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Article(id=1198628507690562491, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628499750744699, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-1266, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1669219200000, receivedDateStr=2022-11-24, revisedDate=1674144000000, revisedDateStr=2023-01-20, acceptedDate=null, acceptedDateStr=null, onlineDate=1763704905673, onlineDateStr=2025-11-21, pubDate=1683820800000, pubDateStr=2023-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763704905673, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763704905673, creator=13701087609, updateTime=1763704905673, updator=13701087609, issue=Issue{id=1198628499750744699, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='5', pageStart='0', pageEnd='1400', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763704903781, creator=13701087609, updateTime=1766137655840, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208832201509172104, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628499750744699, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208832201509172105, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198628499750744699, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1338, endPage=1346, ext={EN=ArticleExt(id=1198628509074681859, articleId=1198628507690562491, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=T cell immunotherapy mediated by dual-affinity aptamer targeted liposome, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Redirecting immune cells to the tumor cells and enhancing its anti-tumor immune response is a very promising cancer treatment strategy. AS1411 aptamers have high affinity for malignant tumors with high nucleolin expression, and cytotoxic T lymphocyte associated protein 4 (CTLA-4) aptamers can specifically bind to CTLA-4, which is expressed by T cells. In this study, a dual-affinity aptamer targeted liposome (Dat. Lipo) was constructed based on AS1411 aptamer and CTLA-4 aptamer, and its immunotherapeutic effect on T cells was studied. After the aptamer was modified with cholesterol, Dat. Lipo was prepared by instillation method; its effect of redirecting T cells was determined by confocal micrographs; its T cell immunotherapy effect was evaluated by cell counting kit-8 (CCK8) and T cell penetration was evaluated by tumor spheroids. The results showed that compared with liposomes loaded with one type aptamer, Dat. Lipo could effectively promote the redirection of T cells to tumor cells; Dat. Lipo had good biosafety and immunotherapeutic effect on MCF-7 and HepG2 cells in a concentration-dependent manner; Dat. Lipo could also promote T cells to infiltrate into the tumor spheroids and enhance the immunotherapy effect of T cells in different dimensions. In summary, Dat. Lipo can use the high affinity of aptamers to redirect T cells to tumor cells, enhance the effect of immunotherapy, and has a promising application prospect in tumor therapy. This study was approved by the Examination Committee of Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital.

, correspAuthors=Chao-nan ZHU, Shan WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Huan-huan REN, Guo-ping JIA, Jing HUANG, Meng-di WANG, Ding-ya SUN, Chao-nan ZHU, Shan WANG), CN=ArticleExt(id=1198628513705193669, articleId=1198628507690562491, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=双亲和性适配体靶向脂质体介导的T细胞免疫治疗, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

将免疫细胞重定向至肿瘤部位并增强抗肿瘤免疫反应是一种有前景的癌症治疗策略。AS1411适配体对高表达核仁素的恶性肿瘤有高亲和结合力, 细胞毒性T淋巴细胞相关蛋白4 (cytotoxic T-lymphocyte-associated protein 4, CTLA-4) 适配体可特异性结合T细胞表达的免疫检查点CTLA-4。本研究基于AS1411适配体和CTLA-4适配体构建了一种可同时靶向肿瘤细胞和T细胞的双亲和性适配体靶向脂质体(dual-affinity aptamer targeted liposome, Dat. Lipo), 并在细胞水平研究其促T细胞免疫治疗效果。将适配体修饰上胆固醇后, 用滴入法制备Dat. Lipo; 用成像系统检测其T细胞重定向作用, CCK8 (cell counting kit-8) 评价其促T细胞免疫治疗作用, 用肿瘤球评价其促T细胞渗透作用。结果表明, 与只负载一种适配体的脂质体相比, Dat. Lipo可有效促进T细胞重定向至肿瘤细胞; 对MCF-7和HepG2细胞具有良好的促免疫治疗作用, 且呈浓度依赖性, 具有良好的生物安全性; Dat. Lipo还能促进T细胞渗透到肿瘤球内部, 在不同维度增强T细胞免疫治疗作用。综上, Dat. Lipo可利用适配体对靶标的高亲和性将T细胞重定向至肿瘤细胞, 增强免疫疗法效果, 在肿瘤治疗方面具有一定的应用前景。本研究获得了湖南省肿瘤医院中南大学湘雅医学院附属肿瘤医院审查委员会的伦理批准。

, correspAuthors=褚超男, 王珊, authorNote=null, correspAuthorsNote=
*褚超男, Tel: 18684983256, E-mail: ;
