-
细胞凋亡是细胞衰老与死亡的主要形式之一,在机体中承担着重要的调控作用。许多疾病和病变与异常的细胞凋亡有关,凋亡过度会诱发获得性免疫缺陷综合征、神经性变性疾病及移植排斥反应等[1-2]。因此,定量检测细胞凋亡及其变化对认识疾病、评价指导疾病的治疗和开发新药等具有重要意义。细胞凋亡检测的实验室技术层出不穷,但由于这些技术较复杂且存在一些不足,因此尚难成为对临床疾病进行辅助诊断、指导治疗、疗效监测和预后判断的有效检测手段[3-4]。目前,科研人员普遍认为,放射性核素显像、MRI和光学成像等分子显像技术有助于解决这一难题[5-7]。一旦细胞凋亡程序启动后,自身凋亡细胞会发生一系列的病理生理改变,产生多种可识别的、特异性的化学信号(即作用靶点),用放射性核素、荧光染料等显像剂标记靶向分子后,进而与凋亡细胞中的特异性作用靶点结合,可达到体内检测的目的。在上述分子影像技术中,放射性核素细胞凋亡显像具备无创、早期发现、定量以及灵敏度高等特点,是目前较为成熟的体内检测方法。细胞凋亡分子显像技术的关键是选择合适的靶点和高度特异性的分子探针。根据不同靶点,目前用于细胞凋亡显像的分子探针主要分为4大类:磷脂酰丝氨酸(phosphatidylserine,PS)、磷脂酰乙醇胺、半胱天冬氨酸蛋白酶3(Caspase-3)、线粒体膜去极化。本文从这4方面逐一阐述。
放射性核素显像探针在细胞凋亡中的研究进展
Research progress of radionuclide imaging probes in apoptosis
-
摘要: 目前细胞凋亡的体外检测方法很多,但这些检测方法在取材、组织活检时具有创伤性,大多需要处死动物,且只能离体研究,限制了其在临床中的应用与转化。体内检测方法因可在活体内无创、实时监测凋亡,成为目前研究的热点。放射性核素凋亡细胞显像技术因具备无创、早期、动态、灵敏、定量、可在活体内检测等优势,具有良好的研究前景,是目前研究最为广泛、技术最为成熟的体内细胞凋亡检测技术。核素凋亡显像已广泛应用于心血管疾病、中枢神经系统疾病、器官移植排斥反应中的细胞凋亡检测,以及恶性肿瘤放化疗的疗效评价和预后判断等方面。笔者主要通过对放射性核素显像探针在细胞凋亡中的研究进展作一综述。Abstract: At present, there are many methods for detecting apoptosis in vitro, but these methods just are traumatic in material extraction and tissue biopsy by sacrificing of animals in vitro, which limits their clinical application and transformation. In vivo detection methods have become the focus of current research because of non-invasive and real-time monitoring of apoptosis in vivo. Radionuclide apoptotic cell imaging technology among has good research prospects in non-invasive, early stage, dynamic, sensitive, quantitative, and detection intravital. It is the most widely studied and mature technology for detecting apoptosis intravital. Radionuclide apoptosis imaging has been widely used in the detection of apoptosis in cardiovascular diseases, central nervous system diseases, organ transplant rejection, and the evaluation of efficacy and prognosis of malignant tumor after radiotherapy and chemotherapy. This article reviews the progress of radionuclide imaging probes in apoptosis.
-
Key words:
- Molecular imaging /
- Radioisotopes /
- Molecular probes /
- Apoptosis
-
[1] Wang F, Wei ZL, Sun XR, et al. Apoptosis Inducing Factor Is Involved in Stretch-Induced Apoptosis of Myoblast via a Caspase-9 Independent Pathway[J]. J Cell Biochem, 2017, 118(4):829-838. DOI:10.1002/jcb.25759. [2] Blankenberg FG, Robbins RC, Stoot JH, et al. Radionuclide imaging of acute lung transplant rejection with annexin V[J]. Chest, 2000, 117(3):834-840. DOI:10.1378/chest.117.3.834. [3] Jibran SM, Muhammad IG. Clinical patterns of seronegative spondyloarthropathies in a tertiary centre in Pakistan[J]. J Taibah Univ Med Sci, 2018, 13(3):298-301. DOI:10.1016/j.jtumed.2018. 03.002. [4] 王小龙, 赵建民, 刘瑞, 等.细胞凋亡在激素诱导性股骨头坏死中的研究进展[J].实用骨科杂志, 2015, 21(1):56-59.
