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Article(id=1308459208479896170, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308459188263342104, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-1191, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1733155200000, receivedDateStr=2024-12-03, revisedDate=1746979200000, revisedDateStr=2025-05-12, acceptedDate=null, acceptedDateStr=null, onlineDate=1789890585298, onlineDateStr=2026-09-20, pubDate=1757606400000, pubDateStr=2025-09-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789890585298, onlineIssueDateStr=2026-09-20, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789890585298, creator=13701087609, updateTime=1789890585298, updator=13701087609, issue=Issue{id=1308459188263342104, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='9', pageStart='2649', pageEnd='2912', issueExtLink='null', onlineDate='null', pubDate='1757606400000', pubDateStr='2025-09-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789890580478, creator='13701087609', updateTime=1789893297273, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308470583390401503, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308459188263342104, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308470583390401504, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308459188263342104, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2768, endPage=2775, ext={EN=ArticleExt(id=1308459208672834155, articleId=1308459208479896170, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Research progress on TRAIL and nanocarriers for cancer combination therapy, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown significant potential in cancer therapy due to its ability to selectively induce apoptosis in tumor cells while minimally affecting normal cells. Currently, developed TRAIL-based cancer therapies have demonstrated better therapeutic effects in preclinical trials. However, their clinical application has been limited by issues such as poor stability, insufficient targeting, short half-life in vivo, and low bioavailability. In recent years, nanocarriers, including liposomes, nanoparticles, and micelles, have been widely utilized in the field of drug delivery. Combining TRAIL with these nanocarriers can help overcome these limitations and enhance its antitumor efficacy. This review summarizes the latest research progress on the combination of TRAIL with liposomes, nanoparticles, and micelles in cancer treatment. It explores the mechanisms by which these nanocarriers improve the stability, targeting, and bioavailability of TRAIL, as well as the therapeutic advancements of this combined approach at both the animal and clinical levels. The aim is to provide valuable insights for the development and clinical application of TRAIL-based cancer therapies.

, authors=Bin-ke QIU1, Lei CHANG2, Dan-dan ZHOU1, Li-yu CHEN1, Yu-xin MA1, Rui CHANG1, *, Qing-li LIU1, *, authorsList=Bin-ke QIU, Lei CHANG, Dan-dan ZHOU, Li-yu CHEN, Yu-xin MA, Rui CHANG, Qing-li LIU, authorCompany=null, correspAuthors=Rui CHANG, Qing-li LIU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 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, fund=null), CN=ArticleExt(id=1308459209528472178, articleId=1308459208479896170, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=TRAIL与纳米载体的癌症联合疗法最新进展, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor-related apoptosis-inducing ligand, TRAIL) 因其能选择性诱导肿瘤细胞凋亡而对正常细胞影响较小, 在癌症治疗领域展现出巨大潜力。目前, 以TRAIL为主开发的癌症疗法在临床前试验中显示出较好的治疗效果, 但由于其具有稳定性差、靶向性不足、体内半衰期短、生物利用度低等缺陷, 在临床应用中治疗效果较差。近年来, 以脂质体(liposomes, LPs)、纳米颗粒(nanoparticles, NPs)、胶束(micelles, Mcs) 等为代表的纳米载体, 在药物递送领域被广泛应用。将纳米载体与TRAIL结合, 能够在一定程度上克服以上问题并增强其抗肿瘤作用。本文综述了TRAIL与LPs、NPs、Mcs在联合治疗癌症领域的最新研究进展, 探讨了这3种纳米载体在提高TRAIL的稳定性、靶向性和生物利用度等方面的作用机制, 以及该联合疗法在动物水平和临床水平的治疗进展, 旨在为TRAIL的癌症疗法开发和临床应用提供一定的参考。

, authors=邱彬珂1, 常蕾2, 周丹丹1, 陈俐羽1, 马雨馨1, 常芮1, *, 刘庆礼1, *, authorsList=邱彬珂, 常蕾, 周丹丹, 陈俐羽, 马雨馨, 常芮, 刘庆礼, authorCompany=null, correspAuthors=常芮, 刘庆礼, authorNote=

作者贡献:

邱彬珂负责撰写、修改论文; 常蕾负责撰写临床研究部分、审阅、提供修改意见; 周丹丹负责论文的审阅、提供修改意见; 陈俐羽、马雨馨负责文献查阅、修改; 常芮负责组织文章的框架、思路指导、修改及定稿; 刘庆礼负责审阅、提供资金支持。

