131I-美妥昔单抗联合动脉内化疗栓塞治疗原发性肝癌的内照射吸收剂量估算

Objective Metuximab is a specific monoclonal antibody F(ab')fragment targeted to the hepatocellular carcinoma(HCC)associated antigen of HAb18G/CD147.131I labeled metuximab has shown to be effective response on HCC in phase Ⅰ/Ⅱtrails.To evaluate the feasibility of 131I-metuximab combined with transarterial chemoembolization(TACE)is the treatment of HCC,the anthors estimated the radiation absorbed dose to organs.Methods 131I-metuximab(27.75 MBq/kg)and the mixture of anticancer drug and Lipiodol with interval 20 min later were administered to 21 patients with HCC via a transfemoral catheter.The pharmacokinetie and desimetric data were collected by means of venous blood samples.urine collections,and 4 or 5 γ-scintigraphies (SPECT) over7 d.The total amount of activity in percent of iniected activity (%ID)of main organ and the total body were calculated by regions of interest(ROI).The cumulated activities were determined from integration of the time-%ID curves using the SPSS 12.0 software.Absorbed doses to organ and red marrow were estimated according to the medical internal radiation dose (MIRD) formalism and blood-based marrow estimation with a red marrow-to-blood activity concentration ratio.The tumorto-no tumor ratio was calculated as well.Results A mean administered aetivity was 1.89 GBq per session (range 1.47-2.23 GBq).SPECT scans showed the significant accumulation of the radioconjugate in liver tumor and faint uptake in other organs until 14 d.Organ absorbed dose(n=12):the total absorbed dose to liver,spleen,thyroid,lungs,kidney and total-body was(3.19±1.01),(3.65±2.41),(3.61±2.40),(0.97±0.23),(0.96±0.35)and(0.57±1.55)Gy,with(0.55±0.09)Gy to the red marrow(n=7),respectively.From 2.88±1.11 to 1.64±0.39 were observed in tumor-to-liver ratio at 3 h to 168 h.Conclusion Internal absorbed dose estimation based on MIRD formalism is not only to establish reliable dose-response relationships for target tissue and dose-toxicity relationships for normal tissue but also to improve treatment planning in individual patient.     

^131I-美妥昔单抗联合动脉内化疗栓塞治疗原发性肝癌的内照射吸收剂量估算

目的对^131I-美妥昔单克隆抗体（简称单抗）联合动脉内化疗栓塞（TACE）治疗原发性肝癌患者器官的内照射吸收剂量进行估算。方法21例患者肝动脉内按体质量注入^131I-美妥昔单抗（27．75MBq／kg）和混合化疗药物的碘化油乳剂。用1计数仪测量5min和0．5,2,4,24,48,72,120,168h血样和尿样的放射性。用SPECT仪行4或5次全身扫描。用感兴趣区图像处理法计算主要器官和全身放射性活度占给予放射性活度的百分数（％ID）,SPSS12．0软件拟合时间-％ID曲线,计算累积活度,依据医学内照射辐射剂量学（MIRD）方法和血液间接法计算器官和红骨髓的内照射吸收剂量,计算肿瘤／非肿瘤放射性比值。结果^131I-美妥昔单抗的平均剂量为1．89（1．47～223）GBq／次。显像示放射性主要浓聚于肝区肿瘤组织,随时间延长,甲状腺后期有放射性浓聚,体内其他组织未见明显放射性分布。器官吸收剂量（12例）：肝（3．19±1．01）Gy,脾（3．65±2．41）Gy,甲状腺（3．61±2．40）Gy,肺（0．97±0．23）Gy,肾（0．96±0．35）Gy,全身（0．57±1．55）Gy,红骨髓（0．55±0．09）Gy（7例）。肿瘤／肝放射陛比值（7例）：3h为2．88±1．11,64h为2．15±0．53,120h为1．81±0．39,168h为1．64±0．39。结论依据MIRD方法计算获得了主要器官、红骨髓和全身内照射吸收剂量,这对更好评价疗效、不良反应和制订个体化方案有重要意义。     