Wang XL, Zhao JM, Liu R, et al. The research development of cell apoptosis in hormone induced femoral head necrosis[J]. J Pract Orthopaedics, 2015, 21(1):56-59.[5] 赵阳, 彭景, 张雪宁. MR分子探针与分子成像的研究进展[J].国际医学放射学杂志, 2015, 38(5):455-460. DOI:10.3874/j.issn.1674-1897.2015.05.Z0510.
Zhao Y, Peng J, Zhang XN. Progress in magnetic molecular probes and molecular magnetic resonance imaging[J]. Int J Med Radiol, 2015, 38(5):455-460. DOI:10.3874/j.issn.1674-1897. 2015.05.Z0510.[6] 安淑娴, 宋少莉, 黄钢.放射性核素标记的凋亡显像剂的研究进展[J].国际放射医学核医学杂志, 2015, 39(6):470-477. DOI:10.3760/cma.j.issn.1673-4114.2015.06.008.
An SX, Song SL, Huang G. Recent advances in apoptosis imaging using radionuclide-labeled tracers[J]. Int J Radiat Med Nucl Med, 2015, 39(6):470-477. DOI:10.3760/cma.j.issn.1673-4114. 2015. 06.008.[7] 王健, 宋秀宇, 徐文贵, 等.乳腺癌放射性核素分子成像研究进展[J].国际医学放射学杂志, 2015, 38(4):361-365. DOI:10.3874/j.issn.1674-1897.2015.04.Z0411.
Wang J, Song XY, Xu WG, et al. The research progress of radionuclide molecular imaging for breast cancer[J]. Int J Med Radiol, 2015, 38(4):361-365. DOI:10.3874/j.issn.1674-1897. 2015.04.Z0411.[8] 杨桂芬, 朱虹.放射性核素标记Anx Ⅴ细胞凋亡分子成像在肿瘤化疗疗效评估中的价值[J].国际医学放射学杂志, 2013, 36(2):155-159. DOI:10.3874/j.issn.1674-1897.2013.02.Z0212.
Yang GF, Zhu H. Molecular imaging of cell apoptosis with radiolabeled Anx Ⅴ in the evaluation of tumor response to chemotherapy[J]. Int J Med Radiol, 2013, 36(2):155-159. DOI:10.3874/j.issn.1674-1897.2013.02.Z0212.[9] Pietkiewicz S, Schmidt JH, Lavrik IN. Quantification of apoptosis and necroptosis at the single cell level by a combination of imaging flow cytometry with classical Annexin V/propidium iodide staining[J]. J Immunol Methods, 2015, 423:99-103. DOI:10.1016/j.jim.2015.04.025. [10] Head T, Dau P, Duffort S, et al. An enhanced bioluminescence-based Annexin V probe for apoptosis detection in vitro and in vivo[J/OL]. Cell Death Dis, 2017, 8(5): e2826[2018-08-12]. https://www.nature.com/articles/cddis2017141. DOI: 10.1038/cddis.2017.141. [11] Bauwens M, De Saint-Hubert M, Devos E, et al. Site-specific 68Ga-labeled Annexin A5 as a PET imaging agent for apoptosis[J]. Nucl Med Biol, 2011, 38(3):381-392. DOI:10.1016/j.nucmedbio.2010.09.008. [12] Lin MH, Wu SY, Wang HE, et al. 111In-DOTA-Annexin V for imaging of apoptosis during HSV1-tk/GCV prodrug activation gene therapy in mice with NG4TL4 sarcoma[J]. Appl Radiat Isot, 2016, 108:1-7. DOI:10.1016/j.apradiso. 