The lymphoid tissue in the omentum, at the so-called milky spots, is known as an initial place for disseminated cancer cells to develop into solid tumors. In the present study, i.p. macrophages significantly took up oligomannose-coated liposomes (OMLs) that were injected into the peritoneal cavity, and then gradually accumulated in the omentum and the other lymphoid tissues within 24 hours of i.p. injection of OMLs. When 5-fluorouracil (5-FU) was encapsulated in the OMLs, >60% of administered 5-FU accumulated in the omentum. Treatment of macrophages at 39°C for 30 minutes led to the release of 5-FU from the macrophages, suggesting that controlled release from macrophages could be achieved by mild hyperthermia. We encased magnetic nanoparticles, which are known to convert electromagnetic energy to heat in the OMLs to achieve in vivo hyperthermia at the site. Using this system in a mouse i.p. metastasis model, we successfully controlled tumor development by coadministration of OML-encased 5-FU and OML-encased magnetic nanoparticles, followed by treatment with an alternating magnetic field. No apparent reduction was seen in tumor growth with the administration of OML-encased magnetic nanoparticles or OML-encased 5-FU alone. Thus, we have established the use of i.p. macrophages as a novel drug delivery system for the control of cancer metastatic to milky spots. (Cancer Res 2006; 66(17): 8740-8)

Magnetoliposomes (MLs) conjugated with an antibody fragment to give specificity to a tumor were applied to hyperthermia for cancer. The Fab′ ′ ′ ′ fragment of the G250 antibody, which binds to MN antigen on many types of human renal cell carcinoma, was cross-linked to N-(6-maleimidocaproyloxy)-dipalmitoyl phosphatidylethanolamine (EMC-DPPE) in liposomal membrane. The targetability of the G250-Fab′ ′ ′ ′ fragment-conjugating MLs (G250-FMLs) was investigated using the mouse renal cell carcinoma (mRCC) and MN antigen-presenting cell, MN-mRCC. The amount of G250-FMLs uptake reached 67 pg/cell against MN-mRCC cells in an in vitro experiment using plastic dishes and this value was about 6 times higher than that in the case of MLs. In an in vivo experiment using MN-mRCC-harboring mice, 1.5 mg of the FMLs per carcinoma tissue accumulated (tumor weight was 0.19 g), which corresponded to approximately 50% of the total injection. This value was 27 times higher than that of the MLs. After injection of the FMLs, mice were exposed to intracellular hyperthermia using alternating magnetic field irradiation. The temperature of tumor tissue increased to 43°C and the growth of the carcinoma was strongly arrested for at least 2 weeks. These results indicate the G250-FMLs could target renal cell carcinoma cells in vitro and in vivo, and are efficiently applicable to the hyperthermic treatment of carcinoma.

Magnetoliposomes (MLs) were conjugated with an antibody fragment to give specificity to a tumor. The antibody fragment was cross-linked to N-(6-maleimidocaproyloxy)-dipalmitoyl phosphatidylethanolamine (EMC-DPPE) in liposomal membrane. The immobilization of the antibody fragment was optimal when the content of EMC-DPPE was 10-wt% and the reaction time for immobilization was 18 h. The Fab′ fragment-conjugating MLs (FMLs) were 2.4 times higher molar immobilization density compared with the method using the whole antibody. The targetability of the FMLs to the glioma cells, U251-SP, was then investigated. The amount of FMLs uptake reached 85 pg/cell in an in vitro experiment using plastic dishes. In an in vivo experiment using glioma-harboring mice, 260 µg of the FMLs per 1 g of tumor tissue accumulated (tumor sizes was 0.1 cm 3 ), which corresponded to approximately 60% of the total injection. This value was 7 times higher than that of the MLs. After injection of the FMLs, mice were exposed to intracellular hyperthermia using the alternating magnetic field irradiation. The temperature of tumor tissue increased to 43°C and the growth of the tumor was found to be arrested over 2 weeks. These results indicate the FMLs could target the glioma cells in vitro and in vivo, and are efficiently applicable to the hyperthermia of tumor.

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In this study, the benzimidazole derivatives were synthesized and evaluated as imaging agents for the NR2B subype of NMDA receptor. Among these ligands, Although the brain uptake of these benzimidazole derivatives was too low to allow for in vivo SPECT imaging, these compounds might be useful scaffolds for the development of imaging probes specific for the NMDA receptors.