王珊, Tel: 18008425007, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2023, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=N6ovvWOQaXuOM+BFsnO58Q==, magXml=9G9NWua6lPjqmacyalpmuQ==, pdfUrl=null, pdf=P23gi5QraMj4BYcJSX02Hg==, pdfFileSize=3017406, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=4wr58UCSpFTMJGF+RGAZWA==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=/qYaR7k/oYW+RsmemHJMvQ==, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=任欢欢, 贾国萍, 黄婧, 王梦迪, 孙定亚, 褚超男, 王珊)}, authors=[Author(id=1198960123361194779, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960123491218221, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, authorId=1198960123361194779, language=EN, stringName=Huan-huan REN, firstName=Huan-huan, middleName=null, lastName=REN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1. 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Lipo) retargeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-positive immunocytes to nucleolin-positive tumor cells , figureFileSmall=tczuFjJfIABMLX030NXZYw==, figureFileBig=cReihfGMI7x5KDZBpRLIGw==, tableContent=null), ArticleFig(id=1198960128532771101, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=EN, label=null, caption=null, figureFileSmall=QVoBVK4Ryo1aVg3jbvRbzQ==, figureFileBig=XV6/5W36AF2dKtdN4P2b0w==, tableContent=null), ArticleFig(id=1198960128671183146, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=CN, label=Figure 2, caption= Characterization of the Dat. Lipo. A: Agarose gel electrophoresis to identify the conjugation of AS1411 and CTLA-4 aptamer to liposome surface. Lane 1: The mixture of AS1411 and CTLA-4 aptamer; Lane 2: Dat. Lipo; B: Transmission electron microscope (TEM) images of Dat. Lipo. Scale bar: 0.5 μm (left); 100 nm (right); C: The size distribution of liposome (Lipo) and Dat. Lipo; D: Size stability of Lipo and Dat. Lipo in 10% fetal bovine serum (FBS). <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i> , figureFileSmall=QVoBVK4Ryo1aVg3jbvRbzQ==, figureFileBig=XV6/5W36AF2dKtdN4P2b0w==, tableContent=null), ArticleFig(id=1198960128788623666, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=EN, label=null, caption=null, figureFileSmall=S4ssyYBOW9C/7ApCB/U+lg==, figureFileBig=8XvDILnqSy5XjJTSQkA8VQ==, tableContent=null), ArticleFig(id=1198960128893481276, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=CN, label=Figure 3, caption= Dat. Lipo-mediated T cell redirection. A: Binding ability analysis of Dat. Lipo to Jurkat, A549, MCF-7 and HepG2 cells, determined by flow cytometry; B, C: Representative confocal micrographs (B) of T cells redirection after treatment with Dat. Lipo, and the proportion analysis of Jurkat cells (C). A549 cells were stained with MitoSpy Red, and Jurkat cells were stained with 5, 6-carboxyfluorescein diacetate, succinimidyl ester (CFSE) fluorescence dyes, a mixture of AS1411. Lipo and CTLA-4. Lipo was used as a control. Scale bar: 50 μm. <sup>****</sup><i>P</i> < 0.000 1. <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i> , figureFileSmall=S4ssyYBOW9C/7ApCB/U+lg==, figureFileBig=8XvDILnqSy5XjJTSQkA8VQ==, tableContent=null), ArticleFig(id=1198960129031893323, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=EN, label=null, caption=null, figureFileSmall=mCAzFHUvg8cZEcZ7VVS7UQ==, figureFileBig=wP24MOVCwIsdyB33697LNg==, tableContent=null), ArticleFig(id=1198960129136750932, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=CN, label=Figure 4, caption= <i>In vitro</i> immunotherapeutic effect of Dat. Lipo. A: <i>In vitro</i> immunotherapeutic efficacy of HepG2 cells with treatment of T cells incubated by Dat. Lipo, AS1411. Lipo and CTLA-4. Lipo. Effector cells (E)∶target cells (T) = 3∶1, effector cells represented T cells and target cells represented MCF-7 or HepG2 cells; B: Dose-dependent immunotherapeutic efficacy of Dat. Lipo for MCF-7 and HepG2 cells. E∶T = 3∶1; C: Cytotoxicity of Dat. Lipo against different cells. <i>n</i>= 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>± <i>s</i>. <sup>****</sup><i>P</i> < 0.000 1 , figureFileSmall=mCAzFHUvg8cZEcZ7VVS7UQ==, figureFileBig=wP24MOVCwIsdyB33697LNg==, tableContent=null), ArticleFig(id=1198960129275162979, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=EN, label=null, caption=null, figureFileSmall=SKrAvIpyeORlUDzl95srnw==, figureFileBig=cUXKedaLQnW9u6Sm3k0PBw==, tableContent=null), ArticleFig(id=1198960129442935151, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=CN, label=Figure 5, caption= Immunotherapeutic effect of Dat. Lipo on tumor spheroids. A, B: The specific affinity and permeability of Dat. Lipo to A549 (A) and MCF-7 (B) tumor spheroids. A kind of liposome synthesized by disordered aptamer was used as control; C, D: T cells incubated with Dat. Lipo or Con. Lipo were co-cultured with A549 (C) and MCF-7 (D) tumor spheroids for 48 h to detect their immunotherapeutic effect in 3D dimension; E: PI staining was used to detect the cell death of MCF-7 tumor spheroids after co-culture for 48 h. Scale bar: 200 μm , figureFileSmall=SKrAvIpyeORlUDzl95srnw==, figureFileBig=cUXKedaLQnW9u6Sm3k0PBw==, tableContent=null), ArticleFig(id=1198960129543598462, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Composition AS1411. Lipo CTLA-4. Lipo Dat. Lipo
