Human Anti-Oxidation Protein A1M—A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy

Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.     

正电子核素标记奥曲肽类似物的研究进展

奥曲肽是一种人工合成的含有8个氨基酸的生长抑素类似物,与生长抑素受体(SSTR)能够高特异性地结合。肿瘤细胞组织上常有一些生长抑素受体的过度表达,因此,应用正电子核素标记的奥曲肽及其类似物作为肿瘤示踪剂,对生长抑素受体阳性肿瘤进行诊断与治疗具有潜在的重要的临床意义。本文就正电子核素标记的奥曲肽类似物的研究现状进行综述。     

肿瘤放射性受体显像剂奥曲肽的固相合成

采用苏氨酸转变为苏氨酸乙酯，再用LiAlH4还原该乙酯合成了苏氨醇，用自动多肽合成仪和Fmoc(9-芴甲基羰基)保护的氨基酸合成了7肽-树脂；再用三氟醋酸铊(Tl(Tfa)3)在7肽-树脂上形成7肽的二硫键；用苏氨醇氨解法裂解肽-树脂并在7肽链上接上苏氨醇形成八肽；然后用三氟乙酸脱去氨基酸侧链保护基团，用高效液相色谱法纯化八肽，得到了奥曲肽(OCT)。     

奥曲肽联合灯盏花素治疗重症急性胰腺炎的疗效

目的 探讨奥曲肽联合灯盏花素治疗重症急性胰腺炎（SAP）的临床疗效.方法 将70例SAP患者按治疗方法的不同分为2组：治疗组和对照组,每组35例.2组均采用常规治疗,如禁食、吸氧、抑酸剂、抗生素、胃肠道减压以及胃肠外营养等治疗,并采用醋酸奥曲肽注射液治疗.在此基础上,治疗组加用灯盏花素注射液治疗.观察2组治疗后血肌酐、三酰甘油、淀粉酶、谷丙转氨酶、PO2和APACHEⅡ评分、临床疗效及不良反应的情况.结果 治疗组总有效率明显高于对照组（91.4% 比71.4%,P＜0.05）.与对照组比较,治疗组治疗后血肌酐、三酰甘油、淀粉酶、谷丙转氨酶及APACHEⅡ评分均显著降低（P＜0.05或P＜0.01）,血PO2显著升高（P＜0.01）,不良反应发生率显著降低（P＜0.05）.结论 采用奥曲肽联合灯盏花素治疗SAP疗效显著,提高了患者的生存率.     

~(64)Cu标记两种奥曲肽类似物的比较

对奥曲肽类似物DOTA-TOC和DOTA-TATE进行~(64)Cu标记,研究多肽用量与~(64)Cu活度比值、pH、反应温度、反应时间对标记率的影响,优化标记条件;考察标记物在10%胎牛血清与生理盐水中的体外稳定性;评价标记物在正常小鼠体内分布情况以及在U87MG人脑神经胶质瘤中的摄取情况。结果表明:~(64)Cu-DOTA-TOC和~(64)Cu-DOTA-TATE标记率均95%;在生理盐水中具有良好稳定性,10%胎牛血清中发生缓慢分解;正常小鼠体内分布实验结果显示,两种标记物在血液中清除较快,主要通过肾、肝代谢,~(64)Cu-DOTA-TATE摄取均高于~(64)Cu-DOTA-TOC;~(64)Cu-DOTA-TOC与~(64)Cu-DOTA-TATE给药后肿瘤PET显像清晰,但~(64)Cu-DOTA-TATE显像效果优于~(64)Cu-DOTA-TOC。研究结果可为其医学应用提供依据。     

生长抑素受体介导放射性核素治疗神经内分泌肿瘤的临床研究进展

已进入临床应用的放射性核素标记生长抑素类似物有^111In-奥曲肽、^90Y-奥曲肽、^177Lu-奥曲肽和^90Y-兰瑞肽。这些药物与神经内分泌肿瘤过度表达的生长抑素受体（Somatostatin Receptor，SSTR）相结合，起到内照射和化疗的双重治疗作用。已有的研究表明，SSTR介导的放射性核素治疗神经内分泌肿瘤疗效较好，且无严重的毒副作用，是一种有发展前景的神经内分泌肿瘤的治疗方法。^177Lu-奥曲肽和^90Y-兰瑞肽的疗效更好，完全缓解和部分缓解率可达40％以上，稳定状态高达45％。     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

聚二乙烯基苯微球介质制备及其在奥曲肽层析分离中的应用

以二乙烯基苯为单体,采用微孔膜乳化法制备了尺寸均一的水包油乳液,在75℃下悬浮聚合20 h,制得均一的聚二乙烯基苯微球填料,粒径为14.2μm,粒径分布系数Rspan=0.71,孔径为65 nm,比表面积为160 m2/g.通过高压匀浆法将合成的微球介质高效装填不锈钢液相色谱柱(ψ4.6 mm×250 mm),使柱效达11000塔板数.利用装填的色谱柱进行多肽药物奥曲肽的分离纯化,奥曲肽从固相合成粗品中快速有效分离,纯度由42.89%提高到99.99%.     

奥曲肽持续皮下泵入治疗恶性肠梗阻的临床观察

objective: The aim of the study was to observe the effectiveness of continuously subcutaneous-pumped octreotide infusion in palliative treatment of malignant bowel obstruction (MBO). Methods: Clinical data were retrospectively analyzed in 26 carcinoma patients complicated with MBO, in the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China, from March 2007 to April 2009. All 26 carcinoma patients with MBO were divided into two groups: the controlling group (CG, routine therapy, 15 patients) and the octreotide group (OG, 11 patients). The octreotide group received routine therapy combined with octreotide (0.3 mg/d) by 24 hours continuously subcutaneous octreotide infusion. The changes of curative effectiveness related to symptoms, the times of recovering exsufflation and defecation, the average drain of gastrointestinal drainage tube, the duration of gastrointestinal drainage tube and the rate of extubation, were observed and compared between the two groups. Results: After treatment, remarkable changing rates of MBO related symptoms were 81.8%(9/11)in OG, and 46.7%(7/15) in CG(P＜0.05). The 78% of SG and 30% of CG recovered the exsufflation and defecation, and the mean times they needed were 3.2 d and 5.8 d, respectively (P ＜ 0.05). The durations of gastrointestinal drainage tube of OG and CG were (5 ± 1.2) d and (10 ± 2.3) d, respectively, and the rates of extubation were 54.5% and 20%, respectively. The improvement rate in the octreotide group was better than that in the controlling group and the difference was significant (72.7%and 26.7%, P ＜ 0.05). Conclusion: The administration of octreotide in combination with routine treatment can be very effective in the treatment of MBO. It can relieve the symptoms of MBO effectively and improve the quality of life of the end-stage patients. It has provided one kind of new treating thought and method for treatment of malignant bowel obstruction.     

奥曲肽固相合成及环化的研究

为了研究用固相肽合成法合成奥曲肽(octreotide),采用CTC树脂为载体,Fmoc-哌啶保护基系统,并使用了逐步增长肽合成战略及碘氧化法对线性奥曲肽进行环化,通过反向高效液相色谱纯化.合成纯度达70.26%.结果表明:用固相肽合成法合成奥曲肽具有操作简单、可行、收率较高等特点,适合于工业化生产.