, correspAuthorsNote=
常芮, Tel: 15553677721, E-mail:
刘庆礼, Tel: 18823369825, E-mail:
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DcR1: Decoy receptor 1; DcR2: Decoy receptor 2; OPG: Osteoprotegerin; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; DR4/5: Death receptor 4/5; DISC: Death-inducing signaling complex; FADD: Fas-associated death domain-containing protein; cFLIP: Cellular flice-like inhibitory protein; BID: BH3 interacting domain death agonist; SMAC: Second mitochondria-derived activator of caspase; XIAP: X-linked inhibitor of apoptosis protein, figureFileSmall=D8rFrIUt2PIwmL2TSaNO7w==, figureFileBig=pNHMW704WMcn7CTOzhP5qg==, tableContent=null), ArticleFig(id=1308498588414608022, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308459208479896170, language=EN, label=null, caption=null, figureFileSmall=TxbAVegBsxyVev7Kaz5EKg==, figureFileBig=bCARe9nqCiddlN/JupnAjw==, tableContent=null), ArticleFig(id=1308498588477522583, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308459208479896170, language=CN, label=Fig.2, caption=Mechanisms of TRAIL resistance. 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No.Nanocarrier typeName of nanocarrierDrugExperimental subjectRef.
1LiposomeMTLPsMitomycin CHighly drug-resistant HT-29 nude mouse transplantation tumor model[23]
2LiposomeTRAIL/anti-CD335 liposomes/Eight-week-old male B6(Cg)-Tyrc-2J (albino B6) mice[24]
3NanoparticleERN-TAZD5582Subcutaneous MDA-MB-231 xenograft tumor model[25]
4NanoparticleTM-CQ/NPsChloroquineCT26-luci intraperitoneal tumor model, Huh7 tumor-bearing nude mice model[26]
5NanoparticleDMC-siERCC2/Nude BALB/c mouse model with U87 glioma[27]
6MicelleMILsPiperlongumineHuman prostate cancer cells PC3 and DU145[28]
7Micelleγ-PGA/Sali@P-S/pTRAILSalinomycin, γ-PGAHuman cervical cancer cell line HeLa[29]
), ArticleFig(id=1308498588745958043, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308459208479896170, language=CN, label=Tab.1, caption=

Partial summary of TRAIL coupled to nanocarriers. MTLPs: Multifunctional liposomes; ERN-T: Endoplasmic reticulum-derived nanosomes-TRAIL; CQ: Chloroquine; DMC: DOTAP-mPEG-PCL; MILs: Micelle-in-liposomes

, figureFileSmall=null, figureFileBig=null, tableContent=
No.Nanocarrier typeName of nanocarrierDrugExperimental subjectRef.
1LiposomeMTLPsMitomycin CHighly drug-resistant HT-29 nude mouse transplantation tumor model[23]
2LiposomeTRAIL/anti-CD335 liposomes/Eight-week-old male B6(Cg)-Tyrc-2J (albino B6) mice[24]
3NanoparticleERN-TAZD5582Subcutaneous MDA-MB-231 xenograft tumor model[25]
4NanoparticleTM-CQ/NPsChloroquineCT26-luci intraperitoneal tumor model, Huh7 tumor-bearing nude mice model[26]
5NanoparticleDMC-siERCC2/Nude BALB/c mouse model with U87 glioma[27]
6MicelleMILsPiperlongumineHuman prostate cancer cells PC3 and DU145[28]
7Micelleγ-PGA/Sali@P-S/pTRAILSalinomycin, γ-PGAHuman cervical cancer cell line HeLa[29]
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TRAIL与纳米载体的癌症联合疗法最新进展
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邱彬珂 1 , 常蕾 2 , 周丹丹 1 , 陈俐羽 1 , 马雨馨 1 , 常芮 1, * , 刘庆礼 1, *
药学学报 | 综述 2025,60(9): 2768-2775
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TRAIL与纳米载体的癌症联合疗法最新进展
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Engineering, Qilu Institute of Technology, Jinan 250200, China), AuthorCompanyExt(id=1308498585692504675, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308459208479896170, companyId=1308498585667338849, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1齐鲁理工学院生物与化学工程学院, 山东 济南 250200)])])]
邱彬珂1, 常蕾2, 周丹丹1, 陈俐羽1, 马雨馨1, 常芮1, * , 刘庆礼1, *
作者信息
  • 1齐鲁理工学院生物与化学工程学院, 山东 济南 250200
  • 2山东第一医科大学附属省立医院, 山东 济南 250000
通讯作者:
常芮, Tel: 15553677721, E-mail:
刘庆礼, Tel: 18823369825, E-mail:
作者简介:

作者贡献:

邱彬珂负责撰写、修改论文; 常蕾负责撰写临床研究部分、审阅、提供修改意见; 周丹丹负责论文的审阅、提供修改意见; 陈俐羽、马雨馨负责文献查阅、修改; 常芮负责组织文章的框架、思路指导、修改及定稿; 刘庆礼负责审阅、提供资金支持。