HSPC/mg 5.4   1.8   7.2  
Cholesterol/mg 2.7   0.9   3.6  
CH3-PEG2000-DSPE/mg 0.9   0.3   1.2  
CLS-PEG-AS1411/nmol 2.81 / 2.81
CLS-PEG-CTLA-4/nmol / 0.93 0.93
), ArticleFig(id=1198960129732342159, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198628507690562491, language=CN, label=Table 1, caption=

Formulation of aptamer-liposome. HSPC: Hydrogenated soybean phosphotidylcholine; CLS: Cholesterol; PEG: Polyethylene glycol; DSPE: 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine

, figureFileSmall=null, figureFileBig=null, tableContent=
Composition AS1411. Lipo CTLA-4. Lipo Dat. Lipo
HSPC/mg 5.4   1.8   7.2  
Cholesterol/mg 2.7   0.9   3.6  
CH3-PEG2000-DSPE/mg 0.9   0.3   1.2  
CLS-PEG-AS1411/nmol 2.81 / 2.81
CLS-PEG-CTLA-4/nmol / 0.93 0.93
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双亲和性适配体靶向脂质体介导的T细胞免疫治疗
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任欢欢 1 , 贾国萍 1 , 黄婧 1 , 王梦迪 1 , 孙定亚 1 , 褚超男 2, * , 王珊 1, *
药学学报 | 研究论文 2023,58(5): 1338-1346
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药学学报 | 研究论文 2023, 58(5): 1338-1346
双亲和性适配体靶向脂质体介导的T细胞免疫治疗
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任欢欢1, 贾国萍1, 黄婧1, 王梦迪1, 孙定亚1, 褚超男2, * , 王珊1, *
作者信息
  • 1.中南大学化学化工学院制药工程系, 湖南 长沙 410083
  • 2.湖南省肿瘤医院中南大学湘雅医学院附属肿瘤医院妇瘤科, 湖南 长沙 410013

通讯作者:

*褚超男, Tel: 18684983256, E-mail: ;
王珊, Tel: 18008425007, E-mail:
T cell immunotherapy mediated by dual-affinity aptamer targeted liposome
Huan-huan REN1, Guo-ping JIA1, Jing HUANG1, Meng-di WANG1, Ding-ya SUN1, Chao-nan ZHU2, * , Shan WANG1, *
Affiliations
  • 1. Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China
  • 2. Department of Gynecology Tumor, Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha 410013, China
出版时间: 2023-05-12 doi: 10.16438/j.0513-4870.2022-1266
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摘要
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将免疫细胞重定向至肿瘤部位并增强抗肿瘤免疫反应是一种有前景的癌症治疗策略。AS1411适配体对高表达核仁素的恶性肿瘤有高亲和结合力, 细胞毒性T淋巴细胞相关蛋白4 (cytotoxic T-lymphocyte-associated protein 4, CTLA-4) 适配体可特异性结合T细胞表达的免疫检查点CTLA-4。本研究基于AS1411适配体和CTLA-4适配体构建了一种可同时靶向肿瘤细胞和T细胞的双亲和性适配体靶向脂质体(dual-affinity aptamer targeted liposome, Dat. Lipo), 并在细胞水平研究其促T细胞免疫治疗效果。将适配体修饰上胆固醇后, 用滴入法制备Dat. Lipo; 用成像系统检测其T细胞重定向作用, CCK8 (cell counting kit-8) 评价其促T细胞免疫治疗作用, 用肿瘤球评价其促T细胞渗透作用。结果表明, 与只负载一种适配体的脂质体相比, Dat. Lipo可有效促进T细胞重定向至肿瘤细胞; 对MCF-7和HepG2细胞具有良好的促免疫治疗作用, 且呈浓度依赖性, 具有良好的生物安全性; Dat. Lipo还能促进T细胞渗透到肿瘤球内部, 在不同维度增强T细胞免疫治疗作用。综上, Dat. Lipo可利用适配体对靶标的高亲和性将T细胞重定向至肿瘤细胞, 增强免疫疗法效果, 在肿瘤治疗方面具有一定的应用前景。本研究获得了湖南省肿瘤医院中南大学湘雅医学院附属肿瘤医院审查委员会的伦理批准。

适配体  /  双亲和性  /  T细胞重定向  /  免疫疗法  /  免疫检查点

Redirecting immune cells to the tumor cells and enhancing its anti-tumor immune response is a very promising cancer treatment strategy. AS1411 aptamers have high affinity for malignant tumors with high nucleolin expression, and cytotoxic T lymphocyte associated protein 4 (CTLA-4) aptamers can specifically bind to CTLA-4, which is expressed by T cells. In this study, a dual-affinity aptamer targeted liposome (Dat. Lipo) was constructed based on AS1411 aptamer and CTLA-4 aptamer, and its immunotherapeutic effect on T cells was studied. After the aptamer was modified with cholesterol, Dat. Lipo was prepared by instillation method; its effect of redirecting T cells was determined by confocal micrographs; its T cell immunotherapy effect was evaluated by cell counting kit-8 (CCK8) and T cell penetration was evaluated by tumor spheroids. The results showed that compared with liposomes loaded with one type aptamer, Dat. Lipo could effectively promote the redirection of T cells to tumor cells; Dat. Lipo had good biosafety and immunotherapeutic effect on MCF-7 and HepG2 cells in a concentration-dependent manner; Dat. Lipo could also promote T cells to infiltrate into the tumor spheroids and enhance the immunotherapy effect of T cells in different dimensions. In summary, Dat. Lipo can use the high affinity of aptamers to redirect T cells to tumor cells, enhance the effect of immunotherapy, and has a promising application prospect in tumor therapy. This study was approved by the Examination Committee of Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital.

