Relationship between the biodistributions of radioactive metal nuclides in tumor tissue and the physicochemical properties of these metal ions.

This study was undertaken to elucidate the relationship between the biodistribution of radioactive metal nuclides in tumor tissue and its physicochemical properties. Potassium analogs (86Rb, 134Cs, 201Tl) were taken up into viable tumor tissue, although 22Na concentrated in necrotic tumor tissue. 67Ga and 111In were more predominant in inflammatory tissue than in the viable and necrotic tumor tissue. 169Yb and 167Tm accumulated in viable tumor tissue and tissue containing viable and necrotic tumor tissue. 67Ga, 111In, 169Yb and 167Tm were bound to the acid mucopolysaccharide with a mol. wt. of about 10,000 daltons in the tumor tissue. 46Sc, 51Cr, 95Zr, 181Hf, 95Nb, 182Ta, and 103Ru were highly concentrated in inflammatory tissue and were bound to the acid mucopolysaccharides with a mol. wt. exceeding 40,000 daltons. 65Zn and 103Pd concentrated in viable tumor tissue and were bound to the protein in the tissue. The results suggest that the difference in intra-tumor distribution of these elements is caused by a difference in the binding substances (or status) of these elements in the tissues, and the binding substance is determined by physicochemical properties of the elements. We therefore conclude that the biodistribution of radioactive metal ions in tumor tissue is determined by its own physicochemical properties.

Distribution, kinetics and immunoscintigraphy of 131-I labelled intact antifibrinogen-fibrin antibody (AbFbg) and its F(ab')2 fragment.

131-I-labelled anti fibrin-fibrinogen antibody (AbFbg) was compared with its F(ab')2 fragment in distribution studies and by immunoscintigraphy with a view to tumour visualization in tumour bearing rats. The distribution studies indicated that the intact antibody is more concentrated in tumour tissue than the F(ab')2 fragment. By 168h after injection, when tumour-to-tissue ratios were highest in the majority of tissues, the tumour concentration of intact antibody was 3 to 4 times that of the F(ab')2 fragment. The intact antibody is more suitable than the F(ab')2 fragment for tumour imaging especially in the abdominal region where the highest tumour-to tissue ratios were obtained with intact antibody in liver, spleen, intestines and kidneys.

Determination of the lysosomal role in tumor accumulation of 67Ga by dual-tracer studies.

The lysosomal role in tumor accumulation of 67Ga was determined by dual-tracer (67Ga and 46Sc) studies. It became clear that 67Ga essentially did not accumulate in the tumor lysosome, and that the lysosome did not play a major role in tumor accumulation of 67Ga. In addition, it was revealed that tumor lysosome was hardly disrupted at all in some phases of fractionation procedures.

Relation between the location of elements in the periodic table and various organ-uptake rates.

Fifty four elements and 65 radioactive compounds were examined to determine the organ uptake rates for rats 3, 24 and 48 h after i.v. injection of these compounds. They were prepared as carrier free nuclides, or containing a small amount of stable nuclide. Generally speaking, behaviors of K, Rb, Cs and Tl in all the organs were very similar to one another, but they differed from that of Na. Bivalent hard acids were avidly taken up into bone; therefore, uptake rates in soft tissues were very small. Hard acids of tri-, quadri- and pentavalence which were taken up into the soft tissue organs decreased more slowly from these organs than other ions. Soft acids such as Hg2+ were bound very firmly to the component in the kidney. Anions (with few exceptions), GeCl4 and SbCl3 were rapidly excreted in urine, so that the uptake rates in organs were low.

2-Deoxy-2-[18F]fluoro-D-galactose as an in vivo tracer for imaging galactose metabolism in tumors with positron emission tomography.

The feasibility of 2-deoxy-2-[18F]fluoro-D-galactose ([ 18F]FdGal) for imaging galactose metabolism in tumors with positron emission tomography (PET), was investigated using two hepatomas, Yoshida sarcoma, or glioma in rats, and mouse mammary carcinoma. In hepatoma-bearing rats the highest uptake of [18F]FdGal was observed in the liver followed by the kidney and tumor. The tumor uptake increased with time, and the high uptake ratios of tumor to organ were observed except for the liver and kidney. Tumor uptake was also measured in all tumors. As main metabolites in all tumors, [18F]FdGal 1-phosphate and UDP-[18F]FdGal were found by HPLC. Two hepatomas showed a slightly higher uptake and a larger percentage of UDP derivative than the other three tumors. By autoradiography the brain tumor was visualized clearly. These results indicate that [18F]FdGal has potential as a tracer for imaging galactose metabolism in tumors with PET.