131I标记抗肝癌单克隆抗体片段的内照射吸收剂量估算

目的对给予^131I标记抗肝癌单克隆抗体（简称单抗）片段[HAb18F（ab）2]的志愿者进行脏器内照射吸收剂量估算。方法2例志愿者静脉注射^131I-HAbl8F（ab）2后，分别于5、30min和2、4、8、24h及2、3、4、6、10d共11个时间点收集血样，并分别于治疗后3、24h和2、4、8、16d进行SPECT全身显像；对血样进行放射性测量，测定全身平面图像感兴趣区（ROI）计数；应用SPSS13．0软件对获得的数据进行曲线拟合；计算药物在各脏器的有效半衰期；估算各脏器的吸收剂量。结果^131I-HAb18F（ab）2在人体各脏器内的有效半衰期为1．8～6．4d，甲状腺的吸收剂量最大为28．5Gy，其余脏器不超过3Gy。结论该计算方法简便易行，可应用于内照射吸收剂量的估算。     

^131I—C50放射免疫显像诊断卵巢癌

目的 探讨卵巢癌放免显像在卵巢癌诊断和治疗方面的临床价值。方法 采用氯胺T法制备^131I-CEA McAb(C50)，以静脉滴注方式给药，于不同时间对患者进行显像。结果 经手术和病理检查证实的105例卵巢癌患者中96例显像阳性，9例阴性（假阴性）；23例良性病灶中22例获阴性显像结果，并经手术证实。96例阳性显像中87例放射免疫显像分期与手术分期完全相符。151处转移灶发现141处，阳性率93．4％，最小检出病灶直径1cm。结论 卵巢癌放免显像对卵巢癌的早期发现，指导临床分期和制定治疗方案、预计预后有较高的临床价值。     

131I标记的抗肝癌血管内皮细胞单克隆抗体对肝癌治疗的实验研究

目的运用131I标记的抗肝癌血管内皮细胞单克隆抗体,研究靶向血管内皮细胞治疗肝癌的可行性.方法 建立裸小鼠人肝细胞癌动物模型,取30只裸鼠随机分为3组,分别为实验A组、实验B组和对照组,每组各10只.实验A组在接种肝癌细胞的同时,经腹腔注射抗肝癌血管内皮细胞的单克隆抗体,每只200μg/200μl,2次/周;实验B组在接种肝癌细胞的同时,经腹腔注射同剂量的131I标记的抗肝癌血管内皮细胞的单克隆抗体;对照组在接种肝癌细胞的同时,经腹腔注射等量的生理盐水.观察肿瘤的生长情况,计算肿瘤的体积,计算抑瘤率.结果 实验A组的抑瘤率为74.55%,实验B组为86.36%;实验A、B组与对照组比较肿瘤明显受抑(P<0.05).实验B组与实验A组比较显示了明显的放疗作用(P<0.05).HE及免疫组化染色观察证实,经单抗治疗后肿瘤区微血管内血栓形成,血管内皮细胞变性、坏死,血管周围大片肿瘤细胞坏死,瘤内血管密度明显降低.结论 抗肝癌血管内皮细胞单克隆抗体在动物实验中有明显的抑瘤作用,以此抗体为载体与核素相结合,可明显提高治疗肿瘤的疗效.     

Synthesis and biodistribution of radioarsenic labeled dimethylarsinothiols: derivatives of penicillamine and mercaptoethanol

Arsenic analogs of sulfhydryl containing biomolecules can be derived from dimethylchloroarsine as a precursor. Arsenic-76 labeled dimethylarsinothiols (dimethylarsinopenicillamine and dimethylarsinomercaptoethanol) were synthesized, purified by chromatography, and their biodistributions obtained in mice. The present study demonstrates the possibility of developing a group of radioarsenicals from SH-containing biomolecules.     