2015.11.017. [13] Vangestel C, Peeters M, Mees G, et al. In vivo imaging of apoptosis in oncology:an update[J]. Mol Imaging, 2011, 10(5):340-358. DOI:10.2310/7290.2010.00058. [14] Schaper FL, Reutelingsperger CP. 99mTc-HYNIC-Annexin A5 in Oncology:Evaluating Efficacy of Anti-Cancer Therapies[J]. Cancers (Basel), 2013, 5(2):550-568. DOI:10.3390/cancers5020550. [15] Zhang S, Wu Z, Li J, et al. Evaluation of the clinical relevance of anti-annexin-A5 antibodies in Chinese patients with antiphospholipid syndrome[J]. Clin Rheumatol, 2017, 36(2):407-412. DOI:10.1007/s10067-016-3510-8. [16] Belhocine T, Steinmetz N, Hustinx R, et al. Increased uptake of the apoptosis-imaging agent 99mTc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis[J]. Clin Cancer Res, 2002, 8(9):2766-2774. [17] Van de Wiele C, Vermeersch H, Loose D, et al. Radiolabeled annexin-V for monitoring treatment response in oncology[J]. Cancer Biother Radiopharm, 2004, 19(2):189-194. DOI:10.1089/108497804323071968. [18] Tang C, Wang F, Hou Y, et al. Technetium-99m-labeled annexin V imaging for detecting prosthetic joint infection in a rabbit model[J]. J Biomed Res, 2015, 29(3):224-231. DOI:10.7555/JBR.29. 2013. 01.13. [19] Schaper FL, Reutelingsperger CP. 99mTc-HYNIC-Annexin A5 in Oncology:Evaluating Efficacy of Anti-Cancer Therapies[J]. Cancers, 2013, 5(2):550-568. DOI:10.3390/cancers5020550. [20] Hu Y, Liu G, Zhang H, et al. A Comparison of 99mTc-Duramycin and 99mTc-Annexin V in SPECT/CT Imaging Atherosclerotic Plaques[J]. Mol Imaging Biol, 2018, 20(2):249-259. DOI:10.1007/s11307-017-1111-9. [21] Khoda Me, Utsunomiya K, Ha-Kawa S, et al. An investigation of the early detection of radiation induced apoptosis by 99mTc-Annexin V and 201thallium-chloride in a lung cancer cell line[J]. J Radiat Ras, 2012, 53(3):361-367. DOI:10.1269/jrr.11177. [22] Taki J, Higuchi T, Kawashima A, et al. Effect of postconditioning on myocardial 99mTc-annexin-V uptake:comparison with ischemic preconditioning and caspase inhibitor treatment[J]. J Nucl Med, 2007, 48(8):1301-1307. DOI:10.2967/jnumed.106.037408. [23] Doue T, Ohtsuki K, Ogawa K, et al. Cardioprotective effect of erythropoietin in rats subjected to ischemia-reperfusion injury:assessment of infarct size with 99mTc-AnnexinV[J]. J Nucl Med, 2008, 49(10):1694-1700. DOI:10.2967/jnumed.107.050260. [24] Keitselaer BL, Reutelingsperger CP, Boersma HH, et al. Noninvasive detection of programmed cell loss with 99mTc-labeled Annexin A5 in heart failure[J]. J Nucl Med, 2007, 48(4):562-567.DOI:10.2967/jnumed.106.039453. [25] Hu S, Kiesewetter DO, Zhu L, et al. Longitudinal PET imaging of doxorubicin-induced cell death with 18F-Annexin V[J]. Mol Imaging Biol, 2012, 14(6):762-770. DOI:10.1007/s11307-012-0551-5. [26] 胡四龙. 18F-ML-10 PET/CT评价胰腺癌放化疗后细胞凋亡的实验研究[D].上海: 复旦大学, 2013.
Hu SL. 18F-ML-10 PET/CT evaluation of pancreatic cancer cell apoptosis after concurrent chemoradiation experimental research[D]. Shanghai: Fudan University, 2013.[27] 陈顺军. 18F-ML-10 PET/CT显像探测化疗后肿瘤细胞凋亡的实验研究[D].郑州: 郑州大学, 2017.