aptamer  /  dual-affinity  /  T-cell redirection  /  immunotherapy  /  immune checkpoint
任欢欢, 贾国萍, 黄婧, 王梦迪, 孙定亚, 褚超男, 王珊. 双亲和性适配体靶向脂质体介导的T细胞免疫治疗. 药学学报, 2023 , 58 (5) : 1338 -1346 . DOI: 10.16438/j.0513-4870.2022-1266
Huan-huan REN, Guo-ping JIA, Jing HUANG, Meng-di WANG, Ding-ya SUN, Chao-nan ZHU, Shan WANG. T cell immunotherapy mediated by dual-affinity aptamer targeted liposome[J]. Acta Pharmaceutica Sinica, 2023 , 58 (5) : 1338 -1346 . DOI: 10.16438/j.0513-4870.2022-1266
正文
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利用人类免疫系统攻击肿瘤细胞的免疫疗法是治疗多种癌症的最新突破之一。其中, 嵌合抗原受体-T细胞疗法[1]对非实体瘤有良好的治疗效果, 已成功应用于临床; 近年来基因工程改造的T细胞受体-T细胞疗法[2]和肿瘤浸润淋巴细胞疗法[3]对实体肿瘤展现出很好的缓解消除效果。这些免疫细胞疗法通过促进免疫细胞重定向至肿瘤周围并增强免疫疗效, 为癌症患者带来了良好的生存获益, 但由于需要为患者量身定制, 涉及复杂耗时的细胞工程和基因工程过程, 并且可能引起严重的细胞因子释放综合征和神经毒性, 阻碍其广泛应用[4]。具有两个不同抗原结合位点的双特异性抗体可通过将免疫细胞重定向至肿瘤促进免疫治疗, 从而缓解癌症, 可制成一种“现成的”产品, 与免疫细胞疗法相比, 其应用方法更简单[5]。但双特异性抗体的制备和纯化过程繁琐, 产率较低和免疫原性较高, 严重影响患者健康和疗效[6], 寻找更好的免疫治疗剂尤其重要。
适配体是在复杂的相互作用中被筛选出来的单链寡核苷酸, 显示出类似或优于单抗的特异性和亲和力, 因可化学合成而具有低免疫原性、低生产成本和便于化学修饰的优点[7]。近年来, 有研究利用碱基互补配对形成的环状双特异性适配体[8-10]或依赖连接体简单组合形成的二价双特异性适配体[11]将免疫细胞重定向至肿瘤, 并在体内体外实验中取得较好的治疗效果。但这些双特异性适配体策略往往只能连接少数几个适配体, 导致其细胞结合能力不够强, 使用浓度偏大。目前急需一种可促进免疫治疗、低免疫原性、低毒副作用、高效和通用的肿瘤治疗药物。
核仁素是一种多功能蛋白, 参与核糖体的生物形成、rRNA的加工和mRNA的稳定等多种过程, 过表达于多种增生活跃的癌细胞膜及细胞质中, 但在正常细胞表面不表达[12]。AS1411是一个富含鸟嘌呤核苷(G) 的核仁素核酸适配体, 具有亲和力高、特异性强和相对分子质量小等显著优势, 可与细胞表面的核仁素结合并在一定程度上阻断肿瘤细胞的增殖且下调致瘤基因[13]。细胞毒性T淋巴细胞相关蛋白4 (cytotoxic T-lymphocyte-associated protein 4, CTLA-4) 是CD28的竞争性结合蛋白, 当CD28与B7家族分子结合时, 可促进细胞因子白细胞介素-2 (IL-2) 的mRNA表达和T细胞存活分化; 而当CTLA-4与B7家族分子结合时, CTLA-4介导的细胞外区域信号具有抑制和关闭T细胞依赖性免疫反应的作用[14, 15]。CTLA-4核酸适配体能以高亲和力与CTLA-4蛋白结合, 阻断CTLA-4信号通路, 释放B7与共刺激分子CD28相互作用, 可增加免疫细胞对肿瘤细胞的敏感度并诱导对继发性肿瘤攻击的免疫[16]。脂质体[17]是目前研究最为广泛的递送系统之一, 具有生物安全性好、免疫原性低和递送效率高等优势, 许多基于脂质体的药物系统已被美国食品和药物管理局批准用于临床疾病治疗, 具有良好的临床应用前景[18]。
本研究构建了一种负载AS1411适配体和CTLA-4适配体的双亲和性适配体靶向脂质体(dual-affinity aptamer targeted liposome, Dat. Lipo), 可同时特异性结合核仁素和CTLA-4蛋白, 促进T细胞重定向至肿瘤细胞(图 1)。一方面, CTLA-4在活化T细胞和调节性T细胞表面高表达, 故Dat. Lipo可特异性靶向活化T细胞和调节性T细胞, 并通过CTLA-4免疫检查点阻断促进T细胞激活、唤醒沉睡的T细胞, 促进免疫治疗效果; 另一方面, 核仁素在多种恶性肿瘤细胞表面的高表达使得Dat. Lipo可靶向多种肿瘤细胞, 具有通用性。此外, 纳米级脂质体是目前药物输送系统中应用极为广泛的药物载体, 具有被动靶向实体肿瘤的能力[19]。本研究在细胞水平探讨Dat. Lipo的促T细胞免疫治疗能力, 为其临床应用提供初步依据。
材料与方法