131I标记抗NRP-1单克隆抗体A6在荷瘤裸鼠体内分布和显像研究

目的制备131I标记的抗神经纤毛蛋白-1（NRP-1）单克隆抗体A6（131I-A6）,探讨其作为NRP-1靶向显像新型分子探针的可行性。方法（1）采用Iodogen法对A6进行131I标记,检测其标记率、放化纯和体外稳定性。（2）以人胶质瘤细胞株U87MG为实验细胞进行体外实验,测定131I—A6生物学活性、结合率及其与受体的亲和力。（3）将荷U87MG胶质瘤模型裸鼠采用随机抽样法分为5组,每组5只,分别于注射1．2MBq 131I-A6后24、48、72、96和120h处死,计算各脏器放射性摄取（％ID／g）、肿瘤／血液（T／B）和肿瘤／肌肉（T／M）比值。（4）取6只荷瘤裸鼠,以随机抽样法分为未阻断组和竞争阻断组,前组注射3．7MBq 131I-A6;后组注射3．7MBq 131I-A6和未标记的700仙gA6,均分别于注射后24、48、72、96和120h行SPECT／CT显像。采用两样本t检验对实验数据进行统计学分析。结果（1）131I—A6标记率为（95．46±3．34）％,放化纯〉95％;131I—A6在室温下PBS溶液中放置至96h,其放化纯仍〉85％。（2） 131I-A6与U87MG胶质瘤细胞特异性结合率1h达到最高值,为（15．80±1．30）％,在加入未标记的抗体A6时,U87MG细胞对131I-A6明显受抑制（t=2．862,P〈0．05）;与细胞表面抗原的亲和力（kd）为（1．67±0．14）nmol／L。（3）24h时131I—A6在荷瘤裸鼠血液放射性最高,为（8．00±1．42）％ID／g;其次是肝脏和肿瘤组织,分别为（7．68±1．56）和（6．00±1．24）％ID／g;脑、骨、肌肉组织放射性计数较低。给药后24h,T／B和T／M分别为0．78±0．10和3．20±0．30,随时间延长比值逐渐增高,在120h达到最高,分别为1．87±0．50和7．13±0．24。（4）体内显像示,注射 131I-A6后24h肿瘤略显影,随时间延长变清晰,120h显影为最清晰,阻断后未见肿瘤显影。结论 131I-A6的标记方法简单易行,标记率高,产物稳定性好,?     

131I-17-丙烯胺基-17-去甲氧基格尔德霉素对人乳腺癌细胞生长的抑制作用

目的 探讨^131I-17-丙烯胺基-17-去甲氧基格尔德霉素（17-AAG）对人乳腺癌细胞生长的影响及其相关机制。方法 采用过氧化氢标记法制备^131I-17-AAG。细胞杀伤实验分为5组：二甲基亚砜（DMSO）对照（A）组，Na^131I370kBq（B）组，17-AAG2．5mg／L（C）组，^131I-17-AAG370kBq（D）组，^131I-17-AAG370kBq＋17-AAG2．5mg／L（E）组。用四甲基偶氮唑蓝（MTT）法检测各种药物对人乳腺癌细胞MCF-7的生长抑制作用，流式细胞术分析细胞凋亡及细胞周期变化，RT—PCR检测药物处理前后MCF-7细胞中Akt2基因的mRNA表达情况。结果 ^131I-17-AAG的标记率为83％，放化纯为96．6％，比活度为1．48×10^5MBq／μmol。各组药物对细胞的杀伤呈时间效应，随着时间的延长，细胞的抑制率都呈明显上升趋势，尤以E组趋势明显。A～E组药物作用48h后，通过亚G1峰检测MCF-7细胞凋亡率分别为（1．54±0．13）％，（5．72±1．05）％，（12．97±1．44）％，（20．65±1．36）％，（35．39±4．15）％，各组细胞凋亡率差异有统计学意义（P均〈0．05）。C组，D组及E组Akt2基因的mRNA表达均比A组降低，其中E组降低尤为明显。结论 ^131I-17AAG能够抑制MCF-7细胞的生长并促进其凋亡，且能有效抑制Akt2基因的mRNA表达，和17-AAG联合应用能够增强肿瘤细胞对放疗的敏感性。     

