intravenously into the ani- mals. Each preparation (0.4 mL, l-10 pci) was used for injection. Chemical forms, concentrations, and the amounts of carrier (mass at which the compounds were converted into the elements) administered to an animal were as follows: 22NaC1(Na 0.016 pg), 42KCl(K 7 mg), 86RbC1(Rb 3 pg), ‘34CsCl (Cs 2.9 pg), “OmAgNOJ(Ag 1.3 pg), H’98A~C14(A~ 3 pg), 64CuC12(Cu 0.56 mg), ‘BeC&(Be 1.5 pg), 47CaC12(Ca 7/Jg), 85SrC12(Sr 2 pg), 85Sr-citrate(Sr 2 1.18) ‘“BaCl, (carrier free), 65 ZnCl, (Zn 1 Pg)t “5mCdC12(Cd 30 pg), “5”‘Cd-citrate(Cd 30 pg), 203Hg-acetate (Hg 3pg), 46ScC13(Sc 6 x lo-‘mg), “%c-citrate(Sc 6 x 10m5 mg), “YCl, (Y 0.25 mg), 67 Ga-citrate(carrier free), 67 Ga(N0, )3 (carrier free), “I In-citrate(carrier free), “4mInC1,(In 25 pg), “‘TlCl(T1 0.02 pg), ““‘LaCl,(La 40 pg), 14’Ce-citrate (Ce 7.2 pg), ‘53 SmCl,(Sm 8.3 pg), ‘53Sm-citrate(Sm 36 pg), ‘53 Gd-citrate(Gd 0.006 pg), laTb-citrate(Tb 5.4 pg), 16’Tm-citrate (carrier free), ‘69Yb-citrate(Yb 0.005 pg), ‘69YbClJ(Yb 0.005 pg), “‘LuClj(Lu 3 pg), “‘Lu-citrate(Lu 3 pg), 95Zr(NOJ)4 (carrier free), 95Zr-oxalate(carrier free), ‘*’ HfCl, (Hf 0.6 pg), 68 GeCl, (carrier free), “3SnCl,(Sn 3.6 pg), “3Sn-citrate(Sn 3.6 pg), 2’oPb(NOJ)2(Pb 0.11 pg), 48v02 Cl(v 0.04 ,ug), 95Nb-oxalate(carrier free), ‘82Ta-oxalate(Ta 0.9 pg), NazH74As04(As 0.003 pg), ‘“SbCl,(Sb 0.17 mg), 206Bi-acetate(carrier free), 5’ CrCl, (Cr 0.38 pg), Na2 5’ CrO, (Cr 0.5 pg), (NH4)299Mo04(Mo 29 pg), Na,‘*’ W04(W 3.3 pg), Na275Se04(Se 0.5 pg), Na2”SeOj(Se 0.1 pg), H ‘27mTe03(Te 74 p g), 54 MnCl,(carrier free), Ni99”Tc04(carrier free), Na’86 ReO,(Re 2.9 pg), NH,*‘Br(Br 0.23 mg), Na”’ I(carrier free), 59 FeCl, (carrier free), lo3 RuCl,(Ru 20 /Jg), lo3 PdCl,(carrier free), H2’850sC16(Os 40 pg), 58CoC12(carrier free), Hzi921rC16(Ir 1.8 pg).

Tumor accumulation

Each preparation was injected intravenously through the tail vein of rats implanted with Yoshida sarcoma. Three hours, 24 h and 48 h after the admin- istration of these nuclides, the animals were anesthe- tized by sodium pentobarbital injection, and approx- imately 1 mL of blood was collected from the carotid artery. After this, the tumor tissue, liver, kidney, spleen, etc. were excised. These tissues and the blood were weighed and counted on a gamma counter against an appropriate standard to obtain the per- centage of injected dose per gram of tissue (% dose/g). This value was normalized to a body weight (BW) of 1OOg by multiplying by BW/lOO. Furthermore, cumulative urinary excretion (O-3 h) was assayed.

