ORIGINAL 
Annals of Nuclear Medicine Vol. 3, No. 3, 135-138, 1989 
111In (III) uptake by inflammatory and normal tissues 
Yasuhito OHKUBO,* Kenichi ABE,* Hiroyuki KOHNO,* Shinsuke KATOH* and Akiko KUBODERA** 
*Department of Radiopharmacy, Tohoku College of Pharmacy, Sendai 981, Japan 
**Department of Radiopharmacy, School of Pharmaceutical Sciences, Science University of Tokyo, Tokyo 162, Japan 
Tissue distributions of 111In (III) in the rats bearing granuloma, inflammatory tissue induced by turpentine oil, were compared with those of 67Ga. The results showed that indium-111 resembles 67Ga in the manner of uptake by inflammatory and normal soft tissues. The effect of cold-InCl3 on 111In (III) uptake showed that transferrin is not involved in the uptake of 111In (III) into inflammatory tissues but is involved in the uptake into liver and spleen. 
Key words : 111In (III) uptake, Inflammatory tissue, Transferrin 
INTRODUCTION 
BECAUSE 111In(III) is taken up by malignant tissues, it has been widely used for tumor-imaging.1 Ever since the observation of 67Ga accumulation in tumors,2 67Ga has also been used for the detection of various tumors.3 It has been reported, however, that the distribution of 111In(III) differs from that of 67Ga(III) in tumor-bearing mice.4 In the blood 111In(III) is present in a transferrin-bound form,5,6 and 67Ga(III) is also exclusively bound with transferrin both in vitro and in vivo.7-9 Hara10 reported that the binding affinity of indium for transferrin was stronger than that of gallium. Ando et al.11 reported that 111In(III) and 67Ga(III) were remarkably taken up by inflammatory tissue adjacent to areas of tumor tissues. We have recently reported that the uptake of 67Ga(III) into normal soft tissues, such as liver and spleen, occurs in a transferrin-bound form, but into inflammatory tissue, such as granuloma, in an unbound form.12 In the present study, we have investigated whether or not the distribution of 111In(III) differs from that of 67Ga(III) differ from each other in inflammatory tissues and whether or not transferrin is involved in the uptake of 111In(III). 

Received May 11, 1989 ; revision accepted July 31, 1989. 
For reprints contact : Yasuhito Ohkubo, Department of Radiopharmacy, Tohoku College of Pharmacy, 4-4-1, Komatsushima, Aoba-ku, Sendai 981, JAPAN. 

MATERIALS AND METHODS 
Animals 
Male Wistar rats weighing 150-200 g were purchased from Shizuoka Laboratory Animal Center (Hamamatsu, Japan), and were housed in wire mesh cages at a room temperature of 23+-1deg.C and in relative humidity of 55+-5%. 
Production of inflammatory tissue 
The production of an inflammatory tissue, granuloma, was carried out by the method described in the previous report13 as follows. A paper pellet (size 8 mm) was dipped in turpentine oil and implanted bilaterally in the subcutaneous tissues of the abdomen in each animal. 
111In and 67Ga solutions 
Indium-111 chloride and Gallium-67 citrate (kindly supplied by Nihon Mediphysics Co. Ltd., Takarazuka, Japan) were diluted with saline to 185 kBq (5 uCi)/ml. 
Administration of 111In and 67Ga 
Each rat, at 6 days after the administration of turpentine oil, was intravenously injected with 111In or 67Ga solution in a dose of 37 kBq (200 ul). 
Administration of cold-InCl3 
Each rat, at 6 days after the administration of turpentine oil, was intravenously injected with InCl3 (1.25 and 2.50 umole/ml saline) in a dose of 100 ul 5 min before the administration of 111In. 
Removal of granuloma and other tissues 
At 4 h or 24 h after the administration of 111In and 67Ga solution, rats were anesthetized with urethane (1.5 g/kg, i.p.) and immediately perfused with cold saline. The inflammatory lesion and other tissues were then removed. The granuloma tissue was obtained from the inflammatory lesion with complete removal of the implanted paper pellet and abscess. 
Determination of radioactivity 
The radioactivity of the removed tissues was determined with a well-type NaI-scintillation counter (Aloka, ARC-300). The uptake ratios of 111In in various tissues were expressed in the following formula : 
RESULTS 
Time course of 111In(III) uptake by inflammatory and normal tissues 
Twenty-four hour tissue distributions of 111In(III) at 3, 6, and 9 days after the administration of turpentine oil are shown in Fig. 1. The uptake ratios of 111In(III) in liver and spleen reached a maximum at 6 days after the administration of turpentine oil. On the other hand, in granuloma the uptake ratios at 3 and 6 days after the administration of turpentine oil were nearly the same as each other, whereas at 9 days after the uptake ratio decreased. 