A comparative study of 131I and 177Lu labeled somatostatin analogues for therapy of neuroendocrine tumours

This work analysed the influence of the chelating group and radioligand on somatostatin analogues in vivo and in vitro properties. The presence of DOTA in the radioiodinated peptide produced a labeled analogue with similar blood kinetics and biodistribution to ¹⁷⁷Lu-DOTATATE and with lower abdominal uptake than ¹³¹I-TATE. In addition, ¹³¹I-DOTATATE showed significative tumour uptake, despite not so persistent after 24 h. ¹³¹I-DOTATATE can represent a cost-effective alternative to lutetium labeled peptide for neuroendocrine tumours therapy.     

Isolating effects of microscopic nonuniform distributions of (131)I on labeled and unlabeled cells.

Radiopharmaceuticals are generally distributed nonuniformly in tissue. At the microscopic level, only a fraction of the cells in tissue are labeled. Consequently, the labeled cells receive an absorbed dose from radioactivity within the cell (self-dose) as well as an absorbed dose from radioactivity in surrounding cells (cross-dose). On the other hand, unlabeled cells only receive a cross-dose. This work uses a novel approach to examine the lethal effects of microscopic nonuniformities of (131)I individually on the labeled and unlabeled cells. METHODS: A multicellular tissue model was used to investigate the lethality of microscopic nonuniform distributions of (131)I. Mammalian cells (V79) were dyed with CFDA-SE (carboxy fluorescein diacetate succinimidyl ester) and labeled with (131)I-iododeoxyuridine ((131)IdU). The dyed labeled cells were then mixed with equal numbers of unlabeled cells, and 3-dimensional tissue constructs (4 x 10(6) cells) were formed by centrifugation in a small tube. This resulted in a uniform distribution of (131)I at the macroscopic level but nonuniform distribution at the multicellular level, wherein 50% of the cells were labeled. The multicellular clusters were maintained at 10.5 degrees C for 72 h to allow (131)I decays to accumulate. The clusters were then dismantled and the labeled (dyed) and unlabeled (undyed) cells were separately seeded for colony formation using a fluorescence-activated cell sorter. RESULTS: The unlabeled cells, which received only a cross-dose, exhibited a mean lethal dose D(37) of 4.0 +/- 0.3 Gy. In contrast, the labeled cells received both a self-dose and a cross-dose. Isolating the effects of the self-dose resulted in a D(37) of 1.2 +/- 0.3 Gy, which was about 3.3 times more toxic per unit dose than the cross-dose. The reason for these differences appears to be primarily related to the higher relative biological effectiveness of the self-dose delivered by (131)IdU compared with the cross-dose. Theoretical modeling of the killing of labeled and unlabeled cells was achieved by considering the cellular self-doses and cross-doses. CONCLUSION: Cellular self-doses and cross-doses play an important role in determining the biological response of tissue to microscopic nonuniform distributions of (131)I. Prediction of the biological response requires that both self-doses and cross-doses be considered along with their relative lethality per unit dose.     

Synthesis and evaluation of (18)F labeled alanine derivatives as potential tumor imaging agents

IntroductionThis paper reports the synthesis and labeling of ¹⁸F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine–serine–cysteine preferring (ASC) transporter system.MethodsThree new ¹⁸F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labeling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[¹⁸F]fluoromethyl)-L-alanine (L-[¹⁸F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma).ResultsNew ¹⁸F alanine derivatives were prepared with 7%–34% uncorrected radiochemical yields, excellent enantiomeric purity (> 99%) and good radiochemical purity (> 99%). In vitro uptake of the L-[¹⁸F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than that observed for the other two alanine derivatives and [¹⁸F]FDG in the first 1 h. Inhibition of cell uptake studies suggested that L-[¹⁸F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[¹⁸F]FMA remained stable and was not incorporated into protein within 2 h. In vivo biodistribution studies demonstrated that L-[¹⁸F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[¹⁸F]FMA in both 9L rat and transgenic mouse.ConclusionL-[¹⁸F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation.     

Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent

Monoclonal antibodies such as L8A4, reactive with the epidermal growth factor receptor variant III, internalize after receptor binding resulting in proteolytic degradation by lysosomes. Labeling internalizing mAbs requires the use of methodologies that result in the trapping of labeled catabolites in tumor cells after intracellular processing. Herein we have investigated the potential utility of N-succinimidyl-3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), an acylation agent that couples the corresponding negatively charged acid [131I]IPMBA to the protein, for this purpose. Biodistribution studies demonstrated that [131I]IPMBA cleared rapidly from normal tissues and exhibited thyroid levels < or =0.1% injected dose, consistent with a low degree of dehalogenation. Biodistribution experiments in athymic mice bearing subcutaneous D-256 human glioma xenografts were performed to compare L8A4 labeled using [131I]SIPMB to L8A4 labeled with 125I using both the analogous positively charged acylation agent N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB) and Iodogen. Tumor uptake of [131I]SIPMB-L8A4 (41.9+/-3.5% ID/g) was nearly threefold that of L8A4 labeled using Iodogen (14.0+/-1.1% ID/g) after 2 days, and tumor to tissue ratios remained uniformly high throughout with [131I]SIPMB-L8A4. Thyroid uptake increased for the Iodogen labeled mAb (3.55+/-0.36 %ID at 5 days) whereas that of [131I]SIPMB labeled mAb remained low (0.21+/-0.04% ID at 5 days). In the second biodistribution, L8A4 labeled using [131I]SIPMB and [125I]SGMIB showed no difference in normal tissue uptake and had nearly identical tumor uptake ([131I]SIPMB, 41.8+/-14.2% ID/g; [125I]SGMIB, 41.6+/-15.8% ID/g, at 4 days). These results suggest that [131I]SIPMB may be a viable acylation agent for the radioiodination of internalizing mAbs.     

^131I—抗HBxAg人／鼠嵌合抗体在裸鼠人肝癌模型定位的初步研究

在抗ＨＢｘＡｇ人／鼠嵌合抗体基因构建及表达成功后，进行了放射免疫显像研究，以评价在其在动物模型中的导向活性。＾１３１Ｉ标记嵌合抗体，经腹腔注射１，５，７天后行裸鼠人肝癌模型放射免疫显像，于第７天作组织分布测定，并以单区抗体及原鼠源抗体对照进行比较，结果显示实验组在标记抗体注入后２天即获肿瘤阳性显像，第７天更清晰，此时嵌合抗体，单区抗体，抗ＨＢｘ单抗及对照组的瘤／肝放射性比值分别为２．８，２．４４，     

Synthesis of carbon-11 labeled celecoxib derivatives as new candidate PET radioligands for imaging of inflammation

Cyclooxygenase (prostaglandin endoperoxide synthase or COX) enzyme represents a particularly attractive target in inflammation processes for the development of both therapeutic agents and imaging agents. This study was designed to develop new radioligands for imaging of inflammation using the biomedical imaging technique positron emission tomography (PET). Carbon-11 labeled celecoxib derivatives, [¹¹C]methyl 2-(4-(5-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonamidooxy)acetate ([¹¹C]6e), [¹¹C]methyl 2-methyl-2-(4-(5-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonamidooxy)propanoate ([¹¹C]6f), [¹¹C]methyl 2-(4-(5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonamidooxy)acetate ([¹¹C]6g), and [¹¹C]methyl 2-methyl-2-(4-(5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenylsulfonamidooxy)propanoate ([¹¹C]6h), were prepared by O-[¹¹C]methylation of their corresponding precursors using [¹¹C]CH₃OTf under basic condition and isolated by a simplified solid-phase extraction (SPE) method in 50–60% radiochemical yields based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 15–20 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 111–185 GBq/μmol.