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Unlabelled: Auger electrons can create breaks in nucleic acids, giving them possible therapeutic utility. We investigated the therapeutic effect of Auger electrons emitted by 111In-labeled phosphorothioate antisense oligonucleotides on human neuroblastoma cells in which N-myc was overexpressed., Methods: Human SK-N-DZ neuroblastoma cells (5 x 10(6) cells) were treated with cationic reverse-phase evaporation vesicles (REVs) encapsulating 111In-labeled antisense (40 MBq/2 nmol of oligonucleotides/mumol of total phospholipids) that had an average diameter of 250 nm. Hybridization of the radiolabeled oligonucleotides with N-myc messenger RNA (mRNA), N-myc expression, and cell proliferation were investigated. The tumorigenicity of treated cells was analyzed in nude mice. Nonradiolabeled antisense, 111In-labeled sense, or empty cationic REVs were used as controls., Results: 111In-Labeled antisense, which hybridized with N-myc mRNA, was detected in cells at 12 and 24 h after the initiation of treatment. Reduced N-myc expression and inhibited cell proliferation were shown in the same cells at 48 h after the completion of treatment. N-myc expression-suppressed cells produced intraperitoneal tumors in nude mice, but the average weight of the tumors was lower than that of tumors in control mice., Conclusion: Auger electrons emitted from 111In in close proximity to their target N-myc mRNA may prolong the time to cell proliferation in human neuroblastoma cells due to inhibition of the translation of N-myc. Auger electron therapy therefore has potential as an internally delivered molecular radiotherapy targeting the mRNA of a tumor cell.

Unlabelled: To visualize the regional localization of glutathione (GSH) in the brain, the relationship between the concentrations of tissue GSH and uptake of [99mTc]meso-hexamethyl propyleneamine oxime ([99mTc] meso-HMPAO) or [99mTc]d,l-hexamethyl propyleneamine oxime ([99mTc]d,l-HMPAO) was studied in mice., Methods: The uptake of [99mTc]meso-HMPAO in the mouse brain was decreased to 35% of control paralleling the decrease in GSH content by pre-loading of diethyl maleate (DEM), an agent to reduce GSH. In contrast, pre-treatment with DEM scarcely affected the 99mTc-d,l-HMPAO uptake in the brain., Results: The DEM treatment decreased the GSH content in liver, kidney, spleen, fat and lung but did not affect the uptake of [99mTc]meso-HMPAO in those tissues except lung. The images of rat brain acquired with a gamma camera showed a significant reduction of [99mTc]meso-HMPAO uptake by DEM treatment., Conclusion: Technetium-99m-meso-HMPAO may be a potential tool to assess GSH content and to estimate antioxidative ability in the brain.

Unlabelled: We conducted a systematic study of the effects of liposome formulation and encapsulated radionuclides on imaging ability., Methods: Various types of liposomes were prepared and labeled with 67Ga, 111In or 99mTc. Their tumor-imaging potential was evaluated in terms of tumor accumulation and tumor-to-blood ratios of radioactivity delivered by the liposomes. Mouse sarcoma 180 and Ehrlich solid tumor were the tumor models., Results: Liposomes could be labeled rapidly and with high efficiency, which was sufficient for clinical application. Tumor accumulation of liposome-encapsulated radionuclides that have intrinsic tumor affinity, such as 67Ga-NTA or 111In-NTA, was larger than that of the other nuclides. Liposomes that were fairly small, cholesterol-rich and composed of so-called rigid phospholipids, could deliver large amounts of encapsulated radionuclides to the tumor. We also found that tumor uptake of such liposomes was large and their blood retention was prolonged. Liposomal lipid dose also influenced tumor delivery and blood retention. The results suggest that these factors extended liposomal blood retention and, consequently, increased tumor uptake of the liposomes and tumor delivery of encapsulated radionuclides. Not all liposomes with long blood retention, however, are suitable for tumor imaging. Incorporation of monosialo-ganglioside in the liposomal membrane greatly extended blood retention but increased tumor uptake only slightly and, consequently, made the tumor-to-blood value worse. One of the 67Ga-labeled liposome formulations resulted in high tumor uptake and tumor-to-blood ratios in various tumor models as well as clearly visualized tumors clearly in sarcoma 180-bearing mice., Conclusion: For tumor imaging with radiolabeled liposomes, we should choose liposomal formulations and dose to give prolonged blood retention for large tumor delivery. We must then select liposomes that give good tumor-to-blood values. For the best results, the radionuclide should have intrinsic tumor affinity. Labeled liposomes that meet these criteria result in excellent tumor images.

Gallium-67 chelated to nitrilotriacetic acid was encapsulated in liposomes composed of various phospholipids, and 67Ga delivery potential to the tumor after intravenous injection of these liposomes was examined. Tumor uptake of the liposomes themselves and their stability in the serum were also studied. It was found that liposomes composed of distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, or sphingomyelin with cholesterol (molar ratio of phospholipid:cholesterol, 2:1) could be taken by the tumor effectively and could deliver large amounts of 67Ga to the tumor. They could also give high 67Ga accumulation ratios (tumor to the other tissues). The study of liposomal stability in the serum suggested that the marked 67Ga accumulation in the tumor resulted from the serum stability of the liposomal bilayer, i.e., the stable liposomes in the blood circulation could reach the tumor in large quantities after i.v. injection. These observations indicate that liposomes with an appropriate lipid composition may be an excellent tool to accumulate 67Ga in tumors.