131I标记17-丙烯胺基-17-去甲氧基格尔德霉素的制备及生物分布

目的 建立131I标记17-丙烯胺基-17.去甲氧基格尔德霉素(17-AAG)的方法,并观察其在动物体内的生物分布.方法 采用过氧化氢法对17-AAG进行131I标记.测定131I.17.AAG注射后0.5,1,4,8和24 h在ICR健康小鼠体内的生物分布,通过显像动态观察131I-17-AAG在兔Vχ2肝癌模型中的分布.结果 建立了131I过氧化氢法标记17-AAG的最佳条件,131I-17-AAG标记率达85.65%,纯化后其乙酸乙酯相、生理盐水水溶液和4℃下放置5 d的生理盐水水溶液的放化纯分别为(96.51±0.80)%,(95.57±0.09)%和(90.96±1.29)%.尾静脉注射131I-17-AAG,健康ICR小鼠胆囊的摄取(每克组织百分注射剂量率,%ID/g)在0.5 h达到峰值(3.0963±1.3394)%ID/g,胃和小肠的摄取均在4 h达到高峰,24 h时肠道放射性明显减少,肝、肾摄取较少.瘤体给药后于2 h和4,6,14 d进行显像,可见131I-17-AAG在兔肿瘤中持续浓聚,肿瘤/非肿瘤组织放射性(T/NT)比值分别为10.36,3.62,4.32和3.50,其他脏器未见显影.结论 成功建立了131I-17-AAG标记方法,标记物保留了17-AAG生物学活性,体外稳定性好.兔肝肿瘤间质给药提示131I-17-AAG对肿瘤具有理想靶向性作用.     

131I标记纳米脂质体靶向治疗结肠癌的实验研究

目的 研究¹³¹I-antiEGFR-BSA-PCL对LS180细胞结肠癌裸鼠移植瘤内照射的治疗效果。方法 构建抗表皮生长因子受体(EGFR)标记的纳米脂质体及EGFR靶向性。通过荧光共聚焦显微镜、细胞摄碘实验观察纳米载体的靶向性及LS180细胞对其摄取情况。将裸鼠40只按随机数字表法分为4组,通过瘤体内注射的方式向移植瘤内分别注射74 MBq (740 MBq/ml) ¹³¹I-antiEGFR-BSA-PCL、¹³¹I-BSA-PCL、¹³¹I及相同体积的生理盐水。通过研究裸鼠体重、肿瘤体积、SPECT显像及组织病理学方法,观察纳米脂质体的抑瘤效果。结果 共聚焦实验显示,与BSA-PCL组相比,antiEGFR-BSA-PCL组细胞内绿色荧光较明显,其介导的胞吞效应显著。摄碘率实验中,LS180细胞对¹³¹I-antiEGFR-BSA-PCL的摄取率明显高于¹³¹I-BSA-PCL(t=2.77~5.40,P<0.01)。¹³¹I-antiEGFR-BSA-PCL组与¹³¹I-BSA-PCL组裸鼠肿瘤增殖均较慢,二者差异无统计学意义(P>0.05)。给药后72 h,¹³¹I-antiEGFR-BSA-PCL与¹³¹I-BSA-PCL的肿瘤摄取率分别为(21.61±1.01)和(20.58±0.65)% ID/g,均明显高于¹³¹I组(t=9.36、8.69,P<0.01)。SPECT显像显示纳米脂质体主要特异性积聚在肿瘤区。结论 ¹³¹I-antiEGFR-BSA-PCL对LS180结肠癌裸鼠移植瘤有明显的抑制作用。     

Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with <Superscript>99m</Superscript>Tc- and <Superscript>123</Superscript>I-labelled probes

Purpose  The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of ¹²³I- and ^99mTc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake. Methods  A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D₂ receptor ligand [¹²³I]IBZM and the cerebral perfusion tracer [^99mTc]HMPAO (1.2–0.4 MBq/g body weight) in healthy mice. The fatty acid [¹²³I]IPPA (0.94 ± 0.05 MBq/g body weight) and the perfusion tracer [^99mTc]sestamibi (3.8 ± 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP₃ receptor. Results  In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [¹²³I]IBZM and of cardiac [^99mTc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [¹²³I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [^99mTc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [¹²³I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight. Conclusion  Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of ¹²³I- and ^99mTc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Renal excretion of iodine-131 labelledmeta-iodobenzylguanidine and metabolites after therapeutic doses in patients suffering from different neural crest-derived tumours