Research progress on TRAIL and nanocarriers for cancer combination therapy
Bin-ke QIU1, Lei CHANG2, Dan-dan ZHOU1, Li-yu CHEN1, Yu-xin MA1, Rui CHANG1, * , Qing-li LIU1, *
Affiliations
  • 1College of Biological and Chemical Engineering, Qilu Institute of Technology, Jinan 250200, China
  • 2Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250000, China
出版时间: 2025-09-12 doi: 10.16438/j.0513-4870.2024-1191
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肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor-related apoptosis-inducing ligand, TRAIL) 因其能选择性诱导肿瘤细胞凋亡而对正常细胞影响较小, 在癌症治疗领域展现出巨大潜力。目前, 以TRAIL为主开发的癌症疗法在临床前试验中显示出较好的治疗效果, 但由于其具有稳定性差、靶向性不足、体内半衰期短、生物利用度低等缺陷, 在临床应用中治疗效果较差。近年来, 以脂质体(liposomes, LPs)、纳米颗粒(nanoparticles, NPs)、胶束(micelles, Mcs) 等为代表的纳米载体, 在药物递送领域被广泛应用。将纳米载体与TRAIL结合, 能够在一定程度上克服以上问题并增强其抗肿瘤作用。本文综述了TRAIL与LPs、NPs、Mcs在联合治疗癌症领域的最新研究进展, 探讨了这3种纳米载体在提高TRAIL的稳定性、靶向性和生物利用度等方面的作用机制, 以及该联合疗法在动物水平和临床水平的治疗进展, 旨在为TRAIL的癌症疗法开发和临床应用提供一定的参考。

肿瘤坏死因子相关凋亡诱导配体  /  脂质体  /  纳米颗粒  /  胶束  /  癌症治疗

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown significant potential in cancer therapy due to its ability to selectively induce apoptosis in tumor cells while minimally affecting normal cells. Currently, developed TRAIL-based cancer therapies have demonstrated better therapeutic effects in preclinical trials. However, their clinical application has been limited by issues such as poor stability, insufficient targeting, short half-life in vivo, and low bioavailability. In recent years, nanocarriers, including liposomes, nanoparticles, and micelles, have been widely utilized in the field of drug delivery. Combining TRAIL with these nanocarriers can help overcome these limitations and enhance its antitumor efficacy. This review summarizes the latest research progress on the combination of TRAIL with liposomes, nanoparticles, and micelles in cancer treatment. It explores the mechanisms by which these nanocarriers improve the stability, targeting, and bioavailability of TRAIL, as well as the therapeutic advancements of this combined approach at both the animal and clinical levels. The aim is to provide valuable insights for the development and clinical application of TRAIL-based cancer therapies.