Chen SJ. 18F-ML-10 PET/CT imaging detection experiment research of tumor cell apoptosis after chemotherapy[D]. Zhengzhou: Zhengzhou University, 2017.[28] Liu M, Zheng S, Zhang X, et al. Cerenkov luminescence imaging on evaluation of early response to chemotherapy of drug-resistant gastric cancer[J]. Nanomedicine, 2018, 14(1):205-213. DOI:10.1016/j.nano.2017.10.001. [29] 张毅, 郭瀛军, 王芳, 等. Annexin B1:一种新的细胞凋亡检测用蛋白[J].第二军医大学学报, 2003, 24(3):333-334. DOI:10.3321/j.issn:0258-879X.2003.03.031.
Zhang Y, Guo YJ, Wang F, et al. Annexin B1 as a novel protein for detecting apoptosis[J]. Acad J Sec Mil Med Univ, 2003, 24(3):333-334. DOI:10.3321/j.issn:0258-879X.2003.03.031.[30] 郑宇佳, 王明伟, 张建平, 等. 18F-SFB-Annexin B1探测化疗后肿瘤细胞凋亡的实验研究[J].中国癌症杂志, 2013, 23(10):798-803. DOI:10.3969/j.issn.1007-3969.2013.10.004.
Zheng YJ, Wang MW, Zhang JP, et al. Experimental study on tumor response to chemotherapy with 18F-SFB-Annexin B1[J]. Chin Oncol, 2013, 23(10):798-803. DOI:10.3969/j.issn.1007-3969. 2013. 10. 004.[31] 赵庆, 章英剑, 王芳, 等. 18F-SFB-Annexin B1探测细胞凋亡实验研究[J].中华核医学杂志, 2011, 31(2):112-116. DOI:10.3760/cma.j.issn.0253-9780.2011.02.010.
Zhao Q, Zhang YJ, Wang F, et al. Evaluation of 18F-SFB-Annexin B1 in detecting apoptosis[J]. Chin J Nucl Med, 2011, 31(2):112-116. DOI:10.3760/cma.j.issn.0253-9780.2011.02.010.[32] Wang MW, Wang F, Zheng YJ, et al. An in vivo molecular imaging probe 18F-Annexin B1 for apoptosis detection by PET/CT preparation and preliminary evaluation[J]. Apoptosis, 2013, 18(2):238-247. DOI:10.1007/s10495-012-0788-0. [33] Zhao M, Zhu X, Ji S, et al. 99mTc-labeled C2A domain of synaptotagmin I as a target-specific molecular probe for noninvasive imaging of acute myocardial infarction[J]. J Nucl Med, 2006, 47(8):1367-1374. [34] 方纬, 王峰, 季顺东, 等. 99Tcm-FM2心肌细胞凋亡显像的实验研究[J].中华核医学杂志, 2006, 26(3):137-140. DOI:10.3760/cma.j.issn.2095-2848.2006.03.008.
Fang W, Wang F, Ji SD, et al. Experimental study of myocardial cell apoptosis with 99Tcm-FM2 imaging[J]. Chin J Nucl Med, 2006, 26(3):137-140. DOI:10.3760/cma.j.issn.2095-2848.2006.03.008.[35] Wang F, Fang W, Zhang MR, et al. Evaluation of chemotherapy response in VX2 rabbit lung cancer with 18F-labeled C2A domain of synaptotagmin I[J]. J Nucl Med, 2011, 52(4):592-599. DOI:10.2967/jnumed.110.081588. [36] 黄斌, 方纬, 田伟, 等. 68Ga-NOTA-Duramycin的标记与生物分布实验研究[J].中华核医学与分子影像杂志, 2012, 32(4):286-290. DOI:10.3760/cma.j.issn.2095-2848.2012.04.011.
