PEGylated N-methyl-S-methyl dithiocarbazate as a new reagent for the high-yield preparation of nitrido Tc-99m and Re-188 radiopharmaceuticals

A novel nitrido nitrogen atom donor for the preparation of ^99mTc and ¹⁸⁸Re radiopharmaceuticals containing a metal-nitrogen multiple bond is presented. HO₂C-PEG₆₀₀-DTCZ was obtained by conjugation of N-methyl-S-methyl dithiocarbazate [H₂N–N(CH₃)–C(S)SCH₃, HDTCZ] with polyethylene glycol 600 (PEG₆₀₀). Asymmetrical heterocomplexes of the type [M(N)(PNP)(B)]^0/+ (M=^99mTc, ¹⁸⁸Re; PNP=diphosphine ligands, B=DBODC, DEDC, NSH, H₂OS, CysNAc, HDTCZ) and symmetrical nitride compounds of the type [M(N)(L)₂] (L=DEDC, DPDC) have been prepared in high yield by using the newly designed nitride nitrogen atom donor HO₂C-PEG₆₀₀-DTCZ. A two-step procedure was applied for preparing the above symmetrical and asymmetrical complexes. The first step involved the preliminary formation of a mixture of nitride Tc-99m or Re-188 precursors, which contained the [MN]²⁺ core, through reduction of generator-eluted ^99mTc-pertechnetate or ¹⁸⁸Re-perrhenate with thin (II) chloride in the presence of HO₂C-PEG₆₀₀-DTCZ. In the second step, the intermediate mixture was converted either in the final mixed asymmetrical complex by the simultaneous addition of diphosphine ligand and the suitable bidentate ligand B, or in the final symmetrical complex by the only addition of the bidentate ligand L. It was also demonstrated that the novel water-soluble nitride nitrogen atom donor HO₂C-PEG₆₀₀-DTCZ did not show coordinating properties toward the MN (^99mTc, ¹⁸⁸Re) core. Biodistribution studies in rats of the hitherto unreported [^99mTc(N)(PNP₃)DTCZ]⁺ and [^99mTc(N)(PNP₅)DTCZ]⁺ complexes showed that they selectively localize in the myocardium of rats with a favourable heart-to-lung and heart-to-liver uptake ratios. In particular, the heart-to-lung and heart-to-liver uptake ratios dramatically increased in the interval between 60 and 120 min postinjection. Hence, the combination of the favourable chemical and biological properties of HO₂C-PEG₆₀₀-DTCZ might confer to this novel compound an important role for the development of new ^99mTc and ¹⁸⁸Re-nitrido radiopharmaceuticals.     

Intracoronary β-brachytherapy using a rhenium-188 filled balloon catheter in restenotic lesions of native coronary arteries and venous bypass grafts

Purpose We have previously demonstrated the efficacy of intracoronary β-brachytherapy using a liquid ¹⁸⁸Re-filled balloon in a randomised trial including de novo lesions. Percutaneous coronary interventions in restenotic lesions and in stenoses of venous bypass grafts are characterised by a high recurrence rate for restenosis and re-interventions. Against this background, we wanted to assess the impact of intracoronary β-brachytherapy using a liquid ¹⁸⁸Re-filled balloon in restenotic lesions in native coronary arteries and venous bypass grafts.Methods In 243 patients, β-brachytherapy with 22.5 Gy was applied at a tissue depth of 0.5 mm. Patients were followed up angiographically after 6 months and clinically for 12 months. The primary clinical endpoint was the incidence of MACE (death, myocardial infarction, target vessel revascularisation). Secondary angiographic endpoints were late loss and binary restenosis rate in the total segment.Results All irradiation procedures were successfully performed. A total of 222 lesions were in native coronary arteries; 21 were bypass lesions. Mean irradiation length was 41.6±17.3 mm (range 20–150 mm) in native coronary arteries and 48.1±33.9 mm (range 30–180 mm) in bypass lesions; the reference diameter was 2.57±0.52 mm and 2.83±0.76 mm, respectively. There was no vessel thrombosis during antiplatelet therapy. Angiographic/clinical follow-up rate was 84%/100%. MACE rate was 17.6% in the native coronary artery group and 38.1% in the CABG group (p<0.03). Binary restenosis rate was 22.5% and 55.6% (p<0.01), and late loss was 0.38±0.72 mm and 1.33±1.11 mm (p<0.001), respectively.Conclusions We conclude that intracoronary β-brachytherapy with a liquid ¹⁸⁸Re-filled balloon using 22.5 Gy at a tissue depth of 0.5 mm in restenotic lesions is safe. It is associated with a low binary restenosis rate, resulting in a low occurrence rate of MACE within 12 months in restenotic lesions in native coronary arteries but not in vein grafts.     

