68Ga-radiolabeled AGuIX nanoparticles as dual-modality imaging agents for PET/MRI-guided radiation therapy.

AIM: The aim of this study was to develop a dual-modality positron emission tomography/magnetic resonance (PET/MR) imaging probe by radiolabeling gadolinium-containing AGuIX derivatives with the positron-emitter Gallium-68 (68Ga). MATERIALS & METHODS: AGuIX@NODAGA nanoparticles were labeled with 68Ga at high efficiency. Tumor accumulation in an appropriate disease model was assessed by ex vivo biodistribution and in vivo PET/MR imaging. RESULTS:  68Ga-AGuIX@NODAGA was proven to passively accumulate in U87MG human glioblastoma tumor xenografts. Metabolite assessment in serum, urine and tumor samples showed that 68Ga-AGuIX@NODAGA remains unmetabolized up to at least 60 min postinjection. CONCLUSION: This study demonstrates that 68Ga-AGuIX@NODAGA can be used as a dual-modality PET/MR imaging agent with passive accumulation in the diseased area, thus showing great potential for PET/MR image-guided radiation therapy.

Studies on 67Ga uptake by mouse granuloma tissues.

In connection with the uptake of 67Ga into the inflammatory tissues, such as granuloma tissues produced with turpentine oil, the influence of Fe3+ on the uptake of 67Ga into mouse granuloma and normal tissues and on the uptake of 125I-labeled transferrin and 59Fe were investigated. Fe3+ decreased the uptake of 67Ga into the liver and spleen, but had no influence on the uptake of 67Ga into the granuloma tissues. The uptake patterns of 125I-labeled transferrin and 59Fe in the granuloma tissues were not consistent with that of 67Ga at all. These results show that the uptake of 67Ga into the granuloma tissues occurs in a free, transferrin-unbound form, but into the liver and spleen in a transferrin-bound form.

Clinical study of urinary excretion of Ga-67.

Ga-67 urinary excretion was examined in 59 patients. The 72-hour urinary excretion rate ranged from 4.3 to 67.8% of the injected dose. Within the first 24 hours, 60.9% of the 72-hour urinary excretion was excreted. There was no significant difference in the Ga-67 urinary excretion rate between males and females, nor between the Ga-67 positive and negative cases. A significant negative correlation was found between the 72-hour Ga-67 urinary excretion rate and the unsaturated iron binding capacity. Notably, four patients with hyperferremia, which was considered secondary to leukemia and/or chemotherapy or liver cirrhosis, excreted more than 46.8% of Ga-67 within 72 hours. A significant negative correlation was also found between the 72-hour Ga-67 urinary excretion rate and age. Urinary excretion of Ga-67 may be related to the glomerular filtration rate, which decreases with age.

Biological behavior of 67Ga-citrate in New Zealand White rabbits.

The pharmacokinetics, protein binding, excretion and tissue distribution of 67Ga after the administration of 67Ga-citrate to New Zealand White rabbits is described. Data for 67Ga blood levels were best described by an equation with three exponential components exhibiting half lives of 0.25 h, 7.4 h and 19.5 h, with almost all of the activity in a protein bound form. Weekly urinary excretion (approximately 27%), possibly in a metabolized form, and fecal elimination (approximately 20%) were greater than the reported values in man, but there was a similar organ distribution pattern in these animals as in man. The overall biological handling was judged to be similar in both species making the rabbit a suitable model for further 67Ga-citrate studies in vivo.

Retention and subcellular distribution of 67Ga in normal organs.