Huang B, Fang W, Tian W, et al.Experimental study of labeling and biodistribution of 68Ga-NOTA-Duramycin[J]. Chin J Nucl Med Mol Imaging, 2012, 32(4):286-290. DOI:10.3760/cma.j.issn.2095-2848. 2012.04.011.[37] Hasim S, Allison DP, Mendez B, et al. Elucidating Duramycin's Bacterial Selectivity and Mode of Action on the Bacterial Cell Envelope[J]. Front Microbiol, 2018, 9:219. DOI:10.3389/fmicb.2018.00219. [38] Huo L, Ökesli A, Zhao M, et al. Insights into the Biosynthesis of Duramycin[J]. Appl Environ Microbiol, 2017, 83(3):e02698-16.DOI:10.1128/AEM.02698-16. [39] Mills JC, Stone NL, Erhardt J, et al. Apoptotic membrane blebbing is regulated by myosin light chain phosphorylation[J]. J Cell Biol, 1998, 140(3):627-636. DOI:10.1083/jcb.140.3.627. [40] Liu Z, Larsen BT, Lerman LO, et al. Detection of atherosclerotic plaques in ApoE-deficient mice using 99mTc-duramycin[J]. Nucl Med Biol, 2016, 43(8):496-505. DOI:10.1016/j.nucmedbio.2016.05.007. [41] Wang L, Wang F, Fang W, et al. The feasibility of imaging myocardial ischemic/reperfusion injury using 99mTc-labeled duramycin in a porcine model[J]. Nucl Med Biol, 2015, 42(2):198-204. DOI:10.1016/j.nucmedbio.2014.09.002. [42] Zhang Y, Stevenson GD, Barber C, et al. Imaging of rat cerebral ischemia-reperfusion injury using 99mTc-labeled duramycin[J]. Nucl Med Biol, 2013, 40(1):80-88. DOI:10.1016/j.nucmedbio.2012.09. 004. [43] Montiel-Cervantes LA, Reyes-Maldonado E, Garcia-Chavez J, et al. Prognostic Value of CD95, Active Caspase-3, and Bcl-2 Expression in Adult Patients with De Novo Acute Lymphoblastic Leukemia[J]. Arch Med Res, 2018, 49(1):44-50. DOI:10.1016/j.arcmed.2018. 04. 006. [44] Zhou D, Chu W, Rothfuss J, et al. Synthesis, radiolabeling, and in vivo evaluation of an 18F-labeled isatin analog for imaging caspase-3 activation in apoptosis[J]. Bioorg Med Chem Lett, 2006, 16(19):5041-5046. DOI:10.1016/j.bmcl.2006.07.045. [45] 葛青山.新型双光子纳米探针的构建及用于caspase-3活性检测研究[D].长沙: 湖南大学, 2017.
Ge QS. The construction of a new two-photon nanoprober and used in the study of caspase 3 activity detection[D]. Changsha: Hunan University, 2017.[46] Xia CF, Chen G, Gangadharmath U, et al. In vitro and in vivo evaluation of the caspase-3 substrate-based radiotracer 18F-CP18 for PET imaging of apoptosis in tumors[J]. Mol Imaging Biol, 2013, 15(6):748-757. DOI:10.1007/s11307-013-0646-7. [47] Madar I, Ravert H, Nelkin B, et al. Characterization of membrane potential-dependent uptake of the novel PET tracer 18F-fluorobenzyltriphenyl phosphonium cation[J]. Eur J Nucl Med Mol Imaging, 2007, 34(12):2057-2065. DOI:10.1007/s00259-007-0500-8. [48] Higuchi T, Fukushima K, Rischpler C, et al. Stable delineation of the ischemic area by the PET perfusion tracer 18F-fluorobenzyl triphenyl phosphonium after transient coronary occlusion[J]. J Nucl Med, 2011, 52(6):965-969. DOI:10.2967/jnumed.110.085993. [49] 王腾腾, 张锦明, 张涛, 等. PET小分子凋亡显像示踪剂的研究进展[J].解放军医学院学报, 2015, 36(6):637-639. DOI:10.3969/j.issn.2095-5227.2015.06.032.
Wang TT, Zhang JM, Zhang T, et al. Advances in small molecule radiotracer for PET imaging apoptosis[J]. Acad Chin PLA Med Sch, 2015, 36(6):637-639. DOI:10.3969/j.issn.2095-5227. 2015.06.032.[50] Oborski MJ, Laymon CM, Lieberman FS, et al. First use of 18F-labeled ML-10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy[J]. Brain Behav, 2014, 4(2):312-315. DOI:10.1002/brb3.217.
计量
- 文章访问数: 13237
- HTML全文浏览量: 12262
- PDF下载量: 24