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药品与试剂  胆固醇-聚乙二醇-N-羟基琥珀酰亚胺(CLS-PEG-NHS, 批号A2219353, 上海阿拉丁生化科技股份有限公司); Cy3 (cyanine 3) 标记的5′ NH2-AS1411 (5′-NH2-TTGGTGGTGGTGGTTGTGGTGGT-GGTGG-3′)、5′ NH2-CTLA-4 (5′-NH2-TCCCTACGG-CGCTAACGATGGTGAAAATGGGCCTAGGGTGGA-CGGTGCCACCGTGCTACAAC-3′) (苏州贝信生物技术有限公司); 氢化大豆卵磷脂(hydrogenated soybean phosphotidylcholine, HSPC, 批号C00257, 上海艾伟拓医药科技有限公司); 胆固醇(批号P1880718, 中国Adamas-beta公司); 甲基-PEG2000-二硬脂酰基磷脂酰乙醇胺(1, 2-distearoyl-sn-glycero-3-phosphoethanolamine, DSPE, 批号9IRUR51R, 上海萨恩化学技术有限公司); 无水乙醇(批号20180930, 上海沪试实验室器材股份有限公司); Ficoll淋巴细胞分离液(批号10316369, 瑞典Cytiva Sweden AB公司); 人白细胞介素-2 (HIL-2, 批号021812-3, 美国Peprotech公司); 抗人CD3抗体(批号B284044, 美国BiosLegend公司); 细胞增殖-毒性检测试剂盒(cell counting kit-8, CCK8, 批号22153558, 北京兰杰柯科技有限公司); HBSS (Hank's balanced salt solution, 批号14170112)、细胞培养基(批号C11875500BT)、胎牛血清(fetal bovine serum, FBS, 批号C0235)、MitoSpy Red (批号424801) (赛默飞世尔科技公司); 双抗(批号PB180120, 武汉普诺赛生命科技有限公司); CFSE (5, 6-carboxyfluorescein diacetate, succinimidyl ester, 批号GC14056, 上海宏叶生物科技有限公司)。
仪器  电泳仪、凝胶成像仪(新加坡Bio-Rad公司); 磁力搅拌加热器(德国IKA公司); CO2培养箱(德国Binder公司); 马尔文激光粒度仪(英国Malvern Instruments公司); 高内涵成像系统(美国PerkinElmer公司); 酶联免疫检测仪[赛默尔世尔(上海) 仪器有限公司]; 倒置显微镜(厦门麦克迪奥有限公司); 流式细胞仪(美国碧迪医疗器械有限公司)。
适配体-脂质体的制备  将5′端修饰-NH2的AS1411和CTLA-4适配体于95 ℃加热5 min, 0 ℃冷却10 min变复性, 以适配体∶CLS-PEG-NHS按1∶5摩尔比混合, 室温反应10 h, 制得胆固醇-适配体, 即CLS-PEG-AS1411和CLS-PEG-CTLA-4。用滴入法制备3种适配体-脂质体: AS1411适配体修饰的脂质体(AS1411. Lipo)、CTLA-4适配体修饰的脂质体(CTLA-4. Lipo) 和双亲和性适配体脂质体(Dat. Lipo)。按处方量(表 1) 准确称取各种成分, 加入6 mL无水乙醇, 并将其置于50 ℃充分溶解, 得脂质体储液。将6 mL无酶PBS (phosphate buffer saline) 加热至65 ℃, 然后将脂质体储液滴加入无酶PBS中, 65 ℃、120~200 r·min-1搅拌反应体系, 反应1~2 h后停止。将最终所得溶液超声3 min, 透析48 h纯化产物, 得到适配体-脂质体。
细胞培养  肺癌人类肺泡基底上皮细胞(A549)、人乳腺癌细胞(MCF-7)、人肝癌细胞(HepG2) 用含1%双抗(100 u·mL-1青霉素和100 μg·mL-1链霉素) 和10%胎牛血清(FBS) 的DMEM培养基培养。人正常卵巢上皮细胞(IOSE-80)、人T淋巴细胞瘤细胞(Jurkat) 用含1%双抗和10% FBS的RPMI1640培养基培养。所有细胞购自汉恒生物技术(上海) 有限公司。A549、MCF-7、HepG2和Jurkat细胞每2天传代, IOSE-80细胞每3天传代。将细胞置于5% CO2、恒温37 ℃培养箱中培养。
PBMC (peripheral blood mononuclear cell) 的提取及激活  离心管分装5 mL外周血, 2 000 r·min-1离心10 min去除血浆, 加2.5 mL HBSS到血细胞中。将5 mL Ficoll分离液加至离心管中, 缓缓加入血细胞混悬液。2 000 r·min-1离心20 min。用移液枪吸取白膜层细胞至新离心管中, 加10 mL HBSS充分吹打混匀, 1 500 r·min-1离心10 min, 沉淀为PBMC。加入RPMI1640完全培养基充分吹打混匀, 加入100 ng·mL-1 CD3抗体和200 ng·mL-1 HIL-2刺激PBMC活化为T细胞。本研究获得了湖南省肿瘤医院中南大学湘雅医学院附属肿瘤医院审查委员会的伦理批准。
流式分析  用Cy3分别标记AS1411适配体和CTLA-4适配体, 然后合成含Cy3荧光的Con. Lipo (CTLA-4对照核酸制备的脂质体)、CTLA-4. Lipo和Dat. Lipo。分别将2×105个Jurkat细胞与Con. Lipo和Dat. Lipo在4 ℃孵育0.5 h; 作为阴性对照, 将2×105个Jurkat细胞悬浮在缓冲溶液中, 于4 ℃孵育0.5 h。分别将细胞数为2×105个的A549、MCF-7和HepG2细胞各自与CTLA-4. Lipo和Dat. Lipo在4 ℃孵育0.5 h; 作为阴性对照, 将2×105个A549、MCF-7和HepG2细胞各自悬浮在缓冲溶液中, 于4 ℃孵育0.5 h。孵育结束后, 用流式细胞仪检测各分组中材料与细胞的结合情况。
