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Article(id=1308841299541848177, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841198224240856, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0906, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1754150400000, receivedDateStr=2025-08-03, revisedDate=1761667200000, revisedDateStr=2025-10-29, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981682905, onlineDateStr=2026-09-21, pubDate=1781193600000, pubDateStr=2026-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981682905, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981682905, creator=13701087609, updateTime=1789981682905, updator=13701087609, issue=Issue{id=1308841198224240856, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='6', pageStart='1881', pageEnd='2376', issueExtLink='null', onlineDate='null', pubDate='1781193600000', pubDateStr='2026-06-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981658750, creator='13701087609', updateTime=1789984187230, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851803500933401, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841198224240856, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851803500933402, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308841198224240856, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2266, endPage=2274, ext={EN=ArticleExt(id=1308841299873198194, articleId=1308841299541848177, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Preparation and evaluation of intestinal epithelial cell-targeting curcumin micelles, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

This study utilized monomethoxyl poly (ethylene glycol) 2000-poly (ε-caprolactone) 2000 (mPEG2K-PCL2K) and a self-synthesized functional carrier material, fructose-polyethylene glycol 2000-deoxycholic acid (Fru-PEG2K-DC), which targets the apical sodium-dependent bile acid transporter (ASBT) and glucose transporter 5 (GLUT5) on intestinal epithelial cells, to construct fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles/curcumin (FD-PMs/Cur) with the aim of improving drug transintestinal transport efficiency. First, Fru-PEG2K-DC was synthesized via an azide-alkyne click chemical reaction, and the structure of the synthesized product was confirmed by nuclear magnetic resonance (NMR) and infrared spectroscopy (IR). Subsequently, the film dispersion method was employed to prepare curcumin-loaded targeted micelles. The preparation process and formulation of the drug-loaded nanomicelles were optimized and screened based on evaluation indicators such as particle size, polymer dispersity index (PDI), encapsulation efficiency, and drug loading capacity. Finally, in vitro cell experiments were conducted to evaluate the cellular uptake of the constructed targeted formulation and lysosomal escape function. The prepared FD-PMs/Cur exhibited a near-spherical shape, uniform size, and good dispersibility, with an average particle size of 25.86 ± 0.160 4 nm, PDI of 0.169 ± 0.015, and surface charge of -5.74 ± 0.707 mV. The encapsulation efficiency and drug loading capacity were (92.31 ± 0.40)% and (7.69 ± 0.04)%, respectively. The micelles demonstrated slow release and high stability in gastrointestinal fluids. In vitro cell experiments revealed that the targeted micelles significantly enhanced cellular uptake compared to free drugs and non-targeted micelles, indicating excellent intestinal targeting ability and lysosomal escape function. The constructed FD-PMs/Cur exhibited good gastrointestinal stability, intestinal epithelial cell-targeting capability and lysosomal escape function, effectively enhancing transintestinal transport efficiency. This study provides a novel strategy for improving the oral bioavailability of lipophilic drugs.

, authors=Yu-fei LIU1, 2, Yu-wen JIAO1, 2, Qian-nian YANG2, Xue-mei LIU2, Jin-ling WANG1, *, authorsList=Yu-fei LIU, Yu-wen JIAO, Qian-nian YANG, Xue-mei LIU, Jin-ling WANG, authorCompany=null, correspAuthors=Jin-ling WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 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=1308841302729519229, articleId=1308841299541848177, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=肠上皮细胞靶向姜黄素胶束的构建与评价, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本研究以甲氧基聚乙二醇-聚己内酯[monomethoxyl poly (ethylene glycol) 2000-poly (ε-caprolactone) 2000, mPEG2K-PCL2K]、自合成的靶向肠上皮细胞顶端钠依赖性胆汁酸转运蛋白(apical sodium-dependent bile acid transporter, ASBT), 以及葡萄糖转运蛋白5 (glucose transporter 5, GLUT5) 的功能性载体材料果糖-聚乙二醇2000-脱氧胆酸(fructose-polyethylene glycol 2000-deoxycholic acid, Fru-PEG2K-DC) 为载体材料, 以姜黄素为模型药物, 构建肠上皮细胞靶向姜黄素胶束(fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles/curcumin, FD-PMs/Cur), 旨在提高药物的肠吸收及跨肠转运效率。首先采用叠氮-炔基点击化学反应合成了果糖-聚乙二醇-脱氧胆酸(Fru-PEG2K-DC), 并通过核磁共振法及红外光谱法确证合成产物的结构; 然后, 采用薄膜分散法制备肠上皮细胞靶向FD-PMs/Cur, 并以粒径、多分散系数(polymer dispersity index, PDI)、包封率和载药量为评价指标, 对载药纳米胶束的制备工艺和处方进行了优化和筛选; 最后, 通过体外细胞实验考察所构建靶向制剂的细胞摄取及溶酶体逃逸功能。结果表明, 制得的FD-PMs/Cur呈近球形, 大小均一, 分散性良好, 平均粒径为25.86 ± 0.160 4 nm, PDI为0.169 ± 0.015, 表面电荷为-5.74 ± 0.707 mV, 包封率和载药量分别为(92.31 ± 0.40)%和(7.69 ± 0.04)%; 在胃肠液中释放缓慢, 稳定性高; 体外细胞实验结果显示, 与非靶向胶束相较, 靶向胶束能显著提高药物的细胞摄取, 有较好的肠细胞靶向能力; 同时靶向胶束由于修饰胆酸的存在, 具有溶酶体逃逸功能。所构建的FD-PMs/Cur具有良好的胃肠道稳定性、肠上皮细胞靶向能力和溶酶体逃逸功能, 可以有效靶向肠上皮细胞, 提高跨肠转运效率, 为提高脂溶性药物口服生物利用度提供新的思路。