tumor necrosis factor-related apoptosis-inducing ligand  /  liposome  /  nanoparticle  /  micelle  /  cancer therapy
邱彬珂, 常蕾, 周丹丹, 陈俐羽, 马雨馨, 常芮, 刘庆礼. TRAIL与纳米载体的癌症联合疗法最新进展. 药学学报, 2025 , 60 (9) : 2768 -2775 . DOI: 10.16438/j.0513-4870.2024-1191
Bin-ke QIU, Lei CHANG, Dan-dan ZHOU, Li-yu CHEN, Yu-xin MA, Rui CHANG, Qing-li LIU. Research progress on TRAIL and nanocarriers for cancer combination therapy[J]. Acta Pharmaceutica Sinica, 2025 , 60 (9) : 2768 -2775 . DOI: 10.16438/j.0513-4870.2024-1191
正文
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肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor-related apoptosis-inducing ligand, TRAIL) 作为肿瘤坏死因子超家族的一员, 通过与两种死亡受体(death receptor 4/5, DR4/5) 结合, 能够选择性诱导肿瘤细胞凋亡, 而对正常细胞影响较小, 因此被视为一种具有潜力的抗癌药物[1]。然而, TRAIL在临床应用中存在稳定性差、靶向性不足、体内半衰期短、生物利用度低等问题, 在一定程度上限制了其疗效。为了解决这些问题, 研究人员将TRAIL与LPs、NPs、Mcs等纳米载体相结合, 以提高其稳定性、靶向性和生物利用度, 进而增强其抗肿瘤作用。本文旨在综述TRAIL与LPs、NPs、Mcs等纳米载体联合治疗癌症的研究进展。
1　TRAIL
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1.1　TRAIL及其受体
TRAIL是一种Ⅱ型跨膜蛋白, 能够选择性地诱导肿瘤细胞凋亡, 在杀死癌细胞的同时对正常细胞的毒性极小[2]。TRAIL通过与分布在细胞表面的特异性受体结合, 激活细胞内的凋亡信号通路, 导致细胞凋亡的发生(图1)。TRAIL受体家族包括两种死亡受体(DR4/5)、两种诱饵受体(decoy receptor 1/2, DcR1/2) 及可溶性受体骨保护素(osteoprotegerin, OPG)。死亡受体能够直接传递凋亡信号, 当TRAIL与DR4或DR5结合后, 可募集Fas相关死亡结构域蛋白(Fas-associated death domain-containing protein, FADD), 进而招募半胱天冬酶8/10前体(pro-caspase-8/10) 形成死亡诱导信号复合物(death-inducing signaling complex, DISC), 从而触发外源性细胞凋亡途径。DISC通过激活caspase-8/10, 继而激活caspase-3/6/7, 最终诱导细胞凋亡[3]。
此外, 外源性细胞凋亡途径可通过caspase-8介导的裂解作用触发内源性细胞凋亡途径。Caspase-8通过切割BID蛋白(BH3 interacting domain death agonist) 生成tBID (truncated BID), tBID转移至线粒体并激活促凋亡蛋白BAX (BCL2 associated X protein, BAX)/BAK (BCL2 antagonist/killer, BAK)。活化的BAX/BAK增加线粒体外膜通透性, 促使第二型线粒体来源的caspase激活剂(second mitochondria-derived activator of caspase, SMAC) 和细胞色素c (cytochrome c) 释放。其中, 细胞色素c与凋亡蛋白酶活化因子-1 (apoptotic protease activating factor-1, Apaf-1) 和Pro-caspase-9结合形成凋亡体(apoptosome), 进而激活caspase-9, 最终导致caspase-3活化并诱导细胞凋亡。同时, 释放的SMAC通过与X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis protein, XIAP) 结合, 解除其对caspase-3的抑制作用, 进一步促进细胞凋亡。诱饵受体DcR1和DcR2在结构上与DR受体具有相似的结构域, 能够结合TRAIL, 但由于DcR1缺乏含有死亡结构域的胞质区, 且DcR2的死亡结构域不完整, 它们通过竞争性结合TRAIL来抑制其与死亡受体的结合[4], 从而减少TRAIL介导的细胞凋亡, 起到保护细胞的作用。