Iodine-131 labelledmeta-iodobenzylguanidine ([¹³¹I]MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. After administration of therapeutic doses of [¹³¹I]MIBG (3.1–7.5 GBq) to 17 patients (n=32 courses), aged 2–73 years, 56%±10%, 73%±11%, 80%±10% and 83%±10% of the dose was cumulatively excreted as total radioactivity in urine att=24 h, 48 h, 72 h and 96 h, respectively. Except for two adult patients, who showed excretion of 14%–18% of [¹³¹I]meta-iodohippuric acid ([¹³¹I]MIHA), the cumulatively excreted radioactivity consisted of >85% [¹³¹I]MIBG, with 6% of the dose excreted as free [¹³¹I]iodide, 4% as [¹³¹I]MINA and 2.5% as an unknown iodine-131 labelled metabolite. Cumulative renal excretion rates of total radioactivity and of [¹³¹I]MIBG appeared to be higher in neuroblastoma and phaeochromocytoma patients than in carcinoid patients. Based on the excretion of small amounts of [¹³¹I]meta-iodobenzoic acid in two patients, a possible metabolic pathway for [¹³¹I]MIBG is suggested. The degree of metabolism was not related to the extent of liver uptake of radioactivity.     

Effect of distance between decaying 125I and DNA on Auger-electron induced double-strand break yield

Abstract

Purpose: To determine the possible effects of ¹²⁵I-to-DNA distance on the magnitude and mechanism of Auger-electron induced-double-strand break (DSB) production.

Materials and methods: We have synthesized a series of ¹²⁵I-labeled Hoechst (H) derivatives (¹²⁵IE–H, ¹²⁵IB–H, ¹²⁵I-C₈–H and ¹²⁵I-C₁₂–H). While all four molecules share a common DNA minor groove binding bis-benzimidazole motif, they are designed to position ¹²⁵I at varying distances from the DNA helix. Each Hoechst derivative was incubated at 4°C in phosphate buffered saline (PBS) together with supercoiled (SC) ³H-pUC19 plasmid DNA (ratio 3:1) ± the ?OH scavenger dimethyl sulfoxide (DMSO) (0.2 M). Aliquots were analyzed on agarose gels over time and DSB yields per decay of ¹²⁵I atom were determined. Docking of the iodinated compounds on a DNA molecule was carried out to determine the distance between the iodine atom and the central axis of DNA.

Results: In the absence of DMSO, the results show that the DSB yields decrease monotonically as the ¹²⁵I atom is distanced – by 10.5 Å to 13.9 Å – from the DNA helix (¹²⁵IEH: 0.52 ± 0.01; ¹²⁵IB–H: 0.24 ± 0.03; ¹²⁵I-C₈–H: 0.18 ± 0.02; ¹²⁵I-C₁₂–H: 0.10 ± 0.00). In the presence of DMSO, DSB yields for ¹²⁵IEH (0.49 ± 0.02) and ¹²⁵IB-H (0.26 ± 0.04) remain largely unchanged indicating that DSB are entirely produced by direct effects. Strikingly, ¹²⁵I-C₈–H or ¹²⁵I-C₁₂–H, did not produce detectable DSB in the presence of DMSO under similar conditions suggesting when ¹²⁵I atom is positioned >?12 Å from the DNA, DSB are entirely produced by indirect effects.

Conclusion: These results suggest that at a critical distance between the ¹²⁵I atom and the DNA helix, DSB production switches from an ‘all’ direct to an ‘all’ indirect mechanism, the latter situation being comparable to the decay of ¹²⁵I free in solution. These experimental findings were correlated with theoretical expectations based on microdosimetry.     