[Investigation of 99mTc labeled tumor seeking agents--usefulness of 99mTc-isoniazid].

For the development of 99mTc labeled tumor seeking agents, 273 drugs and chemicals were evaluated. Agents labeled by SnCl2-HCl method were injected to rats bearing Yoshida sarcoma. Scintigrams of the rats 2 hours after injection and the excised tumor and organs placed on a plate were taken and evaluated their affinity to the tumor. Isoniazid (INH) was found to be the most useful agent as a result of this screening study. Intensive study on 99mTc-INH was subsequently performed. Another labeling method, FeSO4-H2SO4 method, was evaluated and shown to be superior in both absolute tumor uptake and tumor to muscle ratio. Uptake of 99mTc-INH to Yoshida sarcoma occurred early after injection and maintained its level until later time. On the other hand, radioactivity in the blood and muscle decreased rapidly; that is, tumor to blood and muscle ratio showed rapid increase. Other animal tumor models, mouse bearing Ehrlich tumor or Sarcoma 180, were also used to evaluate the usefulness of 99mTc-INH. The labeled agent showed good localization in these tumors too. In conclusion 99mTc-INH might be a good tumor seeking agent and further clinical trials would be warrant.

Distribution of 46Sc and 51Cr in tumor-bearing animals and the mechanism for accumulation in tumor and liver.

Tumor uptake rates, concentrations in mitochondrial fraction (containing lysosome) of liver and tumors, avid accumulations in connective tissue (especially inflammatory tissue) and binding substances in these tissues for 46Sc3+ and 51Cr3+ were essentially similar to those for 67Ga3+, 111In3+, 169Yb3+, 167Tm3+, 95Zr4+ and 181Hf4+. However, the main binding substance of 46Sc3+ and 51Cr3+ in tumor and liver was the acid mucopolysaccharide (as described concerning 95Zr and 181Hf) whose molecular weight exceeded 40,000, although the main binding substance of 67Ga3+, 111In3+, 169Yb3+ and 167Tm3+ was the acid mucopolysaccharide with a molecular weight of about 10,000.

Differential uptake of gallium-67-labeled liposomes between tumors and inflammatory lesions in rats.

The differential gallium-67 (67Ga) accumulation in tumors and inflammatory lesions in rats after i.v. injection of liposome encapsulated 67Ga ([67Ga]liposomes) was studied. The 67Ga accumulation in the tumor was much greater than that in the granulation tissue regardless of the surface charge of liposomes; however, the difference between the two tissues was the greatest when using positive charged liposomes. Gallium-67 delivery to tumors by liposomes was greater than that to granulation tissue in all stages of growth. After i.v. injection, the accumulation of 67Ga in the tumor reached a maximum at 12 hr, whereas in the granulation tissue it was delayed to 24 hr postinjection. In the study of tissue distribution of 67Ga in rats bearing both tumor and granulation tissue, positively charged liposomes preferentially delivered 67Ga to the tumor than to the granulation tissue. These results suggest that [67Ga]liposomes are able to discriminate between the tumor and the inflammatory lesion.

Distribution of 95Zr and 181Hf in tumor-bearing animals and mechanism for accumulation in tumor and liver.

Tumor uptake rates, concentrations in the mitochondrial fraction (containing lysosome) of liver and tumors, avid accumulations in connective tissue (especially inflammatory tissue) and binding substances in these tissues of 95Zr and 181Hf were essentially similar to those for 67Ga, 111In, 169Yb and 167Tm. However, the main binding substance of the above elements in group IV in tumor and liver was acid mucopolysaccharide whose molecular weight exceeded 40,000, although the above elements in group III were bound mainly to the acid mucopolysaccharide with a molecular weight of about 10,000.

Immunoscintigraphy and distribution study of experimental tumours using 131I-labelled anti-fibrinogen antibodies.