, authors=刘雨菲1, 2, 焦煜雯1, 2, 杨千年2, 刘雪梅2, 王金铃1, *, authorsList=刘雨菲, 焦煜雯, 杨千年, 刘雪梅, 王金铃, authorCompany=null, correspAuthors=王金铃, authorNote=

#

共同第一作者.

作者贡献:

刘雨菲负责细胞摄取定性实验、溶酶体逃逸实验与结果处理, 并负责文章撰写与修改; 焦煜雯负责制剂制备表征、细胞毒性实验、细胞摄取定量实验与结果处理; 杨千年、刘雪梅负责文章修改; 王金铃负责论文设计、实验指导、文章修改与审核。

, correspAuthorsNote=
王金铃，E-mail:
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Nano Res, 2024, 17: 7621-7630., articleTitle=null, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1308841302981177470, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, xref=1, ext=[AuthorCompanyExt(id=1308841302993760383, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, companyId=1308841302981177470, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Modern Research Center for Traditional Chinese Medicine, Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China), AuthorCompanyExt(id=1308841303002148992, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, companyId=1308841302981177470, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1北京中医药大学, 北京中医药研究院, 中药现代研究中心, 北京 102488)]), AuthorCompany(id=1308841303090229377, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, xref=2, ext=[AuthorCompanyExt(id=1308841303094423682, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, companyId=1308841303090229377, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China), AuthorCompanyExt(id=1308841303107006595, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, companyId=1308841303090229377, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2北京中医药大学中药学院, 北京 102488)])], figs=[ArticleFig(id=1308841306672165033, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=EN, label=null, caption=null, figureFileSmall=am7iBIcqDKRoWwx8Z8FHaw==, figureFileBig=nhcwUJMyegRcLyeGafTjlA==, tableContent=null), ArticleFig(id=1308841306751856810, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=CN, label=Fig.1, caption=Synthetic route and verification of targeted materials. A: Synthetic route of Fru-PEG2K-DC; B: 1H NMR spectrum of N3-PEG2K-DC and Fru-PEG2K-DC (CDCl3, 600 MHz); C: IR spectrum of alkynylated fructose and Fru-PEG2K-DC. Fru-PEG2K-DC: Fructose-polyethylene glycol 2000-deoxycholic acid; N3-PEG2K-DC: 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido (polyethylene glycol)-2000], figureFileSmall=am7iBIcqDKRoWwx8Z8FHaw==, figureFileBig=nhcwUJMyegRcLyeGafTjlA==, tableContent=null), ArticleFig(id=1308841306953183403, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=EN, label=null, caption=null, figureFileSmall=Wh0J8eP5060Fm08u0uvc6w==, figureFileBig=jrkxX8a5bCGbmClTM508JQ==, tableContent=null), ArticleFig(id=1308841307049652396, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=CN, label=Fig.2, caption=Formulation characterization and screening of targeted material modification ratio. A: Transmission electron microscope (TEM) analysis of FD-PMs/Cur. Scale bar = 100 nm; B: Cumulative release of cur from FD-PMs/Cur in simulated gastric fluid for 2 h and simulated intestinal fluid for another 24 h; C: Cellular uptake of FD-PMs/Cur in different mass ratio of Fru-PEG2K-DC and mPEG2K-PCL2K. n = 3, $ \overline{x} $ ± s. *P < 0.05. ns: No significant difference; PMs/Cur: Polymeric micelles/curcumin; mPEG2K-PCL2K: Monomethoxyl poly (ethylene glycol) 2000-poly (ε-caprolactone) 2000, figureFileSmall=Wh0J8eP5060Fm08u0uvc6w==, figureFileBig=jrkxX8a5bCGbmClTM508JQ==, tableContent=null), ArticleFig(id=1308841307116761261, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=EN, label=null, caption=null, figureFileSmall=UUxYkSMAKU03Nfau08E0OA==, figureFileBig=2xkTfbn4OxanpY87PjJTJA==, tableContent=null), ArticleFig(id=1308841307188064430, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=CN, label=Fig.3, caption=Gastrointestinal