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.     

188Re-DTPA-DG的制备及其在正常小鼠体内分布的研究

用氯化亚锡作还原剂,以^188Re标记二乙三胺五乙酸-脱氧葡萄糖（DTPA—DG）,纸层析法鉴定^188Re—DTPA-DG的放化纯度、标记稳定性。取昆明种小鼠经尾静脉注射^188Re—DTPA—DG,观察其体内分布及显像情况。结果^188Re—DTPA—DG放化纯度〉95％,室温体外稳定;^188Re—DTPA—DG在正常小鼠血液中清除快,脑、肺、小肠、肌肉未见明显分布,主要经肾脏随尿液排出体外。提示^188Re—DTPA—DG有望成为集肿瘤SPECT显像、诊断和治疗于一体的新型葡萄糖类似物。     

Monte Carlo dose simulation for intracoronary radiation therapy with a rhenium 188 solution-filled balloon with contrast medium

BACKGROUND: The therapeutic efficacy of percutaneous transluminal coronary angioplasty is limited by the incidence of restenosis. Intracoronary irradiation has shown to be effective in restenosis control by inhibiting the neointimal proliferation. METHODS AND RESULTS: Monte Carlo simulation has been performed to calculate the dose to the vessel wall for intracoronary irradiation with a rhenium 188 solution-filled balloon for restenosis inhibition. With a 3-mm-diameter and 30-mm-long balloon, the radiation dose at 1 mm from the balloon surface was 5.3% lower when the balloon structure was included in geometric modeling of the angioplasty catheter, as compared with that obtained by ignoring the structure. The additional dose reduction due to Hexabrix 320 contrast medium added in 30% of volume ratio was 4.7%. With regard to axial dose distribution, the dose was uniform over the balloon length except near the balloon end, at which the dose was reduced by 35% at a 1-mm-deep layer in the vessel wall. With the Re-188 solution mixed with 30% of Hexabrix 320 in volume ratio, the Re-188 activity to be injected for delivery of 15 Gy to the 1-mm-deep layer by 1-minute irradiation was 27.3 GBq/mL. CONCLUSIONS: Dose estimates produced in this study should be helpful in determining the Re-188 activity to be injected or the irradiation time for a varying situation in terms of length and diameter of the irradiated arterial segment and depth of the target layer.     

水飞蓟宾固体分散体的制备及体外溶出研究

目的：制备了水飞蓟宾的固体分散体,并检测其体外溶解度及溶出速度。方法：选择尿素、聚乙烯吡咯烷酮（ＰＶＰ）、泊洛沙姆１８８等３种载体,用熔融法和共沉淀法制备水飞蓟宾固体分散体,并进行差热分析,Ｘ－射线粉末衍射分析以鉴别药物在载体中的存在状态,最后进行了体外溶出研究。结果：水飞蓟宾在ＰＶＰ中以无定型存在,在泊洛沙姆１８８中以微细结晶存在,在尿素中大部分仍以晶体形式存在,少量以分子状态存在。溶出研究结果表明泊洛沙姆１８８载体的水飞蓟宾固体分散体的溶解度最大,溶出速度最快。结论：泊洛沙姆是提高水飞蓟宾溶解度及溶出速度的理想载体。