131I-labelled antibodies to the fragment E of human fibrin, anti-rat fibrinogen, non-immune rabbit IgG and 67Ga-citrate were used for scintigraphy and distribution studies in experimental tumours in rats. The best visualisation was achieved with 131I-labelled anti-rat fibrinogen antibodies at intervals longer than 48 h after administration. Tumour to tissue ratios found in distribution studies performed formed more than 48 h after administration were higher in most examined tissues when using 131I-labelled antibodies than those obtained with 67Ga-citrate.

Affinity of 167Tm-citrate for tumor and liver tissue.

Strong affinity of 167Tm-citrate for tumor tissue was reconfirmed by using Ehrlich tumor. Excellent tumor imaging was obtained with 167Tm-citrate because of its strong tumor affinity and because of the suitable physical characteristics of 167Tm. A large number of 167Tm had accumulated in the connective tissue which contained inflammatory tissue, quite large amounts were found in areas containing viable and necrotic tumor tissue, and small amounts were present in viable tumor tissue. 167Tm was not seen in necrotic tumor tissue. It was concluded that lysosomes did not play a major role in the tumor concentration of 167Tm, but played an important role in the liver concentration of this nuclide. In the case of hepatoma AH109A, it was presumed that lysosomes played a considerably important role in the tumor concentration of 167Tm, hepatoma AH109A possessing some residual features of the liver. 167Tm was bound to acid mucopolysaccharides and transposed by the acid mucopolysaccharides in the tumor tissues and liver. The acid mucopolysaccharides to which 167Tm were bound in tumor and liver, were heparan sulfate, chondroitin sulfate (or keratosulfate) and heparin (or keratosulfate).

Deferoxamine mesylate enhancement of 67Ga tumor-to-blood ratios and tumor imaging.

To improve the tumor-to-blood ratio in 67Ga tumor imaging, the effect of administration of deferoxamine mesylate (DFO) was evaluated. DFO improved 67Ga tumor-to-blood ratios in tumor-bearing rats. Administration of DFO 12 h after 67Ga injection did not decrease the concentration of radioactivity in the tumor of rats, but administration of DFO 4 h after 67Ga decreased the concentration of radioactivity in the tumor. Serum unsaturated iron binding capacity in rats was transiently increased by DFO administration, but when DFO was administered before 67Ga injection the tumor uptake showed rather decreased levels. In human studies, DFO accelerated the excretion of 67Ga from the blood, but tumor images were not necessarily improved.

Functional imaging of uptake of radiopharmaceuticals as a method for tumor visualisation in rats.

Dynamic studies of kinetics of 99mTcO4, 57Co-Bleomycin, 67Ga, A2 fraction of 57Co-Bleomycin in Yoshida sarcoma bearing rats were undertaken. Then the regional variations of rate of the initial uptake of a radiopharmaceutical were examined using functional representation of the rate constants as a function of position. It was concluded that--for radiopharmaceuticals with a high initial uptake rate--the method resulted in visualization of tumor and in suppression of the blood background, within five to eight minutes after administration. This approach based on an evaluation of the parameters of the radiopharmaceutical kinetics in organs and tumor makes possible the use of short-lived radionuclides for tumor visualization and could offer some possibilities of distinguishing the tumor from other accumulating organs.

Uptake and excretion of 67Ga-citrate in malignant tumors and normal cells.

Using in vivo and in vitro experimental models, the uptake and excretion of 67Ga-citrate in tumor cells and normal cells were studied. The time-lapse accumulation of 67Ga in the tumor of rats bearing Yoshida sarcoma reached its peak 24 h after the administration of 67Ga and gradually decreased thereafter. However, the excretion of 67Ga from the tumor was less than that from normal lung. For culture cells in vitro, the uptake of 67Ga increased with lapse of contact time between 67Ga and the cells, but there was no distinct difference between the results for tumor cells and normal skin fibroblasts. The excretion of 67Ga from the cells tended to decrease with prolongation of the contact time, the excretion from tumor cells being only about 10% after a contact time of 24 h. This indicated a significant delay in excretion in comparison with that of normal skin fibroblasts. This delay in the excretion of 67Ga may be an important factor in the tumor accumulation of 67Ga.