In vitro adsorption rate to the protein

An amount of 0.1 mL of each preparation was added to test tubes containing 1 mg of human serum albumin and 2 mL of acetic acid-sodium acetate buffer solution (pH 5.5). The mixture was mildly

stirred for 20 min at room temperature. Then the albumin was solidified by heating for 2 min m a boiling water-bath, and centrifuged at 3000 rpm for 10min. The sediment and supernatant were each counted on a gamma counter. Adsorption rate(“,) to albumin was calculated by the following formula:

Adsorption rate(‘,) to albumin =

sediment(net counts) sediment(net counts) + supernatant(net counts)

x lOO(“,)

Results and Discussion

Tumor accumulation andin vitro adsorption rate to the protein

Uptake rates(?; dose/g) of each compound into the tumor at 3, 24 and 48 h after administration are shown in Tables 1, 2 and 3. respectively. Generally speaking, compounds which released radioactive cat- ions, except some bivalent cations, revealed a high tumor uptake rate, as is shown in these Tables. Among the compounds which release radioactive cations, the compounds of Be, Ca, Sr, Ba, Co, Pd, Cu, Cd and Sn(bivalent cations) showed a low tumor uptake rate. On the other hand, many kinds of radioactive anions were only slightly taken up into the tumor, while the compounds NH482Br, H2 ‘27mTe03, Na275 SeO, and Hz’S50sC1, were taken up in a large quantity. Ge and Sb which were bound by covalent bonds to chloride were taken up only to a minor degree. Relations between the uptake rate in the malignant tumor and the adsorption rate to the protein of labeled compounds are indicated in Fig. 1. The compounds of Hg, Au, Bi and OS, except 203Hg-chlormerodrin, had high tumor uptake rates and large adsorption rates to albumin in vitro. Except for the above compounds, most inorganic radioactive compounds exhibited low adsorption rates to albu- min in vitro, but the tumor uptake rate ranged from maximum to minimum. It is known that Hg binds to specific protein and becomes metallothionein in the kidney and the liver. Considering the chemical char- acter of Hg, Au and Bi, one would expect these three elements to have become metallothionein in the tumor tissue. The elements (Ga, Nb, etc.), which had a high tumor uptake rate and small adsorption rate to the protein, had binding power to the tumor tissue other than binding power to the protein.

On the chemical bond of metal compounds, the following rules apply. 15) A number of Lewis acids of diverse types are classified as hard acids and soft acids. Hard acids prefer to bind to hard bases. Soft acids prefer to bind to soft bases. Among the above elements, Ga3+ In-‘+ Cr’+ Lu’+ Sc3+, Mn*+ Sr2+ Ca2+, Zr4+, Hf4+ ark hard acids,’ Hg’+ , Cd2+: Pd2; are soft acids, and Cu’+, Co2+, Zn2+, Sn2+ are borderline cases. Among the body constituents of animals, R-SO;, R-PO:-, and R-COO- are hard bases, and R-S-, and R-SH are soft bases. It is

Table

I Relauon between t

he lo

cation of elements in t

he pe

riodic table and tumor uptake r

ate(y,,dose/g)

3 hours a

fter admmislration or radioactive inorganic co

mpounds. Each value represents the m

ean

of five animals

t

--;;;-~~I~

,,,~~-I~-~I--IyB--~-~~T~vTl--lvnRT.-

1 I

B

1 II

B

1 ,&

-[;A

-] v A

1 VI A

[ VII

A VIII

---

radioactive

inorganic

cowlpound

0.58 *

--

tunlor up

take rate(%dose/g)

"N&l

1.42

-

"CaC12

0.39

*“S

cCl)

1.00

4hS

C-

citrate

0.79

qOYcl,

1.52

I

*2KCl

0.63

'Bvo2cl

0.98

+FeCIJ

1.03

"ZnC12

"Ga-

;itrate

1.11

'Ga(NO1):

1.54

IllIn_

citrate

1.02

'4mInClJ

1.51

“GeC

l b

?ia,H"As(

0.67

0.32

0.18

-

'&RbCI

1.07

n”S

)._

citrate

0.52

--__

"Zr(NO1]

1.51

)5Zr-

oxalate

1.24

"Nb-

oxalate

1.10

:Nll,

,)“‘l4

00~

Na w

’” Tc

t

0.38

0.28

_____~____

Na,'R'WOI Na'86Re&

0.21

0.43

"RuCl,

0.91

-

103PdC12

0.25

+

~~SmcdCl

'OmAgNO~

0.42

i .31

I 1,

s”‘C

d_

citrate

"'SnC12

0.23

113Sn_

:itrate

0.22

'24SbClg

0.12

-.-

6 Iso B

aCl,

0.23

"O LaCl,

0.90

In1 HfClr,

1.21

lazTa_

oxalate

__-

219* I I-cl6

0.22

-I 0.38

203Hg_

"9BAUC'