fluid stability of formulations. A, B: Size of PMs/Cur (A) and FD-PMs/Cur (B) in simulated gastric fluid for 2 h; C, D: Size of PMs/Cur (C) and FD-PMs/Cur (D) in simulated intestinal fluid for 8 hours. n = 3, $ \overline{x} $ ± s, figureFileSmall=UUxYkSMAKU03Nfau08E0OA==, figureFileBig=2xkTfbn4OxanpY87PjJTJA==, tableContent=null), ArticleFig(id=1308841307276144815, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=EN, label=null, caption=null, figureFileSmall=gBdyNijwdqMXbmibylv1pw==, figureFileBig=5FtcPEji27mnwnv9L6Z/Iw==, tableContent=null), ArticleFig(id=1308841307381002416, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=CN, label=Fig.4, caption=Cytotoxicity and cellular uptake. Cytotoxicity of polymer of Fru-PEG2K-DC (A) and blank micelles of FD-PMs (B) on Caco-2 cells; C: The intracellular fluorescence intensity of C6, PMs/C6 and FD-PMs/C6 in Caco-2 cells after incubated for 2 h. n = 3, $ \overline{x} $ ± s. ****P < 0.000 1; D: CLSM images of C6, PMs/C6 and FD-PMs/C6 in Caco-2 cells after incubation for 2 h. Scale bar = 50 μm. CLSM: Confocal laser scanning microscopy; C6: Coumarin 6; DAPI: 4', 6-Diamidino-2-phenylindole; Free-C6: Free coumarin 6; PMs/C6: Polymeric micelles/coumarin 6, figureFileSmall=gBdyNijwdqMXbmibylv1pw==, figureFileBig=5FtcPEji27mnwnv9L6Z/Iw==, tableContent=null), ArticleFig(id=1308841307456499889, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=EN, label=null, caption=null, figureFileSmall=++wKDNO3fQVIrm6BE7/nGQ==, figureFileBig=V6evh7S6YjwMco6xCS+SCw==, tableContent=null), ArticleFig(id=1308841307523608754, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=CN, label=Fig.5, caption=Evaluation of cellular uptake with cell concentration and time dependence, and lysosomal escape. The intracellular fluorescence intensity of PMs/C6 and FD-PMs/C6 in different concentrations after incubation for 2 h (A) and different incubation times (B) in Caco-2 cells; C: Lysosome escape of PMs/C6 and FD-PMs/C6 on Caco-2 cells observed by CLSM. Lysosomes were stained by lyso-tracker red. Green fluorescence indicates coumarin 6. Yellow fluorescence indicates the overlay between C6 and lysosomes. Scale bar = 50 μm. n = 3, $ \overline{x} $ ± s, figureFileSmall=++wKDNO3fQVIrm6BE7/nGQ==, figureFileBig=V6evh7S6YjwMco6xCS+SCw==, tableContent=null), ArticleFig(id=1308841307586523315, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
FactorSize/nmPDIEE/%
Drug-to-carrier ratio (w/w)1∶529.08 ± 0.120.211 ± 0.01081.45 ± 2.28
1∶1024.00 ± 0.120.048 ± 0.01791.36 ± 1.02
1∶1524.76 ± 0.050.071 ± 0.00989.77 ± 2.58
Temperature/℃2525.84 ± 0.150.107 ± 0.00486.94 ± 1.87
3724.00 ± 0.120.048 ± 0.01791.36 ± 1.02
5024.03 ± 0.130.042 ± 0.00684.69 ± 1.18
Sonication time/min326.59 ± 0.100.131 ± 0.00687.02 ± 2.23
424.00 ± 0.120.048 ± 0.01791.36 ± 1.02
532.65 ± 0.480.314 ± 0.01988.78 ± 1.90
Hydration time/min533.79 ± 1.040.380 ± 0.01582.13 ± 0.85
1024.00 ± 0.120.048 ± 0.01791.36 ± 1.02
2024.87 ± 0.230.069 ± 0.01490.59 ± 0.23
), ArticleFig(id=1308841307674603700, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841299541848177, language=CN, label=Tab.1, caption=

Formulation optimization of fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles/curcumin (FD-PMs/Cur) in different preparation factors. PDI: Polymer dispersity index; EE: Encapsulation efficiency. n = 3, $ \overline{x} $± s