高内涵成像  分别用MitoSpy Red和CFSE对A549细胞和Jurkat细胞进行染色, 用冷的缓冲溶液洗细胞2次。将Jurkat细胞与Dat. Lipo、AS1411. Lipo和CTLA-4. Lipo混合物, 或阴性对照PBS组, 在缓冲液中于4 ℃孵育30 min。离心去除未结合材料, 分别与等量A549细胞在RPMI1640完全培养基中混合, 加入96孔板, 于4 ℃孵育5 h。将细胞用PBS洗2次, 1% (w/v) 低聚甲醛固定细胞, 用高内涵成像系统对细胞进行成像。
Dat. Lipo促进T细胞对肿瘤细胞的免疫杀伤作用  分别将1.5×104个活化的T细胞与300 nmol·L-1的AS1411. Lipo、CTLA-4. Lipo和Dat. Lipo及PBS在4 ℃孵育30 min, 然后将5×103个HepG2细胞与上述T细胞混合, 并将细胞混合液接种在96孔板中, 置于5% CO2、37 ℃培养箱中共培养40 h。培养结束后, 用PBS洗细胞2次, 去除悬浮T细胞, 加入10% CCK8溶液检测。在5% CO2、37 ℃培养箱中孵育1~2 h后, 用酶联免疫检测仪在450 nm处测量吸光度(A450) 值。按照公式(1) 计算细胞存活率(survival rate, SR)。
$\mathrm{SR}=\left(A_{\mathrm{s}}-A_{\mathrm{b}}\right) /\left(A_{\mathrm{c}}-A_{\mathrm{b}}\right) \times 100 \%$
其中, As为实验组吸光度, Ac为对照组吸光度, Ab为空白组吸光度。
为了验证Dat. Lipo促进T细胞对肿瘤细胞的免疫杀伤作用呈浓度依赖性, 分别将1.5×104个活化的T细胞与不同浓度的Dat. Lipo在4 ℃孵育30 min, 然后将5×103个A549、MCF-7或HepG2细胞分别与上述T细胞混合, 并将细胞混合液接种于96孔板。置于5% CO2、37 ℃培养箱中共培养40 h。培养结束后, 用PBS洗细胞2次, 去除悬浮T细胞, 加入10% CCK8溶液检测。在5% CO2、37 ℃培养箱中孵育1~2 h后, 测量A450值。按公式(1) 计算细胞SR。
Dat. Lipo的体外生物安全性  将8×103~1×104个A549、MCF-7、HepG2及IOSE-80分别种于96孔板。待贴壁后, 各细胞组分别加入PBS (对照) 和500 nmol·L-1 Dat. Lipo。置于5% CO2、37 ℃培养箱中共培养45 h。用PBS洗细胞2次, 加入10% CCK8溶液检测。在5% CO2、37 ℃培养箱中孵育1 h后, 测量A450值。按公式(1) 计算细胞SR。
肿瘤球渗透能力  将2%琼脂糖溶液平铺于96孔板底部, 每孔80 μL。待琼脂糖胶凝固后, 每孔加2×103~3×103个A549或MCF-7细胞, 细胞悬液每孔体积为200 μL, 5天左右即可观察到明显的细胞圆球。第6天时, 轻轻吸走孔内培养基, 各组分别加入PBS、荧光标记的Con. Lipo和Dat. Lipo, 4 ℃孵育3 h后, 用高内涵成像系统对肿瘤球进行成像。
Dat. Lipo对肿瘤球的促免疫杀伤能力  按前述方法构建A549和MCF-7肿瘤球模型。第5天, 分别将6×103个活化的T细胞与PBS、AS1411. Lipo和Dat. Lipo (500 nmol·L-1)在4 ℃孵育30 min, 孵育结束后, 将T细胞加入肿瘤球中。在5% CO2、37 ℃培养箱中孵育48 h, 在0、24、48 h对肿瘤球用高内涵成像系统对肿瘤球进行成像。最后用PI (propidium iodide) 染料对肿瘤球染色, 用高内涵成像系统分析肿瘤球中的细胞死亡情况。
统计学分析  用GraphPad Prism 8.0.2软件分析, 结果用平均值±标准差(x ± s) 表示, 组间均数用one-way ANOVA方法进行方差齐性分析。P < 0.05表示具有显著性差异。
结果
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1 Dat. Lipo制备和表征
为了促进T细胞重定向至肿瘤细胞, 从而增强T细胞发挥抗肿瘤免疫杀伤能力, 本研究构建了一种双亲和性适配体靶向脂质体(Dat. Lipo)。5′端修饰-NH2的AS1411和CTLA-4适配体与修饰NHS酯基的胆固醇通过氨基和NHS酯基的取代反应, 形成胆固醇修饰的适配体, 使其能负载到脂质体表面[18]。通过乙醇注入法获得Dat. Lipo, 用琼脂糖凝胶电泳对合成的Dat. Lipo进行表征(图 2A), 条带“1”为混合的AS1411和CTLA-4适配体, 条带“2”为Dat. Lipo, 两者中的各种适配体量保持一致。条带“2”比条带“1”亮度明显减小, 说明多数适配体已被负载到Dat. Lipo中。
用透射电子显微镜(TEM) 观察到Dat. Lipo的表面形貌呈球形(图 2B)。使用马尔文激光粒度仪检测空脂质体Lipo和Dat. Lipo的水合粒径(图 2C), 平均粒径约为100 nm, 粒径范围集中, 分散性较好。为了测验Dat. Lipo纳米粒的稳定性, 将Lipo和Dat. Lipo置于10% FBS中, 并连续5天测量其粒径变化。由图 2D可知, Lipo和Dat. Lipo纳米粒尺寸随时间变化较小, 结构稳定性较好。
