188Re-7E11C5.3抑制前列腺癌细胞增殖

目的：探讨铼-188（188Re）标记前列腺特异膜抗原单克隆抗体7E11C5.3（188Re-7E11C5.3）对前列腺癌细胞系LNCaP的体外抑制作用。方法：采用2-巯基乙醇直接还原法制备188Re-7E11C5.3标记物，纸层析法测定标记率和放化纯度，直线回归外推法测定免疫活性分数。四唑盐（MTT）法测定其体外细胞毒作用。结果：188Re-7E11C5.3的标记率为（93.16±2.18）%，放化纯度为（95.62±0.48）%，免疫活性分数为（74.86±1.86）%。188Re-7E11C5.3对LNCaP细胞的生长抑制作用明显强于188Re标记的正常鼠IgG（mIgG）和游离188ReO^-₄，其半数有效抑制浓度（IC₅₀）分别为（23.38±3.73）×10⁷ Bq/L，（59.21±8.02）×10⁷ Bq/L和（68.89±10.91）×10⁷ Bq/L。结论：188Re-7E11C5.3能有效抑制体外培养LNCaP细胞的增殖，可用于前列腺癌的放射免疫治疗。     

Crystal Structure of SARS-CoV-2 Main Protease in Complex with the Non-Covalent Inhibitor ML188

Viral proteases are critical enzymes for the maturation of many human pathogenic viruses and thus are key targets for direct acting antivirals (DAAs). The current viral pandemic caused by SARS-CoV-2 is in dire need of DAAs. The Main protease (M^pro) is the focus of extensive structure-based drug design efforts which are mostly covalent inhibitors targeting the catalytic cysteine. ML188 is a non-covalent inhibitor designed to target SARS-CoV-1 M^pro, and provides an initial scaffold for the creation of effective pan-coronavirus inhibitors. In the current study, we found that ML188 inhibits SARS-CoV-2 M^pro at 2.5 µM, which is more potent than against SAR-CoV-1 M^pro. We determined the crystal structure of ML188 in complex with SARS-CoV-2 M^pro to 2.39 Å resolution. Sharing 96% sequence identity, structural comparison of the two complexes only shows subtle differences. Non-covalent protease inhibitors complement the design of covalent inhibitors against SARS-CoV-2 main protease and are critical initial steps in the design of DAAs to treat CoVID 19.     

A Theoretical Study of the Binding of [Re6Se8(OH)2(H2O)4] Rhenium Clusters to DNA Purine Base Guanine

Hexanuclear rhenium complexes are promising candidates for use as antitumor drugs. However, to date, there has been no investigation into the nature of their binding to DNA. In this study, density functional theory (DFT) was used to examine the binding of [Re₆Se₈(OH)₂(H₂O)₄] to the DNA purine base guanine. The geometrical structures of cluster-guanine adducts in water were modeled at the zero order regular approximation (ZORA)-PW91 level. Calculating the bond energies allowed us to compare the cis and trans forms of the cluster, and a possible manners of interaction between [Re₆Se₈(OH)₂(H₂O)₃] clusters and DNA was obtained and explained.     

Radioembolization for the treatment of unresectable hepatocellular carcinoma： A clinical review

Hepatocellular carcinoma （HCC） is the sixth most common cancer in the world. The majority of patients with HCC present with unresectable disease. These patients have historically had limited treatment options secondary to HCC demonstrating chemoresistance to the currently available systemic therapies. Additionally, normal liver parenchyma has shown intolerance to tumoricidal radiation doses, limiting the use of external beam radiation. Because of these limitations, novel percutaneous liver-directed therapies have emerged. The targeted infusion of radioactive microspheres （radioembolization） represents one such therapy. Radioembolization is a minimally invasive transcatheter therapy through which radioactive microspheres are infused into the hepatic arteries that supply tumor. Once infused, these microspheres traverse the hepatic vascular plexus and selectively implant within the tumor arterioles. Embedded within the arterioles, the ^90y.impregnated microspheres emit high energy and low penetrating radiation doses selectively to the tumor. Radioembolization has recently shown promise for the treatment of patients with unresectable HCC. The objective of this review article is to highlight two currently available radioembolic devices ^90Y, ^188Rh） and provide the reader with a recent review of the literature.     

Effect of Poloxamer 188 on Collateral Blood Flow, Myocardial Infarct Size, and Left Ventricular Function in a Canine Model of Prolonged (3-Hour) Coronary Occlusion and Reperfusion