TRAIL作为关键的细胞凋亡诱导因子, 在免疫调节与肿瘤抑制中起着至关重要的作用, 其生理功能主要通过介导细胞凋亡途径得以实现。Rossin等[5]通过小鼠模型揭示了TRAIL信号通路的双重调控机制: 一方面, TRAIL能维持淋巴系免疫细胞的平衡; 另一方面, 它可作为效应蛋白, 参与细胞毒性细胞清除受损细胞的过程。在该研究中, TRAIL缺陷小鼠具有正常的生命力和生育能力, 但其癌症发生率和自身免疫性疾病易感性显著升高, 进一步证实了TRAIL在预防自身免疫性疾病和癌症中的重要作用。在CD4+ T细胞、自然杀伤(natural killer, NK) 细胞、巨噬细胞和树突状细胞等多种免疫细胞中, TRAIL的表达水平直接影响其细胞毒作用, 证实了TRAIL具有显著的肿瘤抑制功能[6]。Li[7]发现肿瘤细胞可通过TRAIL-DR5信号促进T细胞死亡, 并从分子层面探讨了可能涉及的信号通路, 即肿瘤细胞表达的TRAIL可促进T细胞凋亡及程序性坏死, 这为临床免疫治疗中T细胞的功能障碍提供了一个新的解释。PD-1/PD-L1信号轴通过抑制T细胞功能来防止自身免疫, 从而维持免疫平衡, 而TRAIL途径与免疫检查点PD-L1有功能上的相互作用[8]。靶向PD-L1可增强TRAIL介导的抗肿瘤活性, 这不仅利用了TRAIL在肿瘤免疫监视中的作用, 还为将基于TRAIL的疗法与免疫检查点阻断剂联合用于临床试验奠定了基础。
1.2　TRAIL在临床治疗中的问题
尽管TRAIL作为一种潜在的癌症治疗手段, 在诱导肿瘤细胞凋亡和抑制肿瘤生长方面显示出一定疗效, 但其在临床应用中仍面临诸多挑战。耐药性、靶向性不足、稳定性差以及生物利用度低等问题, 成为限制TRAIL疗效发挥的关键因素。Kundu等[9]总结了TRAIL死亡受体激动剂的临床结果: 尽管其在许多临床前模型(三阴性乳腺癌的体外和体内模型) 中表现出强大的选择性杀伤作用, 但在临床试验中未能改善晚期实体瘤和血液恶性肿瘤患者的预后, 也未显示出明显活性。这一结果为提高TRAIL死亡受体激动剂的临床有效性带来了诸多挑战。Di Cristofano等[1]发现, TRAIL-R单克隆抗体(TRAIL-R mAbs) 在临床前研究中效果显著, 但在临床试验中表现不佳。这主要受两个因素影响: 一是单克隆抗体的二价结构限制了其与死亡受体的交联能力; 二是第一代TRAIL-R mAbs虽能特异性靶向DR4或DR5受体, 但不同组织类型中死亡受体传递凋亡信号的能力存在差异。尽管重组人TRAIL (rhTRAIL) 的药代动力学和特异性已得到改善, 但TRAIL-R单克隆抗体对耐药肿瘤的结合能力仍然有限。
TRAIL的耐药机制可能出现在其信号通路的任一环节(图2)。具体而言, 细胞表面死亡受体的功能障碍、降解或多态性会减少TRAIL与受体的结合, 从而增加癌细胞存活率。诱饵受体(如DcR1、DcR2和OPG) 的过表达会抑制DR4和DR5的激活。细胞FLICE样抑制蛋白(cellular FLICE-like inhibitory protein, c-FLIP) 通过与FADD或pro-caspases-8/10结合, 阻止DISC的形成, 进而抑制TRAIL诱导的细胞凋亡。此外, 抗凋亡蛋白(如BCL-2、BCL-XL) 通过抑制BAX或促凋亡蛋白, 阻碍SMAC/DIABLO (direct IAP-binding protein with low pI, DIABLO) 和细胞色素c的释放, 从而阻断TRAIL的凋亡途径。XIAP和IAP (inhibitor of apoptosis protein, IAP) 也能抑制caspase-9以及caspase-3、caspase-6和caspase-7的激活, 进一步阻止细胞凋亡。
2　癌症治疗中的纳米载体
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2.1　LPs
LPs是由磷脂分子在水性环境中形成的球形双层结构, 其疏水尾基向内, 亲水头基向外, 内部包含一个或多个水性腔室。作为药物载体, LPs可将亲水性药物包裹在水核心中, 而亲脂性药物则嵌入脂质双层之间。由于结构与人类细胞膜相似, LPs具有良好的生物相容性, 其特点还包括可生物降解、免疫原性低、尺寸可控以及毒性低等。另外, LPs不仅能保护敏感药物, 还能减少不良反应并提高药物吸收, 从而增强治疗效果[10]。
LPs可根据磷脂双层的数量分为单层囊泡(unilamellar vesicle, ULV)、寡层囊泡(oligolamellar vesicle, OLV) 和多层囊泡(multilamellar vesicles, MLV)。ULV由单个磷脂双层构成, 直径约50~250 nm, 其内部亲水环境较大, 适合包埋亲水药物。小的单层囊泡(small unilamellar vesicle, SUV) 结构与ULV类似, 但直径小于100 nm。OLV直径通常为0.1~1 μm, 由2~5个大小不一的囊泡组成, 这些囊泡被包裹在一个大的磷脂双层中。MLV直径约为0.5~1.5 μm, 包含多个磷脂双层, 主要用于递送疏水性物质, 而不适合输送亲水性物质[11]。Zhao等[12]设计了一种双重pH响应肽(dual pH-responsive peptide, DPRP), 并以此为基础构建了pH响应性脂质体系统(D-L/si-DTX), 用于联合递送PLK-1特异性siRNA和抗癌药物多西他赛(docetaxel, DTX), 实现协同抗肿瘤效果。体外和体内研究表明, D-L/si-DTX比其他对照LPs更具治疗优势。与单独负载siPLK-1或DTX的LPs以及联合给药相比, D-L/si-DTX能显著下调PLK-1表达并抑制肿瘤生长, 且未检测到毒副作用。该系统为同步递送抗癌药物和治疗基因提供了一种有效工具, 在协同肿瘤治疗中具有广阔应用前景。Wang等[13]开发了一种可以同步递送吉西他滨(gemcitabine) 和环丙沙星(ciprofloxacin) 的新型脂质体(gemcitabine and ciprofloxacin loaded DCPA-H2O liposomes, GC-DCPA-H2O)。该LPs在血液循环(pH = 7.4) 中保持稳定, 进入肿瘤环境(pH < 6.8) 后, 其表面DCPA-H₂O复合物质子化带正电, 通过静电作用靶向带负电的细菌或肿瘤细胞。与细菌结合后, LPs释放环丙沙星杀灭肿瘤内细菌; 进入肿瘤细胞后, 则释放两种药物: 环丙沙星清除细菌并防止吉西他滨失活, 确保其发挥抗肿瘤作用, 实现协同治疗。该LPs显著提高了药物递送效率, 实现了化疗药物与抗生素的联合输送, 既能高效杀伤肿瘤细胞, 又可同步清除肿瘤内病原体。同时, 其良好的稳定性有效防止了化疗药物失活, 为肿瘤治疗提供了新策略。