Difference of tissue distributions of 111In(III) and 67Ga(III) 
Tissue distributions of 111In(III) and 67Ga(III) at 4 and 24 h after injection into rats bearing granuloma induced by turpentine oil are shown in Fig. 2. At 4 h after the injection, the retention of 111In(III) in the blood was considerably higher than that of 67Ga, whereas only small difference in the uptake of 111In(III) and 67Ga(III) was found in the granuloma, liver, and spleen. On the other hand, at 24 h after the injection, not only was there greater blood retention of 111In(III) than 67Ga(III) but also greater uptake of 111In(III) by granuloma, liver, and spleen. Particularly noteworthy was the uptake of 111In(III) into liver and spleen, in comparison with that of 67Ga(III). 
The effect of cold-InCl3 on the uptake of 111In(III) by inflammatory and normal tissues 
To investigate the effect of cold-InCl3 on the retention of 111In(III) in the blood and 111In(III) uptake by inflammatory and normal tissues, in vivo experiments were performed (Fig. 3). Cold-InCl3 dose-dependently reduced 111In(III) retention in the blood. Similarly, the uptake of 111In(III) by the liver and spleen was dose-dependently reduced. In contrast to this, cold-InCl3 had little effect on the uptake of 111In(III) into the inflammatory tissue, granuloma. Table 1 shows the granuloma, liver- and spleen- to -blood ratios of the 111In(III) distribution in rats treated with various amounts of cold-InCl3 5 min before the injection of 111In(III). Cold-InCl3 dose dependently increased the granuloma to blood ratio, whereas the ratios of liver and spleen to blood were nearly constant. 
DISCUSSION 
We have reported that 67Ga uptake can indicate the processes and/or stages of inflammation;13 that is, both 67Ga(III) uptake and granuloma weight reached a maximum at 6 days after the administration of turpentine oil. In the present study, however, 111In(III) uptake by granuloma at 3 and 6 days after the administration was nearly the same ; therefore, 111In(III) uptake cannot indicate the processes and/or stages of inflammation. Additionally, 111In(III) uptakes by liver and spleen at 6 days after the administration of turpentine oil were greater than at 3 and 9 days after, whereas 67Ga(III) uptakes by liver and spleen at 6 days after the administration of turpentine oil were lowest among those at 2 to 12 days after that.13 We think that these differences may be due to different affinities between 111In(III) and 67Ga(III) for transferrin,10 but a final conclusion cannot yet be drawn. We have recently reported that 67Ga(III) is exclusively bound with transferrin9 and FeCl3 decreases the 67Ga(III) retention in blood.12 Indium-111(III) is also present in a transferrin-bound form.5,6 In the present study, it can be said that the much higher retention of 111In(III) than 67Ga(III) in blood is supported by the results, reported by Hara,10 that the binding affinity of indium for transferrin was stronger than that of gallium. At 24 h after the injection, 111In(III) uptake by liver and spleen were greater than 67Ga(III) uptake. This result might also be due to the difference in the affinity of indium and gallium for transferrin. Moreover, 111In(III) uptake by liver and spleen was remarkably decreased by cold-InCl3. We think that 111In(III) uptake, as well as 67Ga(III) uptake, by liver and spleen also occurs in a transferrin-bound form. On the other hand, the results that the uptake of 111In(III) and 67Ga(III) by inflammatory tissue, granuloma, were nearly the same 4 hr and 24 h after the injection suggest that transferrin is not involved in 111In(III) uptake by granuloma. Additionally, the fact that cold-InCl3 did not inhibit 111In(III) uptake by granuloma, but did inhibit that by liver and spleen also shows that transferrin is involved in the uptake by normal tissues, such as liver and spleen, but is not involved in the uptake by inflammatory tissue, granuloma. We have recently reported that transferrin is not involved in the uptake of 67Ga into inflammatory tissue, granuloma.12 Indium-111(III) resembles 67Ga(III) in the manner of uptake by inflammatory and normal soft tissues. Higashi et al.4 reported that 111In(III) and 67Ga(III) were uptaken differently by tumor and normal tissues despite the fact that they belong to the same group in the periodic table. They found that the uptake of 67Ga(III) into tumor tissue was greater than that of 111In(III), whereas 67Ga uptake by the liver was less than that of 111In(III).4 We think that these differences are due to different affinities for transferrin, i.e., these results show that both 67Ga(III) and 111In(III) are taken up into tumor tissue in a transferrin-unbound form, whereas into the liver in a transferrin-bound form. Moreover, it has previously been reported that the uptake of 67Ga(III) into tumor cells occurs in an unbound form.14-17 We conclude that the uptake of 111In(III), as well as that of 67Ga, into inflammatory tissues, such as granuloma, may also be similar to that occurring in tumor tissues. 
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