细胞特异性核酸适配体在疾病治疗中的应用

doi:10.13560/j.cnki.biotech.bull.1985.2023-0289

摘要/Abstract

摘要：

核酸适配体是由20-100个核苷酸组成的单链脱氧核糖核酸（ssDNA）或核糖核酸（RNA），一般是通过指数富集的配体系统进化技术（SELEX）进行筛选。核酸适配体可以与多种靶标物质特异性结合，包括毒素、金属离子、生物大分子、微生物等，已被广泛应用于食品检测、医疗诊断等领域。细胞作为人体最基本的组成单位是大多数疾病病理机制和治疗策略的研究重心。近年来，核酸疗法以更安全更高效的优势成为疾病治疗领域的研究重心，研究人员认识到核酸适配体的靶向结合能力可以应用到细胞的靶向治疗中。因此，开发出Cell-SELEX技术用于筛选可以靶向细胞标志物的核酸适配体。细胞特异性核酸适配体与传统的核酸适配体的区别，在于它们的特异性靶标是细胞成分，它们可以直接结合与细胞生长和代谢相关的物质影响细胞生理活动，也可以作为靶向递送工具递送药物，在疾病的精准治疗中具有突破性影响。因此，细胞特异性核酸适配体引发了广泛关注。本文对细胞特异性核酸适配体在多种疾病治疗中的研究进展进行了综述，以期为其在人类疾病治疗中的应用提供参考。

关键词: 核酸适配体, 细胞特异性, 核酸疗法, 靶向治疗, 疾病治疗

Abstract:

Nucleic acid aptamers are single-stranded deoxyribonucleic acid（ssDNA）or ribonucleic acid（RNA）composed of 20 to 100 nucleotides, and are generally screened by systematic evolution of ligands by exponential enrichment（SELEX）. Aptamers can specifically bind to a variety of target substances, including toxins, metal ions, biological macromolecules, microorganisms, etc., and have been widely used in food detection, medical diagnosis, and other fields. As the most basic unit of the human body, cells are the focus of research on the pathological mechanism and treatment strategy of most diseases. In recent years, nucleic acid therapy has become the focus of research in the field of disease treatment with the advantages of safer and more efficient one. Researchers realized that the targeted binding ability of nucleic acid aptamers can be applied to cell targeted therapy. Cell-specific aptamers are different from traditional aptamers in that their specific targets are cellular components. They can directly bind to substances related to cell growth and metabolism to affect cell physiological activities, and can also be used as targeted delivery tools to deliver drugs, which has a breakthrough effect in the precision treatment of diseases. Cell-specific nucleic acid aptamers have attracted much attention. In this article, we review the research progress of cell-specific nucleic acid aptamers in the treatment of a variety of diseases in order to provide reference for their application in the treatment of human diseases.

Key words: nucleic acid aptamers, cell-specific, nucleic acid therapy, targeted therapy, disease treatment

钟朝滨, 朱龙佼, 张博洋, 张洋子, 陈可仁, 许文涛. 细胞特异性核酸适配体在疾病治疗中的应用[J]. 生物技术通报, 2023, 39(12): 118-127.

ZHONG Zhao-bin, ZHU Long-jiao, ZHANG Bo-yang, ZHANG Yang-zi, CHEN Ke-ren, XU Wen-tao. Application of Cell-specific Nucleic Acid Aptamers in Disease Treatment[J]. Biotechnology Bulletin, 2023, 39(12): 118-127.

图/表 4

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核酸适配体 Nucleic acid aptamer	靶标 Target	疾病 Disease	临床阶段 Clinical phase	用药方式 Medication administration	ClinicalTrials.gov标识符 ClinicalTrials.gov identifier
Macugen	VEGF	年龄相关性黄斑变性	已上市	玻璃体内注射	NCT01573572
E10030（Fovista）	PDGF	新生血管性年龄相关性黄斑变性	临床III期	玻璃体内注射	NCT01944839
ARC1905（Zimura）	C5	年龄相关性黄斑变性	临床II期	玻璃体内注射	NCT03364153
REG1	凝血因子IXa	冠状动脉疾病	临床II期	静脉注射	NCT00715455
ARC1779	血管性血友病因子A1结构域	急性心肌梗死	临床II期	-	NCT00507338
NU172	凝血酶	心脏病	临床II期	冠状动脉旁路移植术中静脉推注后持续输注	NCT00808964
AS1411（AGRO001）	核仁素	原发性难治或复发急性髓系白血病	临床II期	-	NCT01034410
NOX-A12	CXCL12/SDF-1	慢性淋巴细胞白血病	临床II期	-	NCT01486797
NOX-E36	CCL2/MCP-1	2型糖尿病；蛋白尿	临床II期	皮下注射	NCT01547897
NOX-H94	铁调素	慢性病贫血	临床II期	静脉注射	NCT01691040
BAX499（ARC19499）	组织因子途径抑制物（TFPI）	血友病	临床I期	注射	NCT01191372