Poloxamer 188 failed to prevent exercise-induced membrane breakdown in mdx skeletal muscle fibers

We sought to determine the effectiveness of poloxamer 188 (P188) in protecting dystrophin-deficient, mdx skeletal muscle fiber membrane against exercise-induced breaches. mdx mice were treated with either P188 or placebo via intraperitoneal injections and run on a treadmill for 60–90 min. Membrane breakdown was quantified in cross-sections of rectus femoris muscle pretreated with Evans blue dye (in vivo). The mean % dye-penetrated muscle in the P188 and placebo groups was not significantly different in each of three trials. These results contrast with a recent report of P188 being highly effective in protecting the stretch- and dobutamine-stressed mdx heart muscle. The most likely explanations for the disparity are: (1) the exercise stress we used was beyond the protective range of P188, (2) P188 delivery and serum concentration were sub-optimal, or (3) the mdx skeletal myopathy and cardiomyopathy have fundamentally different responses to treatment.     

188Re-β射线诱导肝癌细胞凋亡与细胞周期阻断

目的　探讨放射性核素1 88Re β射线内照射对人肝癌细胞HCC的细胞周期阻断及诱导凋亡的作用。方法　通过MTT实验、形态学观察、琼脂糖凝胶电泳和流式细胞术对核素诱导的HCC细胞进行了检测和观察。结果　1 88Re导致的HCC细胞死亡具有典型的细胞凋亡形态学和生化特征。流式细胞术定量显示各期细胞数发生改变 ,且凋亡率和剂量呈依赖性。结论　1 88Re β射线低剂量和高剂量对HCC细胞周期的影响不同 ,低剂量主要使G0 G1 期阻滞 ,较高剂量则导致G1 阻滞减轻 ,S期和G2 M期细胞数增多。     

A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

Purpose  Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8–13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested. Methods  The synthesis was performed by Boc strategy. Labelling with ^99mTc/¹⁸⁸Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo. NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts. Results  NT-XIX showed much longer half-lives than non-stabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24 h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with ¹⁸⁸Re-NT-XIX (30 MBq, in three or four fractions) decreased tumour growth by 50% after 3 weeks. Conclusion  The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumours. This work was partly funded by the Fund for Scientific Research-Flanders (Belgium), contract No. G.0036.04.     

188Re放射性食管支架的辐射场特性

目的探讨188Re放射性食管支架的辐射场特性,为该技术的临床应用提供科学依据.方法利用核探测技术对仿生食管体模各代表位点测量其β和γ射线、韧致辐射剂量,并以数学公式模拟、绘制计算机软件.结果188Re放射性支架的辐射场有其特性,β射线最大射程为11 mm,90%剂量建成区在1.5 mm之内,95%剂量在2.5 mm范围之内,而在6.5 mm射程外的γ射线、韧致辐射能量仅占总剂量的4.21%.支架0°、90°、180°、270°平行点间轴向距离的吸收剂量均匀平衡一致,P>0.05.结论188Re支架辐射以β射线为主体,γ射线、韧致辐射份额为4.21%.最大剂量建成区恰好落在食管粘膜层0.5～1.5 mm范围内,适合为食管癌姑息性腔内放射治疗核素.     

MCF-7乳腺癌细胞摄取188Re-DTPA-DG的实验研究

目的:研究乳腺癌细胞(MCF-7)对188Re标记二乙三胺五乙酸葡糖胺(DTPA-DG)的摄取。方法:采用γ计数法在不同时间段评价乳腺癌细胞(MCF-7)对188Re-DTPA-DG(3.7kBq/10μl)的摄取。结果:乳腺癌肿瘤细胞(MCF-7)对188Re-DTPA-DG的摄取率明显高于对照组188ReO4-(P<0.05);实验组30min与4h细胞摄取率差异存在显著性意义(P<0.05),而对照组不同时间点细胞摄取率差异无显著性意义(P>0.05)。结论:188Re-DTPA-DG容易被乳腺癌细胞(MCF-7)摄取,使188Re在肿瘤细胞内发挥辐射效应成为可能,从而为临床肿瘤治疗提供理论依据。     

血管内照射对兔血管平滑肌细胞增殖和凋亡的影响

目的:探讨188铼(188Re)血管内照射对血管平滑肌细胞增殖和凋亡的影响.方法:40只新西兰白兔随机分为对照组(n=20只)和照射组(n=20只),均行腹主动脉球囊内皮拉伤术.照射组内皮拉伤后行188Re血管内照射治疗,管腔下0.5 mm处累计吸收剂量为15 Gy;对照组则不行血管内照射.分别于术后1、3周处死动物,取病理组织学标本进行增殖细胞核抗原(PCNA)和凋亡细胞分析.结果:照射组第1、3周PCNA细胞阳性率分别为(27.69±7.04)%与(20.88±4.55)%,明显低于对照组(42.71±6.11)%、(29.48±10.13)%(P均＜0.05);照射组第3周平滑肌细胞凋亡细胞百分比为(40.16±7.93)%,明显高于对照组(28.50±9.39)%(P=0.018).结论:188Re血管内照射能抑制血管平滑肌细胞增殖,促进血管平滑肌细胞凋亡,从而抑制新生内膜增生,减少PTCA术后再狭窄的发生.