In vitro and in vivo evaluation of technetium-99m-labeled propylene amine oxime complexes containing nitroimidazole and nitrotriazole groups as hypoxia markers.

Hypoxia markers have been the subject of intensive research in radiopharmaceuticals, but there is little work on markers with multi-redox centers. It is necessary to further develop and investigate the compounds containing multi-redox centers systematically. Two propylene amine oxime ligands, compound 1, containing 3-nitro-1,2,4-triazole and 4-nitroimidazole and compound 2, containing 3-nitro-1,2,4-triazole and 2-nitroimidazole were synthesized and radiolabeled with (99m) Tc; then these complexes were also evaluated in vitro and in vivo. Some comparisons were made with the other complexes of our previous work, and some interesting conclusions were obtained. (99m) Tc-1 and (99m) Tc-2 displayed significant hypoxic/normoxic differentials in both S180 and H22 cell lines. These complexes held moderate tumor-to-blood and tumor-to-muscle ratios, indicating they might serve as novel hypoxia markers. Some comparisons showed the in vitro evaluation may be connected with the number and the type of the redox centers, and the biodistribution experiments may have relation with the hydrophilicity and the type of redox centers.

Synthesis, radiolabeling and biological evaluation of propylene amine oxime complexes containing nitrotriazoles as hypoxia markers.

Two propylene amine oxime (PnAO) complexes, 1, containing a 3-nitro-1,2,4-triazole and 2, containing two 3-nitro-1,2,4-triazoles, were synthesized and radiolabeled with (99m)Tc in high labeling yields. Cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were tested using a S180 cells line. Under anoxic conditions, the cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were 33.7 ± 0.2% and 35.0 ± 0.7% at 4 h, whereas the normoxic uptakes of the two complexes were 6.0 ± 1.6% and 4.6 ± 0.9%, respectively. Both (99m)Tc-1 and (99m)Tc-2 displayed significant anoxic/normoxic differentials. The cellular uptakes were highly dependent on oxygen and temperature. Biodistribution studies revealed that both (99m)Tc-1 and (99m)Tc-2 showed a selective localization in tumor and slow clearance from it. At 4 h, the tumor-to-muscle ratios (T/M) were 3.79 for (99m)Tc-1 and 4.58 for (99m)Tc-2. These results suggested that (99m)Tc-labeled PnAO complexes (99m)Tc-1 and (99m)Tc-2 might serve as novel hypoxia markers. By introducing a second nitrotriazole redox center, the hypoxic accumulation of the marker was slightly enhanced.

Effect of a second nitroimidazole redox centre on the accumulation of a hypoxia marker: synthesis and in vitro evaluation of 99mTc-labeled bisnitroimidazole propylene amine oxime complexes.

Up to now, most of the hypoxia markers contain only one nitroimidazole redox centre, such as Oxo[[3,3,9,9-tetramethyl-1-(2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioximato] (3-)-N,N',N″,N″']-technetium ((99m)Tc-1, BMS181321). Introducing a second nitroimidazole redox centre may enhance the hypoxic accumulation of the markers. In the present work, four (99m)Tc-1 (BMS181321, containing one 2-nitroimidazole) analogues, that is, (99m)Tc-2 (containing two 2-nitroimidazoles), (99m)Tc-3 (containing one 4-nitroimidazole), (99m)Tc-4 (containing two 4-nitroimidazoles) and (99m)Tc-5 (containing both a 2-nitroimidazole and a 4-nitroimidazole) were synthesized, and the hypoxic accumulation was evaluated in vitro using murine sarcoma S180 cells. (99m)Tc-3 and (99m)Tc-4 displayed no significant anoxic/normoxic differentials, whereas (99m)Tc-1 (BMS181321), (99m)Tc-2 and (99m)Tc-5 showed high anoxic cellular uptakes. The anoxic uptake of (99m)Tc-2 reached up to 59.0±0.9% at 4h, which was 2.4 times as that of (99m)Tc-1. (99m)Tc-2 displayed high hypoxic accumulation, indicating that introducing a second nitroimidazole redox centre, that is, 2-nitroimidazole, affected the hypoxic accumulation. Consequently, (99m)Tc-2 may serve as a viable candidate for hypoxia marker. This finding may eventually lead to the development of compounds containing multi-redox centres as hypoxia markers.

[Histological observation of implant-bone interface in immediate loading implant with platform switching].

OBJECTIVE: To investigate the effect of implant superstructure with platform switching to the osseointegration of implant-bone interface in immediate loading. METHODS: The bilateral mandiblular fourth premolars of 5 beagle dogs were extracted, and 3 months later, 10 implants were implanted and the abutments were accessed immediately to form immediate loading. Using self-control, the abutment with platform switching was used in the experimental side, and the traditional abutment used in the control side. The experimental animals were sacrificed after 3 months, and non-decalcified implant-bone sections were made. RESULTS: A favorable osseointegration of implant-bone interface in 4 animals (8 implants) was observed except for one failed case. A large number of osteoblasts and different mineralized bone were observed. In experimental side, the bone and implant-neck were nearly in the same level, but the bone around the implant-neck was significantly absorbed in control side. CONCLUSIONS: Using different superstructure in immediate loading could affect the osseointegration of implant-neck. The platform switching technology is conducive to the keeping of implant-neck bone.