acetate

1.21

1.39

"' T

lCl

0.51

“Pb(

NO

3 0.82

*06B

j_

acetate

0.84

1.76

‘53

Slll

- citrate

Lanthanides

0.82

'5'slllc

i ,

0.81

L-

~~~~~ 2

. Relation between th

e location of

elements in t

he pe

riodic table and tumor uptake r

ate$;doselg)

24 hours af

ter administration of radioactive

inorganic co

mpounds. E

ach

valu

e re

pres

ents

mea

ll of

liv

e animals

I A

II A

III B

IV 8

VB

VI B

VII

B VIII

I B

II B

III A

IV A

VA

VI A

VI

F - 1 2 - 3 4 - 5 - 6 7 -

I A 4

- - - Itts’

1

- Ial 0

-

- radioactive

inorganic

couq~ound

- tuner

uptake r

ate(ldose/g)

'BeC12

"NaCl

1.34

T

T

1

16

"KC1

0.76

4'CaC1*

0.36

4ssccls

1.13

u6sc-

citrate

1.15

qsvO*C1

0.94

"FeCl,

1.01

azH7#s0,

0.21

laz7*Se0

0.61

la2'sSe0

0.36

L c

Ir H

” Br

.26

'*"SbCll 2'*7mTe(

0.02

1.17

!‘6B

i_

acetate

1.38

‘67T

m_

citrate

1.14

1 7’

Lu_

citrate

1.27

1.07

'69YbCl,

‘77

LUc&

1.

29 1.

1.33

__

~---

‘7&

‘_

:itrate

'sGeCls

1.72

0.02

'Ga(NO&

5ecoc12

0.39

'4CuC12

652nC12

0.39

1.00

"'PdClj

0.22

2.98

"sm Cd_

---L

citrate

0.34

l"sAuC1

20'Hg_

' acetate

0.16

2.05

1.65

2.23

t

"TIC1

"'Pb(NO,)~

0.36

0.81

-’

ssSrCll

0.09

sSSr-

citratl

0.04

90YC13

0.95

“Zr(N

&)

1.47

sZr-

oxalate

1.87

__-

"'HfClu

1.31

'SNb-

oxalate

2.03

4 I

ssRbC1

1.30

34cscl -_

1 *'BaC12

0.65

0.11

[NH+kwMoO1, NasTcO

0.04

0.04

"'RuClr

1.26

ip50sc1

0.97

e

I

-

I- *OLaCII

0.66

‘82T

a_

oxalate

1.40

0.006

0.01

61

- --

-l_-

‘“‘C

l+

citrate

-I 0.47

Lanthanides

3 4 - 5 6 7 -

'EdI,

0.19

- radioactive

inorganic

colllpuund

- twor

uptake rate('Xdose/g)

1.08

___~

="'MnC12

0.60

I- _- 1 H

""Cdl,

0.01

0.23

a ,75Se0,,

/ 0.65

a,75Se0-

0 28

i 7 127”

l~e(

)

0.87

"7CaC1*

0.22

-,7 &q_

litrate

1.27

"Ga(NOJ

1.64

IIn-

zitrate

1.35

@"'InCl,

1.38

5’C

rCI 3

1.05

Na>lCrQ,

0.36

‘6S

cCl3

0.

97

'6S

C-

:itrate

1.07

9OYClj

1.09

syre

t_s3

0.88

O%JCl,

1.05

‘If, C

oCl,

0.20

1,'97YrC

0.13

6’ _

""vo,cl

0.62

95Nb_

oxalate

2.01

lon'AgNC

2.27

‘3S

llCl~

Il.22

‘3 S

n-

:itrate

0.14

a6RbCl

1.26

"SZr(NO,)

1.61

=Zr-

oxalate

1.52

5"'CdC1,

0.25

%lCd_

itrate

0.45

---

2031@

acetate

1.46

O"PdCI,

"+SbC13

0.01

‘98

AuC

l

I .a

9

O'TlCl

'OPb(NO,

0.23

0.43

'34C

sCl

0.34

I40 B

aCl,

0.12

"OLaCl,

0.57

10’ HfClI,

1.35

102

,a_

oxalate

1.28

la,lBIWOI,

0.004

Ja'86Re0,

0.0011

Ij""OsC1

1.24

I I i

169y

b_

citrate

1.19

'hgYbC1)

1. ?

i

1.-

'67T~n-

citrate

"7Luc1,

I.08

, J

Lanthanides

I i

1 .03

120 ATSUSHI ANDO et al.

reasonable to assume that metallothioneins in tumor tissue are composed of protein and soft acids such as Hg’+ and Cd’+. It is also reasonable to assume that hard acids such as Gal+ and Nb’+ would bind to hard bases such as R-SO;, R-PO:- and R-COO-.

Relation between tumor uptake rate and ionic potential of the metal ions

To investigate the mechanism of tumor uptake of hard acids, ionic potentials (valency/ionic radii) of these cations were calculated, and the relation be- tween tumor uptake rate and ionic potential are

shown in Fig. 2. As can be seen in this figure. radioactive compounds were classified into four groups. The compounds in group 3 had a low ad- sorption rate to albumin in cirro (Fig. 1). Most cations, which were released from these compounds in group 3, were hard acids. For these cations. the uptake rate into the tumor is shown as a function of ionic potentials. The cations, which were released from the compounds in group 2 were soft acids.

As is mentioned above, it is reasonable to assume that most cations released from the compounds in group 3 would bind to R-SO,. R-PO:- and