2.2　NPs
NPs是一种直径在1~100 nm间的物质粒子, 在药物递送方面具有重要应用价值[14]。其较大的比表面积和易于修饰的特性, 使其能够通过包裹、吸附或共价结合等方式负载药物, 实现靶向递送和控释。这种特性使NPs可根据治疗需求进行定制, 提高给药精准度。作为药物载体, NPs能提高药物在血液中的浓度, 延长药物半衰期, 同时改善疏水性药物的溶解度和生物利用度, 从而减少给药次数。此外, NPs还具有良好的药物稳定性、缓释特性和低毒性, 在癌症治疗中展现出广阔的应用前景[15]。
通过表面修饰, NPs可以实现对特定肿瘤细胞的靶向递送。Yang等[16]开发的微孔普鲁士蓝纳米颗粒负载3-溴丙酮酸(3-bromopyruvate, 3BP) 和CM-MSIRPα, 能通过MSIRPα与癌细胞表面CD47特异性结合。在808 nm激光照射下, 该纳米颗粒既能进行光热治疗(photothermal therapy, PTT), 又可释放3BP, 协同促进结肠癌细胞死亡。研究表明, 该体系不仅能延长血液循环时间、精准靶向CD47受体, 还可增强巨噬细胞对癌细胞的吞噬作用。体内外实验证实其具有显著抗肿瘤活性和低毒性, 为结直肠癌治疗提供了新方向。Zhang等[17]构建了一种基于CRISPRa (clustered regularly interspaced short palindromic repeats activation) 转录激活技术的纳米药物体系。该体系利用NPs为载体封装能够精准激活趋化因子基因的CRISPRa系统, 成功制备出基因激活纳米药物NPCRISPRa。实验结果表明, 在体外环境中, NPCRISPRa能够有效激活肿瘤细胞内T细胞趋化因子的表达, 进而诱导T细胞发生迁移与浸润。同时, 通过瘤内注射, NPCRISPRa可激活肿瘤区域CXCL9、10、11等趋化因子的表达, 引导活化T细胞向肿瘤组织迁移, 显著抑制小鼠模型中黑色素瘤、胰腺癌、结肠直肠癌及乳腺癌的生长。这一研究为增强T细胞在实体瘤中的浸润、提高免疫治疗效果提供了新思路。
2.3　Mcs
聚合物Mcs是在水性环境中由两亲性共聚物自组装而成的具有核壳结构的纳米级聚集体。当表面活性剂浓度达到临界胶束浓度甚至更高时, 两亲性聚合物将自组装成有亲水外壳和疏水内核的Mcs[18]。通过改变两亲性共聚物的组分, 可以调整多种生理特性, 比如表面电荷、表面性质及粒径[19]。Mcs具有良好的生物相容性、渗透性和滞留性, 作为药物载体, Mcs的疏水内核能够包裹疏水性药物, 提高其水溶性和生物利用度[20]。
替莫唑胺是治疗胶质母细胞瘤(glioblastoma, GBM) 的一线化疗药物, 脂溶性较强, 能够透过血脑屏障(blood-brain barrier, BBB) 发挥治疗作用。但该药物存在稳定性较差、入脑率较低和半衰期短等缺陷, 一定程度上限制了其疗效。因此通过将其负载于药物载体中, 将会是一种改善方案。Cao等[21]通过薄膜水化法制备了PAH-AM载药胶束, 显著改善了替莫唑胺的稳定性。该Mcs粒径157.7 nm、表面电位7.225 mV, 具有良好均一性(多分散指数0.12) 和载药性能(包封率77.42%, 载药量33.51%), 在20日储存期内保持稳定。实验显示Mcs在酸性环境(pH = 2.5) 中药物释放速率显著延缓, 12 h累积释放率约60%, 为后续靶向递送系统开发奠定了基础。Zeng[22]开发的Angiopep-2靶向修饰嵌段共聚物胶束(PHB-PDMAEMA), 通过PDMAEMA链段的静电吸附作用稳定负载治疗性小干扰RNA (small interfering RNA, siRNA), 成功构建RNAi纳米药物。该体系可特异性结合低密度脂蛋白受体相关蛋白1 (low-density lipoprotein receptor-related protein-1, LRP-1) 膜受体, 实现血脑屏障和肿瘤组织的双重靶向, 通过下调致癌基因circ_TNFRSF19表达, 利用ceRNA (competing endogenous RNA) 调控网络抑制胶质瘤进展。该研究为胶质母细胞瘤的RNA干扰治疗提供了新靶点和技术路径。
3　TRAIL与纳米载体的联合
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目前, 为改善TRAIL在临床治疗中的局限性, 科研人员已开发出基于纳米载体的联合治疗策略。通过纳米技术的精准递送与调控, 不仅有效提升TRAIL的稳定性、靶向性和生物利用度, 还为逆转耐药性提供了新的思路。本文主要从TRAIL与LPs、NPs以及Mcs 3种载体的联合疗法进行阐述(图3), 同时给出了TRAIL与纳米载体联合抗癌的部分示例(表1[23-29])。
3.1　TRAIL-LPs递送系统