Poloxamer 188 is a surfactant with hemorheological, antithrombotic, and neutrophil-inhibitory properties. This agent has been demonstrated to reduce infarct size and to improve left ventricular function in animal models of myocardial infarction and reperfusion, and recently in a randomized trial of patients receiving thrombolytic therapy for acute myocardial infarction. In addition to reducing reperfusion injury, poloxamer 188 might be beneficial by increasing collateral blood flow. The purpose of this study was to determine the effect of poloxamer 188 on collateral blood flow, myocardial infarct size, and left ventricular function in a canine model of prolonged (3 hours) coronary occlusion and reperfusion. Closed-chest dogs (n = 21) underwent a 3-hour coronary occlusion and 3 hours of reperfusion. At 1 hour of occlusion, dogs received poloxamer 188, 75 mg/kg IV bolus, followed by 150 mg/kg/h IV for the final 2 hours of coronary occlusion and throughout reperfusion, or a saline placebo. Regional myocardial blood flow was measured using colored microspheres. Myocardial infarct size and area at risk were determined by postmortem histochemical staining. Compared with controls, poloxamer 188–treated dogs showed no significant increase in collateral blood flow during the final 2 hours of a 3-hour coronary artery occlusion. In addition, poloxamer 188 treatment had no beneficial effect on infarct size or left ventricular function in this model. Increased collateral blood flow is unlikely to be a beneficial mechanism of poloxamer 188 in myocardial infarction. These data also question the benefit of this agent to reduce reperfusion injury in the setting of more prolonged (3-hour) coronary occlusion.     

Localization of Small-cell Lung Cancer Xenografts with Iodine-125-, Indium-111-, and Rhenium-188-Somatostatin Analogs

We examined the potential of radiolabeled somatostatin analogs, ¹²⁵I-Tyr-3-octreotide (¹²⁵I-octreotide), ¹¹¹In-DTPA(diethylenetriaminepentaacetatic acid)- d -Phe-1-octreotide (¹¹¹In-octreotide), and ¹⁸⁸Re-octreotide for targeting small-cell lung cancer (SCLC) in a mouse model. Tyr-3-octreotide was labeled with ¹²⁵I by the chloramine T method, and ¹¹¹In-octreotide was obtained as a kit, while ¹⁸⁸Re was eluted from a ¹⁸⁸W/¹⁸⁸Re generator, and octreotide was directly labeled with ¹⁸⁸Re by reducing disulfide bonds. The ¹²⁵I-, ¹¹¹In-, and ¹⁸⁸Re-octreotides were injected i.v. into athymic mice bearing NCI-H69 tumors, and the biodistributions were determined at 15 min, and 2, 4, 8, and 24 h. Tumor uptakes were 0.5±0.2, 0.3±0.1, 0.3±0.1 %ID/g, and tumor-to-blood ratios were 1.8, 11.9, 1.2 at 8 h for ¹²⁵I-, ¹¹¹In-, and ¹⁸⁸Re-octreotides, respectively. Accumulations of ¹¹¹In-octreotide in normal tissues were lower than those of ¹²⁵I- and ¹⁸⁸Re-octreotides. ¹⁸⁸Re-octreotide can be used to localize SCLC lesions as efficiently as radioiodinated octreotide. However, ¹¹¹In-octreotide was the most suitable agent to obtain high tumor-to-normal tissue contrast for localizing SCLC.     

气相色谱法检测泊洛沙姆188中环氧化物杂质

目的 利用气相色谱法建立泊洛沙姆188中环氧乙烷、环氧丙烷及1,4-二氧六环的含量检查方法。方法 以超纯水作为溶剂,采用顶空气相色谱法检测泊洛沙姆188中环氧乙烷、环氧丙烷及1,4-二氧六环含量。结果 该方法的系统适用性、专属性、线性、精密度和准确度均符合规定,9批泊洛沙姆样品中均未检出环氧乙烷,环氧丙烷及1,4-二氧六环。结论 该方法简便、准确、可靠,可用于泊洛沙姆188中环氧乙烷、环氧丙烷及1,4-二氧六环含量检测。     

Comparison of various rhenium-188-labeled diphosphonates for the treatment of bone metastases

In the past, many diphosphonates were introduced as bone scan radiopharmaceuticals. In addition, diphosphonates have been labeled with beta-emitted isotopes and developed into useful therapeutic drugs for bone metastases. However, it is not clear which diphosphonate is the best choice when labeling with Re-188. In this study, we labeled methylene diphosphonate (MDP), hydroxyethylidene diphosphonate (HEDP), and hydroxymethane diphosphonate (HDP) with Re-188. Each radiopharmaceutical was further evaluated in two conditions (with and without carrier). Twenty-four rabbits were used (four in each group) for the analysis of the biodistributions and bone uptakes of these radiopharmaceuticals to assess their potential for clinical applicability. Four hours after intravenous injection of approximately 37 MBq (1 mCi) Re-188-labeled diphosphonate preparations, whole body scans were performed using a large-field gamma camera equipped with a high resolution collimator. Bone-to-soft tissue ratios (B/S ratio) were calculated using a computer program. Our data showed that Re-188 HEDP with carrier (10⁻⁴ M carrier) could accumulate in the skeletal system whereas very little absorption by bone was observed in the rabbits that were injected with carrier-free Re-188 HEDP. In addition, no significant bone uptake was demonstrated for Re-188 MDP or Re-188 HDP, with or without carrier. The B/S ratio was 25.06 in the Re-188 HEDP with carrier group but less than 3 in the other groups. In conclusion, HEDP is the best choice among these three bone-seeking drugs when labeled with Re-188. But, it is necessary to add carrier when preparing Re-188 HEDP for the treatment of bone metastases.