Using normal rats, retention values and subcellular distribution of 67Ga in each organ were investigated. At 10 min after administration of 67Ga-citrate the retention value of 67Ga in blood was 6.77% dose/g, and this value decreased with time. The values for skeletal muscle, lung, pancreas, adrenal, heart muscle, brain, small intestine, large intestine and spinal cord were the highest at 10 min after administration, and they decreased with time. Conversely, this value in bone increased until 10 days after injection. But in the liver, kidney, and stomach, these values increased with time after administration and were highest 24 h or 48 h after injection. After that, they decreased with time. The value in spleen reached a plateau 48 h after administration, and hardly varied for 10 days. From the results of subcellular fractionation, it was deduced that lysosome plays quite an important role in the concentration of 67Ga in small intestine, stomach, lung, kidney and pancreas; a lesser role in its concentration in heart muscle, and hardly any role in the 67Ga accumulation in skeletal muscle. In spleen, the contents in nuclear, mitochondrial, microsomal, and supernatant fractions all contributed to the accumulation of 67Ga.

Effect of cis-platinum treatment on 67Ga-citrate localization and elimination in rabbits.

The treatment of rabbits with a typical dosage schedule of the chemotherapeutic drug cis-platinum resulted in an increased whole body retention of 67Ga-citrate due to decreased urinary and fecal excretion. The biodistribution of the tracer was also affected with most tissues showing greater accumulation. These changes are primarily related to drug-induced renal dysfunction, but other factors may also be involved.

[The influence of whole body 60Co-irradiation on distribution of 67Ga in tumor-bearing mice (author's transl)].

Since the initial findings that 67Ga has a preferential affinity of soft tissue tumors, in humans numerous suggestions have been advanced for the basic mechanism involved. The effects produced by whole-body X-irradiation on the excretion and tissue distribution of 67Ga have been reported by Swartzendruber and others. Bradley and coworkers have shown that these irradiation effects were associated with an increase in serum iron. The present investigation was undertaken in order to study the relationships between the change in the serum iron concentration and 67Ga accumulation in the tumor and soft tissues in mice bearing Ehrlich's ascites tumor. The following results were obtained. (1) The serum iron concentration was significantly decreased between 3 and 6 hours after 10 Gy (1,000 rad) dose whole-body 60Co-irradiation. Subsequently, the serum iron levels were slowly elevated. (2) The uptake of 67GA in the tumor and soft tissues increased if the serum iron concentration was decreased by whole-body 60Co-irradiation during the early phase. On the contrary, if the serum iron concentration was high, the uptake of 67Ga in the tumor was decreased. (3) The excretion of 67Ga from the body was delayed if the serum iron concentration was decreased by whole-body 60Co-irradiation. However, if the serum iron concentration was high, the excretion of 67Ga from the body significantly increased.

The effect of certain variables on the tumor and tissue distribution of tracers. Part 1; Carrier.

Buffalo rats bearing thigh-implanted strain-7777 Morris hepatomas were used as a model for studying the effect of carrier material on the body distribution, tumor uptake, excretion, and tumor-to-background ratios of 67Ga and 54Mn. An effort was also made to observe the changes in 67Ga and 54Mn concentrations induced by carrier in viable tumor and skeletal muscle, relative to their interstitial fluid space. This value is referred to as the Tissue Distribution Index. Carrier manipulation resulted in striking changes in the distribution of the two ions from the carrier-free state. The data also indicated a difference in the pharmacodynamics of 67Ga and 54Mn in malignant and healthy tissues which could be of importance to nuclear medicine and oncology.

The urinary excretion of gallium-67 citrate in patients with neoplastic disease.

The urinary excretion of gallium-67 has been studied in twenty-nine patients with considerable variation, ranging from 2.71 to 35.21 per cent of the injected dose in the first twenty-four hours. The data was analyzed to determine whether differences in excretion could be related to sex, age, plasma level, site or extent of disease but no significant relation could be found. While chemotherapy or radiotherapy has been shown to affect both the plasma clearance and protein binding they have no influence upon the urinary excretion of the isotope in this study. This study shows that all patients with high urinary excretion had bone metastasis from various types of primary tumour. Not all patients with bone metastasis have high urinary excretion of gallium-67. It would appear, however, from our limited series that patients with bone metastasis and normal urinary excretion of gallium-67 show a good response to treatment.