131I-RGD-BSA-PCL用于非小细胞肺癌荷瘤裸鼠SPECT/CT显像及抑瘤作用

目的 探讨¹³¹I-RGD-BSA-PCL核素纳米载体对非小细胞肺癌荷瘤裸鼠模型SPECT/CT显像效果及其对肿瘤的抑制作用。方法 构建纳米脂质体¹³¹I-RGD-BSA-PCL及¹³¹I-BSA-PCL,通过荧光共聚焦显微镜观察该载体在非小细胞肺癌细胞系H460的靶向性结合及细胞摄取情况;采用氯氨T法标记核素纳米载体;流式细胞术观察核素纳米载体对肿瘤细胞的杀伤作用。构建荷瘤裸鼠模型,研究核素纳米载体在荷瘤裸鼠体内的组织分布、肿瘤体积变化及各组荷瘤裸鼠SPECT/CT断层显像。结果 给药后1和8 h,H460细胞质和细胞核对RGD-BSA-PCL、BSA-PCL两种纳米载体均有明显摄取。Na¹³¹I、¹³¹I-BSA-PCL及¹³¹I-RGD-BSA-PCL对H460细胞的早期凋亡率分别为（33.3±12.5）%、（68.4±8.0）%和（70.5±12.2）%。荷瘤裸鼠体内实验中,给药后24和72 h,肿瘤¹³¹I-RGD-BSA-PCL摄取率均高于¹³¹I-BSA-PCL（t=9.53、5.03,P<0.01）。给药后23 d,¹³¹I-RGD-BSA-PCL肿瘤体积抑制最明显（t=126.44,P<0.01）。SPECT/CT显示,给药后21 d,¹³¹I-RGD-BSA-PCL在肿瘤内信号强度明显强于¹³¹I-BSA-PCL。结论 ¹³¹I标记的纳米脂质体¹³¹I-RGD-BSA-PCL对H460细胞裸鼠移植瘤具有明显的抑瘤作用,且¹³¹I-RGD-BSA-PCL能较长时间停留在肿瘤中。     

In vitro characterization of <Superscript>177</Superscript>Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

Purpose   ¹³¹I- and ⁹⁰Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin’s lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (<20 min) with either ¹⁷⁷Lu or ⁹⁰Y. Materials and methods  Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. Results  The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 10⁵ times excess of diethylenetriaminepentaacetic acid (DTPA, 37°C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m² body surface ¹⁷⁷Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314 mGy. The administration of ¹⁷⁷Lu-DOTA-rituximab was tolerated well. Conclusion  Our results show that DOTA-rituximab (4:1) can be labelled with ¹⁷⁷Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. ¹⁷⁷Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NHL. Flavio Forrer and Jianhua Chen contributed equally to this work.     

Cross section measurements of the Xe(p,n) reaction for production of the therapeutic radionuclide Cs

¹³¹Cs is an X-ray emitter radioisotope gaining interest in prostate brachytherapy. It is generally produced via the ¹³⁰Ba(n,γ)¹³¹Ba→¹³¹Cs process in thermal-flux reactors. Here we investigate its cyclotron production possibilities. Excitation function of the ¹³¹Xe(p,n)¹³¹Cs reaction was measured up to 35 MeV using the stacked gascell technique and high-resolution X-ray spectrometry. The experimental data were compared with results of the ALICE-IPPE and EMPIRE-II codes and curves taken from the PADF and TENDL database. The calculated integral yield was 17 MBq/μA h in the energy range E_p=20→7 MeV. Comparison of cyclotron and reactor production routes was given.     

<Superscript>124</Superscript>I-L19-SIP for immuno-PET imaging of tumour vasculature and guidance of <Superscript>131</Superscript>I-L19-SIP radioimmunotherapy