核酸适配体 Nucleic acid aptamer	靶标 Target	疾病 Disease	临床阶段 Clinical phase	用药方式 Medication administration	ClinicalTrials.gov标识符 ClinicalTrials.gov identifier
Macugen	VEGF	年龄相关性黄斑变性	已上市	玻璃体内注射	NCT01573572
E10030（Fovista）	PDGF	新生血管性年龄相关性黄斑变性	临床III期	玻璃体内注射	NCT01944839
ARC1905（Zimura）	C5	年龄相关性黄斑变性	临床II期	玻璃体内注射	NCT03364153
REG1	凝血因子IXa	冠状动脉疾病	临床II期	静脉注射	NCT00715455
ARC1779	血管性血友病因子A1结构域	急性心肌梗死	临床II期	-	NCT00507338
NU172	凝血酶	心脏病	临床II期	冠状动脉旁路移植术中静脉推注后持续输注	NCT00808964
AS1411（AGRO001）	核仁素	原发性难治或复发急性髓系白血病	临床II期	-	NCT01034410
NOX-A12	CXCL12/SDF-1	慢性淋巴细胞白血病	临床II期	-	NCT01486797
NOX-E36	CCL2/MCP-1	2型糖尿病；蛋白尿	临床II期	皮下注射	NCT01547897
NOX-H94	铁调素	慢性病贫血	临床II期	静脉注射	NCT01691040
BAX499（ARC19499）	组织因子途径抑制物（TFPI）	血友病	临床I期	注射	NCT01191372

疾病类型 Disease type	代表性适配体药物 Representative aptamer drugs	药物类型 Types of drugs	靶标 Targets
癌症	AB3-Dox	核酸适配体-药物偶联物（ApDCs）	未成熟层黏连蛋白受体蛋白（OFA/iLRP）
	sgc8c-Dox	核酸适配体-药物偶联物（ApDCs）	蛋白酪氨酸激酶7（PTK7）
	AS1411适配体偶联脂质体	核酸适配体-siRNA缀合物	结直肠癌细胞
	MUC1适配体-CD16适配体	双特异性核酸适配体	MUC1阳性肿瘤细胞和CD16阳性淋巴细胞
	ApEn-NK	核酸适配体工程自然杀伤细胞	多种肿瘤细胞
组织修复与再生	GO-SA凝胶-适配体-GBF	骨髓间充质干细胞核酸适配体支架	骨髓间充质干细胞（BM-MSCs）
眼部疾病	Macugen	核酸适配体	VEGF
	E10030		PDGF
	ARC1905		补体成分5（C5）
脑部疾病	SYL3C-GS24	双功能核酸适配体	转铁蛋白受体（TfR）
血管疾病	REG1	核酸适配体	凝血因子IXa
	ARC1779		血管性血友病因子（VWF）A1结构域
	BAX499		组织因子通路抑制剂（TFPI）
	NU172	G-四链体DNA核酸适配体	凝血酶
炎症疾病	VR11功能化单层石墨烯	核酸适配体纳米传感器（用于检测）	TNFα
	NOX-E36	核酸适配体	趋化因子配体2（CCL 2）
	NOX-H94	核酸适配体	铁调素

疾病类型 Disease type	代表性适配体药物 Representative aptamer drugs	药物类型 Types of drugs	靶标 Targets
癌症	AB3-Dox	核酸适配体-药物偶联物（ApDCs）	未成熟层黏连蛋白受体蛋白（OFA/iLRP）
	sgc8c-Dox	核酸适配体-药物偶联物（ApDCs）	蛋白酪氨酸激酶7（PTK7）
	AS1411适配体偶联脂质体	核酸适配体-siRNA缀合物	结直肠癌细胞
	MUC1适配体-CD16适配体	双特异性核酸适配体	MUC1阳性肿瘤细胞和CD16阳性淋巴细胞
	ApEn-NK	核酸适配体工程自然杀伤细胞	多种肿瘤细胞
组织修复与再生	GO-SA凝胶-适配体-GBF	骨髓间充质干细胞核酸适配体支架	骨髓间充质干细胞（BM-MSCs）
眼部疾病	Macugen	核酸适配体	VEGF
	E10030		PDGF
	ARC1905		补体成分5（C5）
脑部疾病	SYL3C-GS24	双功能核酸适配体	转铁蛋白受体（TfR）
血管疾病	REG1	核酸适配体	凝血因子IXa
	ARC1779		血管性血友病因子（VWF）A1结构域
	BAX499		组织因子通路抑制剂（TFPI）
	NU172	G-四链体DNA核酸适配体	凝血酶
炎症疾病	VR11功能化单层石墨烯	核酸适配体纳米传感器（用于检测）	TNFα
	NOX-E36	核酸适配体	趋化因子配体2（CCL 2）
	NOX-H94	核酸适配体	铁调素