ZZNaCI~“LUCl~

I / “4ml”CIJ .

I )

I/ “*Ta-oxal.t. .

??=e%lcI ??(HYb-citrat.

I H*. / '*'%O, “‘Tm-citrate

. .%cCI Y’Lu-citrate

3 .S’CrCI,

I ) 9’ycI .“FeCI~ .%‘Cl*

. ‘.‘%O*C I

‘%mC I3 . .Z’oPb(N0,)2 .“KCI

6

I

10 20 30 40 50 60 70 60 90 100 Adsorption ratet% 1 of radtoactlve inorganic compounds to albumin in vitro

Fig. I. Relation between the uptake rate into themalignant tumor and adsorption rate to the protein of radioactive inorganic compounds. Each point of uptake rate represents the mean of five animals. Each

point of adsorption rate represents the mean of three experiments.

??67Ga(NO3)3

??6’Ga-citrate 203Hg-.c.tat.

.

Tumor-uptake rates of elements 121

R-COO- in the body, and that the cations released from the compounds in group 2 would bind to R-SH and R-S- in the body. As Ge and Sb were bound by covalent bonds to chloride, cations were not dis- sociated from GeCl, and SbCl, . Therefore, these two compounds behaved differently from the above com- pounds in tumor tissue. Radioactive nuclides con- tained in group 1 (Fig. 2) are alkaline metals (except for Tl), and the chlorides of both alkaline metals and Tl become monovalent cations in the body. On the other hand, it is known that the accumulation of 20’Tl is significantly correlated to that of 42K.(6’ Alkaline metals cannot be bound to ligands by coordinate bonds, but are bound by ionic bonds. As is shown in

Fig. 2, ionic potentials of alkaline metals and Tl are small, although the tumor uptake rates for these elements had a wide range of values. Since large quantities of sodium and potassium are contained in an animal’s body, administered radioactive sodium behaves just as sodium contained in the body, and injected K, Rb, Cs and Tl behave in accordance with the biodistribution of K present in the body.

Ca2+, S?+ , Ba2+ and Be*+ are bivalent hard acids. These cations can be strongly bound to R-SO,, R-PO;- and R-COO- in distilled water. However, these cations showed low tumor uptake rates. From the results of the present study, the following con- cepts became clearer. As hard bases present in the

I ) .‘.’

:’ ."dnlp~NO~ : ‘.

H’99A,,C~ : ’ ‘..,

40: ; q5Nb-oxalateeL : ; :

.’ : ,’

: ; ??q5tr-oxalate : :

i 203 .’

,,, ??Hg-acetatd : ??“Ga-citrate

: ,’

iv : : .q5zrW4)4

. . I .

.,22ryy 2Oi& -acetat+j 962

” 66. RbClj

&&l7~~“C’3

;’ f16syb-citra~Hfc’4 e?3R~C14,.

qjoxalate

??lflln-citrate ,,“‘Wn-

????4 i it rate

“‘LLitr#e scci3 .’ , ,’

:~~5Znclz ??5crc13 ??“FeCl3 :

??“Ya3

‘. .- 66GeCI, _ .*.:. 1 2 3 4 5 6 1 a 9

Ionic potential (valency/ ionic radii )

Fig. 2. Relation between the uptake rate into malignant tumor and ionic potential of the metal ions. Each point of uptake rate represents mean of five animals. Uptake rate into the malignant tumor or inorganic

compounds in group 3 are shown as a function of ionic potential of the metal ions.

122 Arsusm ANW et al.

body had already been saturated with Ca*+ , bivalent hard acids administered would bind to hard bases in the body to only a small degree. But hard acids of trivalence, quadrivalence and pentavalence would replace calcium in calcium salts of hard bases.(‘) These concepts on the accumulation mechanism of radioactive cations agree with the belief of Anghileri er af. that competitive binding of 67Ga3+ to Cat+ -and Mg?+ -binding sites rather than a metabolic process, is involved in the accumulation of 67Ga3+ .@’

Binding substances of hard acid of tri-, quadri-, and pentavalence