Purpose  The human monoclonal antibody (MAb) fragment L19-SIP is directed against extra domain B (ED-B) of fibronectin, a marker of tumour angiogenesis. A clinical radioimmunotherapy (RIT) trial with ¹³¹I-L19-SIP was recently started. In the present study, after GMP production of ¹²⁴I and efficient production of ¹²⁴I-L19-SIP, we aimed to demonstrate the suitability of ¹²⁴I-L19-SIP immuno-PET for imaging of angiogenesis at early-stage tumour development and as a scouting procedure prior to clinical ¹³¹I-L19-SIP RIT. Methods   ¹²⁴I was produced in a GMP compliant way via ¹²⁴Te(p,n)¹²⁴I reaction and using a TERIMO™ module for radioiodine separation. L19-SIP was radioiodinated by using a modified version of the IODO-GEN method. The biodistribution of coinjected ¹²⁴I- and ¹³¹I-L19-SIP was compared in FaDu xenograft-bearing nude mice, while ¹²⁴I PET images were obtained from mice with tumours of <50 to ∼700 mm³. Results   ¹²⁴I was produced highly pure with an average yield of 15.4 ± 0.5 MBq/μAh, while separation yield was ∼90% efficient with <0.5% loss of TeO₂. Overall labelling efficiency, radiochemical purity and immunoreactive fraction were for ¹²⁴I-L19-SIP: ∼80 , 99.9 and >90%, respectively. Tumour uptake was 7.3 ± 2.1, 10.8 ± 1.5, 7.8 ± 1.4, 5.3 ± 0.6 and 3.1 ± 0.4%ID/g at 3, 6, 24, 48 and 72 h p.i., resulting in increased tumour to blood ratios ranging from 6.0 at 24 h to 45.9 at 72 h p.i.. Fully concordant labelling and biodistribution results were obtained with ¹²⁴I- and ¹³¹I-L19-SIP. Immuno-PET with ¹²⁴I-L19-SIP using a high-resolution research tomograph PET scanner revealed clear delineation of the tumours as small as 50 mm³ and no adverse uptake in other organs. Conclusions   ¹²⁴I-MAb conjugates for clinical immuno-PET can be efficiently produced. Immuno-PET with ¹²⁴I-L19-SIP appeared qualified for sensitive imaging of tumour neovasculature and for predicting ¹³¹I-L19-SIP biodistribution. Bernard M. Tijink and Lars R. Perk contributed equally to this article.     

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: Influence of isomeric substitution on radiolabeling and target cell residualization

IntroductionN-succinimidyl 4-guanidinomethyl-3-[^⁎I]iodobenzoate ([^⁎I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [¹³¹I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N-succinimidyl 3-guanidinomethyl-5-[¹³¹I]iodobenzoate (iso-[¹³¹I]SGMIB) wherein this bulky group was moved from ortho to meta position.MethodsBoc₂-iso-SGMIB standard and its tin precursor, N-succinimidyl 3-((1,2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc₂-iso-SGMTB), were synthesized using two disparate routes, and iso-[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors — trastuzumab (Tras) and a nanobody 5 F7 (Nb) — were labeled using iso-[^⁎I]SGMIB and [^⁎I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeric prosthetic agents were performed.ResultsWhen the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc₂-iso-[¹³¹I]SGMIB were significantly higher than those for Boc₂-[¹³¹I]SGMIB (70.7 ± 2.0% vs 56.5 ± 5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso-[¹³¹I]SGMIB than with [¹³¹I]SGMIB (Nb, 33.1 ± 7.1% vs 28.9 ± 13.0%; Tras, 45.1 ± 4.5% vs 34.8 ± 10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5 F7 Nb indicated similar residualizing capacity over 6 h; however, at 24 h, radioactivity retained intracellularly for iso-[¹³¹I]SGMIB-Nb was lower than for [¹²⁵I]SGMIB-Nb (46.4 ± 1.3% vs 56.5 ± 2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso-[¹²⁵I]SGMIB and [¹³¹I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [¹³¹I]SGMIB-Tras.ConclusionGiven the higher labeling efficiency obtained with iso-SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens.     

No evidence of chromosome damage in children and adolescents with differentiated thyroid carcinoma after receiving 131I radiometabolic therapy, as evaluated by micronucleus assay and microarray analysis

Purpose  As ¹³¹I therapy, used to achieve ablation of thyroid gland remnant, can cause chromosome damage in cultured peripheral lymphocytes especially, we investigated whether administration of radioiodine may induce early genome damage in peripheral T lymphocytes of adolescents with differentiated thyroid carcinoma (DTC). Methods  We studied 11 patients, aged 14.8 ± 3.1 years, who assumed ¹³¹I (range: 1.11–4.44 GBq) to ablate thyroid remnant. A blood sample for micronucleus assay and for evaluating expression of some genes involved in the DNA repair or the apoptosis pathways was obtained from each patient 1 h before (T₀) and 24 (T₁) and 48 h (T₂) post-radioiodine administration. Results  Compared to T₀, we did not find any difference in the number of micronucleated cells at both T₁ and T₂ in any subject. Nine out of 11 patients had altered expression levels in a majority of the DNA repair and apoptosis genes at T₁, which decreased at T₂. Conclusions  We demonstrated for the first time that peripheral cells of DTC children and adolescents who received ¹³¹I at a mean dosage of 3.50 ± 0.37 GBq did not show chromosome damage within 48 h from the end of radiometabolic therapy. This may be due to a prompt activation of the cell machinery that maintains the integrity of the genome to prevent harmful double-strand breaks from progressing to chromosome mutations, either by repairing the lesions or by eliminating the most seriously damaged cells via apoptosis. Statement on financial support. The present study did not receive any extramural financial assistance. It was supported exclusively by the Azienda Ospedaliero-Universitaria Pisana.     

