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细胞凋亡是机体通过特定机制密切调控的细胞自发的、有序的死亡现象,它发生于胚胎发育、免疫防御及细胞稳态等阶段,具有广泛的生物学意义。而凋亡异常可引起多种疾病,例如,当机体凋亡过度增强时,往往可引起自身免疫性疾病、神经退行性病变等。与之相反,当机体凋亡缺陷时,突变的细胞增殖失控,最终形成恶性肿瘤[1]。许多抗肿瘤治疗手段(如化疗、放疗)均通过促进肿瘤细胞凋亡来达到治疗肿瘤的目的。
临床实践中,病理学检查常被用来评价肿瘤细胞凋亡情况[2]。但是,病理学检查为有创性检查,需考虑取材的可行性及患者的耐受性。同时,肿瘤具有空间异质性及时间异质性,病理学检查不能评价全身治疗效应,也不能动态地监测凋亡在人体的发生及发展过程。因此,针对细胞凋亡的影像学检查已成为研究热点。目前,用于检测细胞凋亡的影像学检查共有4类:① MRI。细胞出现凋亡时,细胞内水份减少,同时还可以产生脂质体等代谢物,磁共振设备可检测到凋亡细胞弛豫时间和弥散时间改变,而脂质磁共振波谱也可监测代谢物的产生[3]。虽然磁共振成像时间分辨率和空间分辨率较高,但它只能用于凋亡晚期的监测。② 超声检查。凋亡细胞通常可出现DNA断裂、染色体浓集等超微结构表现,超声检查结果会呈现回声增强[4]。但是,超声监测深度较浅,只能用于浅表部位的检查。③ 光学成像。研究者研发出一系列光学成像手段,如Cy5.5-膜联蛋白V(其中Cy5.5是一种荧光团)[5]、双报告基因(Rluc/Flue)生物发光成像[6]等都可用来评价凋亡。虽然光学成像具有无创性,可反复进行动态监测,但荧光染料价格较昂贵,且探测深度较浅,因此未能广泛进入临床。④ 放射性核素标记的凋亡显像剂。它可与凋亡细胞特异性结合,不受探测深度制约,同时又可应用于凋亡的早期检测,因此具有最广泛的应用前景。放射性核素标记的凋亡显像剂分为4类:靶向外翻细胞膜磷脂的显像剂、靶向凋亡细胞膜印迹显像剂、靶向半胱天冬酶(caspases)显像剂、线粒体膜势能改变显像剂(图 1)。理想的肿瘤凋亡放射性显像剂需具备以下特点:① 对凋亡细胞有高度特异性;② 在体内外性状稳定;③ 适宜的药理学特性;④ 便于放化合成及量化分析;⑤ 免疫原性低、毒性小;⑥ 经济上可行[3]。现在已有靶向外翻细胞膜磷脂显像剂、靶向凋亡细胞膜印迹显像剂和靶向半胱天冬酶显像剂进入临床研究阶段,本文对此类显像剂的作用机制及其临床研究应用进行综述。
临床用肿瘤细胞凋亡核医学显像剂研究进展
Progress of nuclear medicine imaging agents for the clinical apoptosis imaging of tumors
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摘要: 凋亡在肿瘤的发生、发展和治疗中发挥重要的作用,因此无创、动态监测凋亡已成为目前抗肿瘤治疗的研究热点。目前已有靶向外翻细胞膜磷脂显像剂99Tcm-4,5-2(硫代乙酰胺)戊酰-膜联蛋白V和99Tcm-联肼尼克酰胺-膜联蛋白V、靶向半胱天冬酶(caspases)显像剂18F-ICMT-11和18F-CP18、靶向凋亡细胞膜印迹显像剂18F-ML-10进入临床试验阶段,虽然它们存在局限性,但当与传统的成像手段比较时,它们在肿瘤的诊断、治疗监测上具备一定的优越性。因此,肿瘤凋亡显像剂具有广泛的应用前景。笔者就目前核医学肿瘤细胞凋亡显像剂在肿瘤诊疗中的研究进展进行综述。Abstract: Apoptosis plays a key role in the development and treatment of tumors; thus, the invasive dynamic monitoring of apoptosis is of considerable interest in the management of cancer.At present, 99Tcm-BTAP-Annexin V, 99Tcm-HYNIC-Annexin V, 18F-ICMT-11, 18F-CP18, and 18F-ML-10 have achieved clinical application.Despite their limitations, these agents are superior to conventional imaging technique in the diagnosis and therapeutic monitoring of cancer and can exhibit potential in clinical applications.This review provides an overview of the recent development in apoptosis imaging by using radionuclide-labeled tracers in the management of cancer.
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Key words:
- Apoptosis /
- Neoplasms /
- Molecular probes /
- In vivo imaging
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