Transferrin,‘9’ ferritin, (‘O’ 45000 molecular weight glycoprotein”“. and lactoferrinu2 were reported at 67Ga-binding substances in the tissues. On the other hand, we have been studying the mechanism of tumor concentration of radioactive inorganic compounds such as 6’Ga-citrate. In 1971, from the experimental results on 26 kinds of radioactive inorganic com- pounds, we classified these compounds into the fol- lowing three groups. The first group contains com- pounds (*03Hg-acetate, etc.) which have high tumor uptake rates and large adsorption rates by albumin; the second group contains compounds (67Ga-citrate, etc.) which exhibit high tumor uptake rates and small adsorption rates by albumin; and the third group includes compounds (85 Q-chloride, etc.) which have low tumor uptake rates and small adsorption rates by albumin, We have reported that binding power to the protein did not play an important role in the tumor uptake of the compounds in the second group, but it seemed to play an important role in the tumor uptake of the compounds in the first group.(‘3’ In 1974, we concluded that the chemical bond of 67Ga, “‘In and ‘69Yb (the elements of group III in the periodic table) to thiol radicals was not of the chelate ring type, but was an ionic bond to sulfonic groups, phosphoryl radicals and carboxyl radicals in the body, and that binding of these elements to body constituents were performed by an ion-exchange reaction to some of the above radicals.“4’ In 1977, we reported that for many hard acids (according to classification of Lewis acids), the uptake rate into the tumor was shown as a function of ionic potentials(valency/ionic radii) of the metal ions. And we presumed the accumulation mechanism for hard acids to be as follows: The chemical bond of these hard acids in tumor tissue was an ionic bond to hard bases (R-COO-, R-PO:-, R-SO;). As hard bases present in the body had already been saturated with Ca2+, bivalent hard acids administered could scarcely be bound to hard bases, but hard acids of trivalence, quadrivalence and pentavalence would replace calcium in the calcium salts of hard bases.“’

In 1977, we presumed that 67Ga, “‘In and ‘69Yb were bound to acid mucopolysaccharides, because the concentration of these nuclides was predominant in connective tissue (especially inflammatory tissues) rather than in viable tumor tissue, regardless of the

time after administration, and because connective tissue (especially inflammatory tissues) contained large amounts of acid mucopolysaccharides which had many sulfonic groups and carboxy radicals in their structures.“” In 1979, Ando originally determined that 67Ga “‘In and ‘69Yb were bound to the acid mucopolysaciharides in two species of tumor tissues (Ehrlich tumor and Yoshida sarcoma).“@ In 1980, it was also reported by Ando et al. that a 67Ga-binding acid mucopolysaccharide had been separated by cellulose acetate electrophoresis from tumor tissue and liver lysosome, and that 67Ga-binding acid mucopolysaccharides in tumor and liver were very similar.“7-‘9’

Later, these reports of ours were also supported by the in vitro study of Kojima et at.‘*” In 1983, we found that keratan polysaccharide (a kind of acid mucopolysaccharides) plays the most important role in the metabolism of 67Ga.‘2” Furthermore, we reported that “I In, ‘69Yb,‘22’ ‘67Tm’23’ and 95Nb”“’ were bound to acid mucopolysaccharides in tumor and liver. For the reasons described above it is presumed that all the hard acids of tri-, quadri- and pentavalence would be bound to acid muco- polysaccharides in tumor and liver.

Acknowledgement-This work was partially supported by Grant-in-Aid for Scientific Research.

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Tumor-uptake rates of elements 123

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