TRAIL-LPs递送系统不仅能提升TRAIL稳定性、靶向性和生物利用度, 还可通过工程化改造免疫细胞增强抗癌效果[23, 24], 为逆转TRAIL耐药提供新思路, 为癌症治疗带来新策略与希望。例如, Chang等[23]为逆转TRAIL耐药, 构建了一种共载TRAIL与丝裂霉素C (mitomycin C, MMC) 的聚乙二醇化脂质体(multifunctional liposomes, MTLPs)。该共载系统通过化学偶联将TRAIL蛋白修饰在聚乙二醇化脂质体表面(连接效率≈ 69%), 并将MMC通过被动包封法包封在LPs内水相中(包封率≈ 12%)。实验结果表明, MTLPs能够在保证生物安全性的条件下, 通过上调DR4/5表达水平、激活caspase通路以及阻滞细胞周期, 在对TRAIL高耐药的HT-29裸鼠移植瘤模型中实现了高达97.8%的肿瘤抑制。相较于游离的TRAIL和MMC联合给药, LPs共递送系统在肿瘤靶向和肿瘤抑制等方面均表现出更显著的特点, 这为临床上逆转TRAIL耐药提供了参考。
进一步研究发现, LPs介导的免疫细胞工程化改造展现出独特优势。Greenlee等[24]开发了一种基于LPs的NK细胞增强疗法, 先通过薄膜水化法制备LPs, 并通过巯基-马来酰亚胺化学键偶联蛋白质, 得到TRAIL/anti-CD335 LPs。该LPs能成功结合到分离的NK细胞上, 形成“超级NK细胞”。相比单独的NK细胞, 超级NK细胞能更有效地通过TRAIL介导的凋亡杀死奥沙利铂耐药的SW620细胞和转移性COLO205结直肠癌细胞。体内实验表明, 在静脉给药后, LPs在脾脏和肿瘤引流的肠系膜淋巴结中至少可持续存在4天, 进一步证实了该疗法的有效性。这些结果表明, 装载有脂质体TRAIL的NK细胞对临床相关结直肠癌细胞有增强凋亡作用, 为结直肠癌的体内治疗研究奠定了基础。TRAIL与LPs联合后, 在药物递送效率、靶向性以及增强抗癌效果等方面展现出显著优势, 为癌症治疗带来了新的策略与希望。
3.2　TRAIL-NPs递送系统
通过将TRAIL修饰在NPs表面、内部或与其共价结合, 可以制备出TRAIL-NPs递送系统。这不仅能够保护TRAIL免受体内酶的降解, 提高其稳定性, NPs表面的靶向配体还可特异性识别肿瘤细胞表面受体, 通过NPs的靶向作用, 将TRAIL特异性地递送到肿瘤组织, 增强TRAIL在肿瘤组织的富集[25]。
Hou等[25]开发的一种携带TRAIL的细胞内质网纳米颗粒(endoplasmic reticulum-derived nanosomes TRAIL, ERN-T), 并将其与IAP拮抗剂AZD5582联合用于癌症治疗。在细胞实验中, 单独ERN-T可以杀死对TRAIL敏感的细胞, 而对TRAIL耐药的细胞作用不明显; 当ERN-T联合小分子药物AZD5582, 可以下调cIAP1、XIAP、MCL1和Survivin等抗凋亡蛋白的表达, 从而杀死部分TRAIL耐药细胞。在动物实验中, 通过静脉注射方式给予ERN-T, 展现出一定的靶向性, 可以在肿瘤部位富集; ERN-T联合小分子药物AZD5582对M231实体瘤的生长产生显著的抑制作用, 而这一过程并未伴随明显的毒副作用, 这为肿瘤治疗提供了一种新的思路。Liu等[26]开发了一种基于成纤维细胞膜涂层的TRAIL/氯喹(chloroquine, CQ) 的纳米颗粒递送系统(TM-CQ/NPs), 该系统能有效地逃逸单核吞噬细胞系统(mononuclear phagocyte system, MPS) 并靶向肿瘤组织, 而且能通过TRAIL及其同源死亡受体的相互作用, 特异性地诱导肿瘤细胞凋亡。同时, 封装的CQ进一步抑制了巨噬细胞对NPs的摄取, 延长了NPs在血液中的循环时间, 并与TRAIL协同诱导肿瘤细胞凋亡。该NPs递送系统有效抑制多种肿瘤模型中的肿瘤生长, 且无明显毒性, 在两种小鼠肿瘤模型中都取得了显著的抗肿瘤疗效, 这一创新成果为精准靶向肿瘤组织、提升抗癌疗效提供了一条可行的路径。切除修复交叉互补组2 (excision repair cross complementation, ERCC2) 在DNA损伤修复中发挥着关键作用, Song等[27]将甲氧基聚乙二醇-聚己内酯(methoxypolyethylene glycols-polycaprolactone, MPEG-PCL) 和1, 2-二油酰基-3-三甲基铵-丙烷(1, 2-dioleoyl-3-trimethylammonium-propane, DOTAP) 组成的纳米颗粒(DMC NPs) 与ERCC2的小干扰RNA (siERCC2) 结合, 制备得到了杂化纳米颗粒(DMC-siERCC2)。该研究发现将TRAIL与纳米颗粒DMC-siERCC2结合使用, 能有效抑制胶质母细胞瘤(glioblastoma multiforme, GBM) 细胞增殖并诱导细胞凋亡。在GBM小鼠原位肿瘤模型中, DMC-siERCC2联合TRAIL显著抑制肿瘤生长, 延长小鼠生存期, 且未引起明显的全身毒性。另外, 研究发现DMC-siERCC2杂化NPs通过诱导细胞周期阻滞增强GBM细胞对TRAIL的敏感性, 为GBM治疗提供了一种有前景的联合治疗策略。因此, 将siERCC2与TRAIL治疗相结合, 可能是治疗GBM的一种有前途的治疗方式。
3.3　TRAIL-Mcs递送系统
TRAIL-Mcs递送系统是通过物理包裹、化学偶联或自组装等方法, 使TRAIL与Mcs表面、内部或组成成分共价结合。该递送系统稳定性高, 不易被蛋白酶等破坏, 显著改善其水溶性, 使药物能更好地扩散和运输。