2 Dat. Lipo介导的T细胞重定向作用
2.1 Dat. Lipo细胞亲和性的流式分析
AS1411适配体对含核仁素蛋白的细胞有特异性亲和力[20], CTLA-4适配体对含CTLA-4蛋白的细胞有特异性亲和力[16], 同时负载AS1411和CTLA-4适配体的Dat. Lipo对相应细胞也具有特异性亲和作用。Jurkat细胞是人T淋巴细胞白血病细胞, 其细胞膜高表达CTLA-4蛋白[21]。作为对照, 合成了由不具备识别能力的随机对照序列组成的对照脂质体(Con. Lipo)。通过流式细胞仪检测单独CTLA-4适配体或AS1411适配体、CTLA-4. Lipo或AS1411. Lipo、Con. Lipo及Dat. Lipo对Jurkat、A549、MCF-7和HepG2细胞的亲和性(图 3A), 结果表明, 将适配体进行胆固醇修饰并负载到脂质体上并不会影响其对细胞的靶向能力, Dat. Lipo对CTLA-4蛋白阳性的T细胞和核仁素阳性的肿瘤细胞皆具有特异性亲和力, 为其促进T细胞重定向至肿瘤细胞提供了理论依据。
2.2 Dat. Lipo介导的T细胞重定向成像
Dat. Lipo能通过靶向两种靶点, 同时对两种细胞显示出特异性亲和力, 本研究用高内涵成像系统分析了Dat. Lipo促进T细胞重定向至肿瘤细胞的能力。高内涵成像结果显示(图 3B), Dat. Lipo孵育过的Jurkat细胞(CFSE染色) 被更多保留在A549细胞(MitoSpy Red染色) 周围, 且与A549细胞紧密相接; 而Mix. Lipo (CTLA-4. Lipo和AS1411. Lipo的混合物) 孵育过的Jurkat细胞绝大多数都被洗掉, 即使未被洗掉也不与A549细胞相接。分析3个分组中Jurkat细胞占总细胞的比例可知(图 3C), Dat. Lipo可有效促进含CTLA-4膜蛋白的T细胞重定向至含核仁素膜蛋白的肿瘤细胞周围。Dat. Lipo的双亲和性使Jurkat细胞与A549细胞紧密结合在一起, 这一结果为Dat. Lipo对T细胞的促免疫治疗作用进一步提供了依据。
3 Dat. Lipo对肿瘤细胞的促免疫杀伤作用
3.1 Dat. Lipo促进T细胞对肿瘤细胞的免疫杀伤作用
T细胞重定向至肿瘤细胞可能会导致T细胞对肿瘤细胞的免疫杀伤作用增强。为了验证这点, 本研究将分别与AS1411. Lipo、CTLA-4. Lipo或Dat. Lipo孵育过的T细胞和HepG2细胞共培养。毒性检测结果如图 4A所示, Dat. Lipo介导的促T细胞免疫杀伤作用显著, 只有68.24% HepG2细胞依然存活, 即促免疫杀伤效果达31.76%; CTLA-4. Lipo介导的杀伤作用几乎为零; 而AS1411. Lipo组也对HepG2细胞表现出一定杀伤作用, 这可能是AS1411适配体对HepG2细胞造成的毒性作用。这表明Dat. Lipo通过促进T细胞重定向至肿瘤细胞, 增强T细胞对肿瘤细胞的免疫杀伤作用。
为了探究Dat. Lipo促进T细胞对癌细胞的免疫杀伤作用与其浓度的关系, 本研究使用与不同浓度Dat. Lipo孵育之后的T细胞和不同肿瘤细胞共培养, 结果如图 4B所示。随着Dat. Lipo浓度的升高, T细胞的免疫杀伤作用也逐渐增强, 当其浓度达1 000 nmol·L-1时, MCF-7细胞的存活率为72.42%, HepG2细胞的存活率为58.1%。该结果也表明Dat. Lipo的促免疫杀伤作用对不同类型的肿瘤细胞会产生不同的疗效。
3.2 Dat. Lipo的体外生物安全性
作为一种治疗剂, 生物安全性尤其重要。为此, 本研究用Dat. Lipo处理胞膜表面表达或不表达核仁素的细胞, 以检测Dat. Lipo的细胞毒性。IOSE-80为人正常卵巢上皮细胞, 细胞表面不表达核仁素; A549、MCF-7、HepG2为肿瘤细胞, 细胞表面高表达核仁素。CCK8结果显示(图 4C), Dat. Lipo对胞膜高表达或不表达核仁素蛋白的细胞都无细胞毒性(对4种细胞活力的抑制作用均不超过5%), 表明Dat. Lipo并不产生直接细胞毒性, 而是通过促进T细胞重定向至肿瘤细胞, 从而增强T细胞对肿瘤细胞的免疫杀伤能力, 生物安全性良好。
4 Dat. Lipo对肿瘤球的促免疫杀伤能力
4.1 肿瘤球渗透能力
在用于实际治疗时, 治疗剂需穿过肿瘤间质才能有效治疗实体肿瘤, 本研究构造了A549肿瘤球和MCF-7肿瘤球模型来测验Dat. Lipo的肿瘤深层渗透能力(图 5A、B)。在经历3 h的孵育后, Dat. Lipo孵育的肿瘤球具有很强的荧光强度, 而Con. Lipo组的肿瘤球荧光极弱, 表明Dat. Lipo能很好地富集并渗透进入A549肿瘤球和MCF-7肿瘤球内部, Con. Lipo由于缺乏对肿瘤细胞的特异亲和性而无法富集到肿瘤球。这为Dat. Lipo治疗实体肿瘤提供了初步依据。
4.2 Dat. Lipo促进T细胞对A549、MCF-7细胞肿瘤球的生长抑制作用