核医学场所空气中131I浓度监测及工作人员内照射剂量评价探讨

目的 了解医疗机构¹³¹I治疗工作场所空气中¹³¹I核素的活度浓度水平，探讨通过空气采样方法估算工作人员内照射剂量的方法并分析其影响因素。方法 选取郑州市10家开展¹³¹I核素治疗的工作场所，采用空气采样方法采集¹³¹I治疗工作场所中放射性气溶胶，用高纯锗γ能谱仪进行γ放射性核素测定并推算工作场所空气中¹³¹I核素的活度浓度水平，根据测量结果和现场调查结果估算放射工作人员因¹³¹I核素吸入导致的内照射剂量。结果 19个分装间空气样品的¹³¹I活度浓度为0.087~570 Bq/m³，平均为（51.04±128.58）Bq/m³；11个病房空气样品的¹³¹I活度浓度为0.162~54.6 Bq/m³，平均为（7.97±15.89）Bq/m³。根据GBZ 129-2016《职业性内照射个人监测规范》推荐的典型工作时间估算，放射工作人员由于吸入¹³¹I核素导致的年待积有效剂量范围为2 μSv~10 mSv，平均为（0.61±1.80）mSv，年有效剂量均未超过国家标准所规定的剂量限值。结论 郑州市10家医疗机构核医学工作场所中¹³¹I核素活度浓度较高的样品多分布在甲状腺癌住院患者较多、核素操作量较大的三甲医院，由此导致的工作人员内照射剂量不容忽视。根据空气样品的测量结果估算内照射剂量带有很大不确定度，但空气采样方法可及时发现异常或事故情况下的放射性污染，为工作人员开展体外直接测量和内照射评价提供预警。     

131I标记共载两种靶向药物的多功能纳米载体的构建

目的构建131I标记的、共载17-丙烯胺基-17-去甲氧基格尔德霉素（17-AAG）与Torin2两种分子靶向性药物的新型多功能介孔二氧化硅（mSiO₂）纳米载体,测定其表征,了解其释药动力学,以及甲状腺未分化癌（ATC）细胞对其摄取的情况。方法采用传统的模板法制作mSiO₂,按照浓度比为1:1的比例装载两种靶向药物17-AAG与Torin2,并在其表面进行氨基化修饰后连接胎牛血清白蛋白（BSA）,测定其基本表征、药物的载药量及包封率。采用高效液相色谱法分析纳米载体所载药物的体外释放情况。采用氯胺T法对纳米载体进行131I标记,测定其标记率及放化纯度。通过核素胞内摄取定量实验了解该纳米载体被ATC细胞的摄取及滞留情况。采用SPSS19.0统计学软件,对数据进行独立样本t'检验。结果成功制备mSiO₂并完成装载（17-AAG+Torin2）@mSiO₂-BSA-131I纳米载体,经测定得到两者的有效直径分别约为170~250 nm和200~300 nm,并证实所得纳米载体的分散性好且具有理想的球形形态。131I标记率为66.31%~78.25%,放化纯度为98.80%~99.42%,mSiO₂对17-AAG及Torin2的载药量分别为（7.31±0.22）%和（6.04±0.79）%,包封率分别为（86.21±1.32）%和（85.17±2.05）%。证实所得纳米载体对17-AAG与Torin2均具有一定的缓释效果。ATC细胞内核素摄取定量实验结果显示（17-AAG+Torin2）@mSiO₂-BSA-131I可被细胞快速摄取且于3 h时达摄取高峰,其细胞摄碘量明显高于Na131I溶液,差异有统计学意义（t=32.63~109.31,均P < 0.01）。结论mSiO₂纳米载体可以实现两种靶向药物的共载及131I的标记,且具有一定的药物缓释作用,ATC细胞能够明显、快速地摄取（17-AAG+Torin2）@mSiO₂-BSA-131I。     

Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy

Purpose  Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA–folate conjugate. Methods  Radiolabelling of the DOTA-folate was carried out via standard procedures using ¹¹¹InCl₃ and ¹⁷⁷LuCl₃, respectively. The distribution coefficient (log D) was determined in octanol/PBS (pH 7.4). Tissue distribution was investigated in nude mice bearing KB tumour xenografts at different time points after administration of ¹¹¹In-DOTA-folate (radiofolate 1) or ¹⁷⁷Lu-DOTA-folate (radiofolate 2) (1 MBq, 1 nmol per mouse). Pemetrexed (PMX, 400 μg) was injected 1 h prior to the radiofolate in order to reduce renal uptake. Images were acquired with a SPECT/CT camera 24 h after injection of the radiofolate (40–50 MBq, 3 nmol per mouse). Results  The hydrophilic character of the DOTA-folate was represented by a low log D value (radiofolate 1 −4.21±0.11). In vivo, maximal tumour uptake was found 4 h after injection (radiofolate 1 5.80±0.55% ID/g; radiofolate 2 7.51±1.25% ID/g). In FR-positive kidneys there was considerable accumulation of the radiofolates (radiofolate 1 55.88±3.91% ID/g; radiofolate 2 57.22±11.05% ID/g; 4 h after injection). However, renal uptake was reduced by preinjection of PMX (radiofolate 1 9.52±1.07% ID/g; radiofolate 2 13.43±0.54% ID/g; 4 h after injection) whereas the tumour uptake was retained (radiofolate 1 6.32±0.41% ID/g; radiofolate 2 8.99±0.43% ID/g; 4 h after injection). SPECT/CT images clearly confirmed favourable tissue distribution of the novel radiofolates and the positive effect of PMX. Conclusion  The preliminary requirements for the therapeutic use of the novel DOTA-folate are met by its favourable tissue distribution that can be ascribed to its hydrophilic properties and combined administration with PMX.     

Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody

IntroductionWith a molecular weight an order of magnitude lower than antibodies but possessing comparable affinities, Nanobodies (Nbs) are attractive as targeting agents for cancer diagnosis and therapy. An anti-HER2 Nb could be utilized to determine HER2 status in breast cancer patients prior to trastuzumab treatment. This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors.Methods5F7GGC Nb was radioiodinated with ¹²⁵I using Iodogen and with ¹³¹I using the residualizing agent N^?-(3-[¹³¹I]iodobenzoyl)-Lys⁵-N^α-maleimido-Gly¹-GEEEK ([¹³¹I]IB-Mal-d-GEEEK) used previously successfully with intact antibodies. Paired-label internalization assays using BT474M1 cells and tissue distribution experiments in athymic mice bearing BT474M1 xenografts were performed to compare the two labeled Nb preparations.ResultsThe radiochemical yields for Iodogen and [¹³¹I]IB-Mal-d-GEEEK labeling were 83.6 ± 5.0% (n = 10) and 59.6 ± 9.4% (n = 15), respectively. The immunoreactivity of labeled proteins was preserved as confirmed by in vitro and in vivo binding to tumor cells. Biodistribution studies showed that Nb radiolabeled using [¹³¹I]IB-Mal-d-GEEEK, compared with the directly labeled Nb, had a higher tumor uptake (4.65 ± 0.61% ID/g vs. 2.92 ± 0.24% ID/g at 8 h), faster blood clearance, lower accumulation in non-target organs except kidneys, and as a result, higher concomitant tumor-to-blood and tumor-to-tissue ratios.ConclusionsTaken together, these results demonstrate that 5F7GGC anti-HER2 Nb labeled with residualizing [¹³¹I]IB-Mal-d-GEEEK had better tumor targeting properties compared to the directly labeled Nb suggesting the potential utility of this Nb conjugate for SPECT (¹²⁹I) and PET imaging (¹²⁴I) of patients with HER2-expressing tumors.     