小分子天然化合物荜茇酰胺(piperlongumine, PL) 能使癌细胞对TRAIL敏感, Zhang等[28]制备了一种新型纳米材料-脂质体胶束(micelle-in-liposomes, MILs), 用于溶解和递送PL。首先用聚合物Mcs溶解PL, 然后使用脂质膜水合方法将其封装到LPs的水核心中制备MIL, MIL将PL的水溶性提高了约20倍, 负载了PL的MILs可以使癌细胞对TRAIL敏感。在生理相关缓冲液中, MILs能够持续7天释放PL, 这表明LPs可防止药物从MILs中的Mcs过早释放。PL MIL与脂质体TRAIL联用可对癌细胞产生有效的协同凋亡效应, 为逆转TRAIL耐药提供了一种新的药物递送策略。Zhong[29]构建了一种共载核酸药物与小分子药物的Mcs递药系统γ-PGA/Sali@P-S/pTRAIL, 用于肿瘤的联合治疗。该系统通过低分子质量聚乙烯亚胺(PEI5K) 与硬脂酸偶联形成的两亲性材料P5k-S自组装成Mcs, 内部包裹盐霉素, TRAIL质粒(pTRAIL) 通过与PEI5K吸附结合, 外层包裹γ-聚谷氨酸(γ-PGA), 形成γ-PGA/Sali@P-S/pTRAIL纳米胶束复合物, 实现了两种药物的共载。该复合物借助高渗透长滞留效应(enhanced permeability and retention effect, EPR) 使Mcs在肿瘤部位蓄积, 进入细胞后发生一系列变化: γ-PGA在肿瘤部位响应酸性环境从Mcs表面脱离, 暴露正电荷, 促进肿瘤细胞对Mcs的摄取。Mcs进入肿瘤细胞后, PEI在溶酶体发挥质子海绵效应, 大量氨基吸附溶酶体中的氢离子, 导致胞浆中大量离子内流, 溶酶体破裂, 释放Mcs进入胞浆。随后, 吸附在Mcs中的pTRAIL被释放出来, 肿瘤细胞表达或分泌的TRAIL蛋白因旁观者效应作用于周围肿瘤细胞, 使其发生凋亡。在HeLa裸鼠移植瘤模型实验中, 未经过γ-PGA包裹的Sali@P-S/pTRAIL组由于带有较强的正电荷进入细胞后被网状内皮系统迅速清除, 治疗效果并不佳, 而γ-PGA/Sali@P-S/pTRAIL复合物则实现了80%的肿瘤抑制, 从而说明了该纳米胶束复合物在胞内环境中具有较好的稳定性。本研究为增强TRAIL的肿瘤靶向性、减少不良反应提供了新的思路。
3.4　TRAIL-纳米载体的临床应用研究
TRAIL与纳米载体的联合应用因其既能选择性诱导肿瘤细胞凋亡, 又能改善TRAIL的药代动力学特性、靶向性以及抗肿瘤效果, 而备受关注。注射用埃普奈明于2023年获批上市, 是全球首个完成多发性骨髓瘤Ⅲ期临床试验的促凋亡激动剂, 也是目前全球唯一批准上市的DR4/DR5激动剂[30]。该激动剂通过外源性细胞凋亡途径发挥抗肿瘤作用, 用于联合治疗复发或难治性多发性骨髓瘤成人患者, 虽不是TRAIL与纳米载体的联合制剂, 但为相关联合疗法的临床应用奠定了基础。以治疗腹膜恶性肿瘤为代表的第二代TRAIL受体激动剂(SCB-313) 目前已完成Ⅰ期临床试验, 展现出良好的生物活性和药代动力学特性(NCT0344367); 经基因修饰表达TRAIL的间充质基质细胞(mesenchymal stromal cells genetically modified to express TRAIL, MSCTRAIL) 已完成Ⅰ/Ⅱ期临床试验(NCT03298763), 评估了其在转移性非小细胞肺癌患者中的安全性和抗肿瘤活性[31]。然而, 新型纳米材料、载体表面修饰和响应性纳米载体的应用, 虽能够显著提升TRAIL的性能, 但基于纳米载体的TRAIL制剂尚未有相关药物进入临床试验阶段。随着纳米技术和肿瘤生物学的不断深入, TRAIL与纳米载体的联合疗法有望克服现有障碍, 实现从临床前到临床应用的转化, 为癌症治疗开辟新路径。
4　展望与挑战
收起
TRAIL作为一种具有选择性诱导肿瘤细胞凋亡的细胞因子, 与LPs、NPs、Mcs这些纳米载体结合, 在癌症治疗中展现出巨大的潜力。本文综述了TRAIL与LPs、NPs、Mcs 3种纳米载体在癌症治疗中的联用策略, 总结了以上联合递药系统的设计方案、药物递送方法以及协同抗肿瘤机制。目前, TRAIL与这些纳米载体相结合, 在癌症治疗方面具有提高TRAIL的稳定性、增强肿瘤靶向性、提高生物利用度、克服肿瘤耐药性、实现多模式治疗等优势[23, 26, 29]。但是, 基于纳米载体的TRAIL制剂在癌症治疗中仍面临着一些挑战, 例如, 现有的TRAIL-纳米载体递药系统仍仅停留在动物水平, 尚未有相关药物进入到临床试验阶段。未来, 随着材料科学、纳米技术以及精准医学的不断发展, TRAIL与纳米载体联合治疗将成为癌症治疗的重要手段之一。

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2025年第60卷第9期
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doi: 10.16438/j.0513-4870.2024-1191
  • 接收时间：2024-12-03
  • 首发时间：2026-09-20
  • 出版时间：2025-09-12
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  • 收稿日期：2024-12-03
  • 修回日期：2025-05-12
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    1齐鲁理工学院生物与化学工程学院, 山东 济南 250200
    2山东第一医科大学附属省立医院, 山东 济南 250000

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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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