为了进一步探究Dat. Lipo在3D维度促进T细胞治疗肿瘤的效力, 在A549和MCF-7肿瘤球生长到第5天时, 加入3倍量经过不同材料孵育后的活化T细胞与肿瘤球共培养。随着共培养时长不断增加, 可观察到施加Dat. Lipo的A549肿瘤球(图 5C) 和MCF-7肿瘤球(图 5D) 形态逐渐变得松散, 且肿瘤球周围存在较多细胞碎片; 而PBS组和Con. Lipo组中的肿瘤球依然保持明显的球形, 表明即使是致密的肿瘤球, Dat. Lipo也能促进T细胞对肿瘤细胞的杀伤作用。利用PI染料对活死细胞的特殊性(不能穿过完整的活细胞膜, 只能在细胞坏死的情况下穿过其破损的细胞膜), 对MCF-7肿瘤球中的死细胞进行染色分析(图 5E), 可观察到Dat. Lipo组中有较强的PI信号, 而对照组中PI信号却较弱, 进一步确定了Dat. Lipo可有效促进T细胞在不同维度对肿瘤细胞的杀伤作用。
肿瘤球实验结果表明, Dat. Lipo对肿瘤细胞有较强特异性亲和作用, 且可渗透进肿瘤球内部。T细胞在Dat. Lipo的协助下不仅能聚集在肿瘤球周围, 还可侵入肿瘤球内部, 促使T细胞在不同肿瘤球深度对肿瘤产生杀伤作用。
讨论
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利用细胞免疫疗法[22]和双特异性抗体[23]实现T细胞重定向至肿瘤细胞, 对癌症展现出良好的治疗效果, 但这两种治疗方式均需涉及复杂繁琐的细胞工程、基因工程和纯化程序, 且可能引起致命的细胞因子释放综合征[5]。适配体由于其独特的三维结构和分子相互作用, 具有高稳定性、高结合亲和力、高特异性和低免疫原性, 能以高亲和力和特异性与其靶标结合, 被视为抗体的理想替代物[17]。AS1411适配体对高表达于多种肿瘤细胞的核仁素蛋白有高亲和力靶向作用, 并可在一定程度上抑制多种肿瘤细胞的生长, 而对正常细胞基本无影响[20]。免疫检查点CTLA-4蛋白表达于T细胞表面, 通过竞争结合B7来减弱CD28的共刺激和抑制信号传导, 阻断CTLA-4蛋白和B7的结合可重塑宿主免疫反应[24]。CTLA-4适配体可特异性结合CTLA-4蛋白, 释放B7与CD28相互作用, 从而促进T细胞的活化增殖。
本研究所构建的Dat. Lipo利用AS1411适配体和CTLA-4适配体, 可通过将T细胞重定向至肿瘤细胞增强免疫治疗效果, 是一个适用于多种肿瘤的T细胞免疫疗法。Dat. Lipo粒径约100 nm, 有利于其蓄积在肿瘤部位, 且纳米级脂质体可装载治疗药物提高疗效。流式和成像结果显示, Dat. Lipo对多种高表达核仁素蛋白的肿瘤细胞具有良好靶向作用, 且可特异性靶向含CTLA-4蛋白的T细胞, 这提示Dat. Lipo可能通过抑制免疫检查点改善肿瘤免疫抑制微环境, 提高T细胞免疫应答, 促进T细胞活化。Dat. Lipo可进一步将T细胞重定向至肿瘤细胞, 促进免疫突触的形成, 增强T细胞的激活。Dat. Lipo孵育过的T细胞对HepG2和MCF-7细胞的的免疫杀伤率分别达到41.9%和27.58%, 这揭示Dat. Lipo可通过T细胞重定向和抑制免疫检查点促进T细胞对不同肿瘤细胞的杀伤作用, 但可能由于不同肿瘤细胞核仁素膜蛋白表达量的不同而导致不同的免疫疗效[25]。令人惊喜的是, Dat. Lipo并不会对细胞产生毒性, 具有良好的生物安全性。Dat. Lipo还可在3D维度促进T细胞对A549和MCF-7肿瘤球的深层渗透和免疫杀伤作用, 为其治疗实体肿瘤提供了初步依据。
综上, 本研究基于AS1411适配体和CTLA-4适配体构建了一种可用于治疗多种肿瘤的Dat. Lipo, 可通过简单的使用方法增强T细胞对肿瘤细胞的免疫治疗, 而无需复杂耗时的制备过程。结果提示, Dat. Lipo可通过CTLA-4阻断改善肿瘤免疫应答, 可招募CTLA-4阳性T细胞渗透到肿瘤中, 从而增强其抗肿瘤效果, 安全性良好, 为进一步探索其在体内的肿瘤靶向性、促免疫治疗作用和体内生物安全性提供了实验基础。
作者贡献: 任欢欢负责材料合成和实验设计; 贾国萍负责对实验过程出现的问题及时解答; 黄婧、王梦迪和孙定亚负责细胞实验; 王珊和褚超男负责文章整理和稿件修改。
利益冲突: 所有作者均声明不存在利益冲突。
基金
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  • 国家自然科学基金资助项目(81872919)
  • 中南大学中央高校基本科研业务费专项资金资助项目(1053320212602)
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doi: 10.16438/j.0513-4870.2022-1266
  • 接收时间：2022-11-24
  • 首发时间：2025-11-21
  • 出版时间：2023-05-12
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  • 收稿日期：2022-11-24
  • 修回日期：2023-01-20
基金
国家自然科学基金资助项目(81872919)
中南大学中央高校基本科研业务费专项资金资助项目(1053320212602)
作者信息
    1.中南大学化学化工学院制药工程系, 湖南 长沙 410083
    2.湖南省肿瘤医院中南大学湘雅医学院附属肿瘤医院妇瘤科, 湖南 长沙 410013

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*褚超男, Tel: 18684983256, E-mail: ;
王珊, Tel: 18008425007, E-mail:
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