6家医院碘治疗场所工作人员甲状腺131I活度测量

目的调查碘治疗场所工作人员甲状腺131I活度水平及其主要影响因素。方法采用配额抽样的方法, 按照碘治疗场所医院的不同类型, 在山西省和山东省共选择6家开展碘治疗的医院, 采用直接测量法, 对76名碘治疗场所工作人员的甲状腺131I活度进行了测量, 并进行内照射剂量估算。结果共有5家医院的29人甲状腺131I活度高于仪器的探测限, 占全部被检测人员的38.16%, 其中最高值为2 468.45 Bq, 是1名负责手动分装放射性碘的医师。6家医院碘治疗场所工作人员甲状腺131I活度差异无统计学意义(P>0.05), 但手动分装131I的医院测量结果高于自动分装的医院, 差异有统计学意义(Z=1.75, P<0.01), 两家手动分装131I医院的12名碘治疗场所工作人员甲状腺测量结果全部高于探测限, 中位数分别为324.59 Bq和331.98 Bq, 4家使用自动分装仪的医院测量结果的中位数均低于探测限, 甲状腺131I检出率分别为32.61%、25.00%、10.00%和0。对于同一家医院, 参与分装131I的医生和保洁人员甲状腺131I活度高于不参与分装的医生, 差异有统...     

Dual-time-point <Superscript>18</Superscript>F-FDG PET imaging for diagnosis of disease type and disease activity in patients with idiopathic interstitial pneumonia

Purpose  Individual clinical courses of idiopathic interstitial pneumonia (IIP) are variable and difficult to predict because the pathology and disease activity are contingent, and chest computed tomography (CT) provides little information about disease activity. In this study, we applied dual-time-point [¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) positron emission tomography (PET), commonly used for diagnosis of malignant tumours, to the differential diagnosis and prediction of disease progression in IIP patients. Methods  Fifty patients with IIP, including idiopathic pulmonary fibrosis (IPF, n = 21), non-specific interstitial pneumonia (NSIP, n = 18) and cryptogenic organizing pneumonia (COP, n = 11), underwent ¹⁸F-FDG PET examinations at two time points: scan 1 at 60 min (early imaging) and scan 2 at 180 min (delayed imaging) after ¹⁸F-FDG injection. The standardized uptake values (SUV) at the two points and the retention index (RI-SUV) calculated from them were evaluated and compared with chest CT findings, disease progression and disease types. To evaluate short-term disease progression, all patients were examined by pulmonary function test every 3 months for 1 year after ¹⁸F-FDG PET scanning. Results  The early SUV for COP (2.47 ± 0.74) was significantly higher than that for IPF (0.99 ± 0.29, p = 0.0002) or NSIP (1.22 ± 0.44, p= 0.0025). When an early SUV cut-off value of 1.5 and greater was used to distinguish COP from IPF and NSIP, the sensitivity, specificity and accuracy were 90.9, 94.3 and 93.5%, respectively. The RI-SUV for IPF and NSIP lesions was significantly greater in patients with deteriorated pulmonary function after 1 year of follow-up (progressive group, 13.0 ± 8.9%) than in cases without deterioration during the 1-year observation period (stable group, −16.8 ± 5.9%, p < 0.0001). However, the early SUV for all IIP types provided no additional information of disease progression. When an RI-SUV cut-off value of 0% and greater was used to distinguish progressive IIPs from stable IIPs, the sensitivity, specificity and accuracy were 95.5, 100 and 97.8%, respectively. Conclusion  Early SUV and RI-SUV obtained from dual-time-point ¹⁸F-FDG PET are useful parameters for the differential diagnosis and prediction of disease progression in patients with IIP.     

Regional alterations in myocardial sympathetic innervation in patients with transient left-ventricular apical ballooning (Tako-Tsubo cardiomyopathy)

Background  Excess sympathetic nervous activity was proposed to play a crucial role in the pathogenesis of transient left-ventricular apical ballooning (TLVAB, also known as Tako-Tsubo cardiomyopathy). This study was conducted to assess presynaptic adrenergic alterations in the dysfunctional myocardium of patients with TLVAB. Methods and Results  Ten consecutive patients undergoing coronary angiography for acute coronary syndrome who fulfilled the proposed Mayo Clinic criteria for the diagnosis of TLVAB were investigated. Myocardial iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) studies (planar and single-photon emission computed tomography [SPECT]) were performed to evaluate adrenergic innervation. Concomitantly, myocardial perfusion was assessed by means of technetium-99m methoxyisobutylisonitrile (^99mTc-MIBI) SPECT. In all patients, angiography revealed typical ballooning of the left-ventricular (LV) apex and hyperkinesis of the basal LV segments (overall ejection fraction, 41%±5% [mean±SEM]). Planar ¹²³I-MIBG scans revealed decreased heart-to-mediastinum ratios at early (20 minutes) and delayed (4 hours) images (2.1±0.1 and 1.9±0.1, respectively). The cardiac washout rate of ¹²³I-MIBG on the late images was increased to 34%±3%. The ¹²³I-MIBG uptake on SPECT scans was obviously reduced in the akinetic LV apex (defect score, 3.30±0.34), whereas ^99mTc-MIBI SPECT indicated normal or only mildly reduced perfusion within this region (defect score, 0.89±0.35). Conclusions  Our study indicates a functional alteration in presynaptic sympathetic neurotransmission in patients with TLVAB, and suggests a pathophysiologic explanation of the impairment of LV function.     

Prediction of functional recovery after revascularization using quantitative gated myocardial perfusion SPECT: a multi-center cohort study in Japan

Backgrounds  Prediction of left ventricular functional recovery is important after myocardial infarction. The impact of quantitative perfusion and motion analyses with gated single-photon emission computed tomography (SPECT) on predictive ability has not been clearly defined in multi-center studies. Methods  A total of 252 patients with recent myocardial infarction (n = 74) and old myocardial infarction (n = 175) were registered from 25 institutions. All patients underwent resting gated SPECT using ^99mTc-hexakis-2-methoxy-isobutyl isonitrile (MIBI) and repeated the study after revascularization after an average follow-up period of 132 ± 81 days. Visual and quantitative assessment of perfusion and wall motion were performed in 5,040 segments. Results  Non-gated segmental percent uptake and end-systolic (ES) percent uptake were good predictors of wall motion recovery and significantly differed between improved and non-improved groups (66 ± 17% and 55 ± 18%, p < 0.0001 for non-gated; 64 ± 16% and 51 ± 17% for ES percent uptake, p < 0.0001). The area under the curve of receiver operating characteristics curve for non-gated percent uptake, ES percent uptake, end-diastolic percent uptake and visual perfusion defect score was 0.70, 0.71, 0.61, and 0.56, respectively. Sensitivity and specificity of percent uptake were 68% and 64% for non-gated map and 80% and 52% for ES percent uptake map. An optimal threshold for predicting segmental improvement was 63% for non-gated and 52% for ES percent uptake values. Conclusion  Segmental ^99mTc-MIBI uptake provided a useful predictor of wall motion improvement. Application of quantitative approach with non-gated and ES percent uptake enhanced predictive accuracy over visual analysis particularly in a multi-center study.     

Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [<Superscript>11</Superscript>C]PE2I

Purpose We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [¹¹C]PE2I. Methods PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [¹¹C]PE2I. Carrier-added [¹¹C]PE2I was administered to identify metabolites with high-performance liquid radiochromatography (RC) or RC with mass spectrometry (LC-MS and MS-MS). The stability of [¹¹C]PE2I was assessed in rat brain homogenates. Results After peak brain uptake of no-carrier-added [¹¹C]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [¹¹C]PE2I represented 10.9 ± 2.9% of the radioactivity in plasma, 67.1 ± 11.0% in cerebellum, and 92.5 ± 3.2% in striata, and was accompanied by two less lipophilic radiometabolites. [¹¹C]PE2I was stable in rat brain homogenate for at least 1 h at 37°C. LC-MS identified hydroxylated PE2I (1) (m/z 442) and carboxyl-desmethyl-PE2I (2) (m/z 456) in brain. MS-MS of 1 gave an m/z 442→424 transition due to H₂O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [¹¹C]PE2I, [¹¹C]1, and [¹¹C]2 in striata to their cognates in cerebellum were 6.1 ± 3.4, 3.7 ± 2.2 and 1.33 ± 0.38, respectively, showing binding selectivity of metabolite [¹¹C]1 to striata. Conclusion Radiometabolites [¹¹C]1 and [¹¹C]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [¹¹C]PE2I, respectively. The presence of the pharmacologically active [¹¹C]1 and the inactive [¹¹C]2 is a serious impediment to successful biomathematical analysis.