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FactorSize/nmPDIEE/%
Drug-to-carrier ratio (w/w)1∶529.08 ± 0.120.211 ± 0.01081.45 ± 2.28
1∶1024.00 ± 0.120.048 ± 0.01791.36 ± 1.02
1∶1524.76 ± 0.050.071 ± 0.00989.77 ± 2.58
Temperature/℃2525.84 ± 0.150.107 ± 0.00486.94 ± 1.87
3724.00 ± 0.120.048 ± 0.01791.36 ± 1.02
5024.03 ± 0.130.042 ± 0.00684.69 ± 1.18
Sonication time/min326.59 ± 0.100.131 ± 0.00687.02 ± 2.23
424.00 ± 0.120.048 ± 0.01791.36 ± 1.02
532.65 ± 0.480.314 ± 0.01988.78 ± 1.90
Hydration time/min533.79 ± 1.040.380 ± 0.01582.13 ± 0.85
1024.00 ± 0.120.048 ± 0.01791.36 ± 1.02
2024.87 ± 0.230.069 ± 0.01490.59 ± 0.23
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肠上皮细胞靶向姜黄素胶束的构建与评价
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刘雨菲 1, 2 , 焦煜雯 1, 2 , 杨千年 2 , 刘雪梅 2 , 王金铃 1, *
药学学报 | 研究论文 2026,61(6): 2266-2274
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药学学报 |研究论文 2026 , 61 (6) : 2266 -2274
肠上皮细胞靶向姜黄素胶束的构建与评价
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刘雨菲1, 2, 焦煜雯1, 2, 杨千年2, 刘雪梅2, 王金铃1, *
作者信息
  • 1北京中医药大学, 北京中医药研究院, 中药现代研究中心, 北京 102488
  • 2北京中医药大学中药学院, 北京 102488
通讯作者:
王金铃，E-mail:
作者简介:

#

共同第一作者.

作者贡献:

刘雨菲负责细胞摄取定性实验、溶酶体逃逸实验与结果处理, 并负责文章撰写与修改; 焦煜雯负责制剂制备表征、细胞毒性实验、细胞摄取定量实验与结果处理; 杨千年、刘雪梅负责文章修改; 王金铃负责论文设计、实验指导、文章修改与审核。

Preparation and evaluation of intestinal epithelial cell-targeting curcumin micelles
Yu-fei LIU1, 2, Yu-wen JIAO1, 2, Qian-nian YANG2, Xue-mei LIU2, Jin-ling WANG1, *
Affiliations
  • 1Modern Research Center for Traditional Chinese Medicine, Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
  • 2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
出版时间: 2026-06-12 doi: 10.16438/j.0513-4870.2025-0906
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摘要
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本研究以甲氧基聚乙二醇-聚己内酯[monomethoxyl poly (ethylene glycol) 2000-poly (ε-caprolactone) 2000, mPEG2K-PCL2K]、自合成的靶向肠上皮细胞顶端钠依赖性胆汁酸转运蛋白(apical sodium-dependent bile acid transporter, ASBT), 以及葡萄糖转运蛋白5 (glucose transporter 5, GLUT5) 的功能性载体材料果糖-聚乙二醇2000-脱氧胆酸(fructose-polyethylene glycol 2000-deoxycholic acid, Fru-PEG2K-DC) 为载体材料, 以姜黄素为模型药物, 构建肠上皮细胞靶向姜黄素胶束(fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles/curcumin, FD-PMs/Cur), 旨在提高药物的肠吸收及跨肠转运效率。首先采用叠氮-炔基点击化学反应合成了果糖-聚乙二醇-脱氧胆酸(Fru-PEG2K-DC), 并通过核磁共振法及红外光谱法确证合成产物的结构; 然后, 采用薄膜分散法制备肠上皮细胞靶向FD-PMs/Cur, 并以粒径、多分散系数(polymer dispersity index, PDI)、包封率和载药量为评价指标, 对载药纳米胶束的制备工艺和处方进行了优化和筛选; 最后, 通过体外细胞实验考察所构建靶向制剂的细胞摄取及溶酶体逃逸功能。结果表明, 制得的FD-PMs/Cur呈近球形, 大小均一, 分散性良好, 平均粒径为25.86 ± 0.160 4 nm, PDI为0.169 ± 0.015, 表面电荷为-5.74 ± 0.707 mV, 包封率和载药量分别为(92.31 ± 0.40)%和(7.69 ± 0.04)%; 在胃肠液中释放缓慢, 稳定性高; 体外细胞实验结果显示, 与非靶向胶束相较, 靶向胶束能显著提高药物的细胞摄取, 有较好的肠细胞靶向能力; 同时靶向胶束由于修饰胆酸的存在, 具有溶酶体逃逸功能。所构建的FD-PMs/Cur具有良好的胃肠道稳定性、肠上皮细胞靶向能力和溶酶体逃逸功能, 可以有效靶向肠上皮细胞, 提高跨肠转运效率, 为提高脂溶性药物口服生物利用度提供新的思路。

姜黄素  /  胶束  /  跨肠转运  /  果糖  /  脱氧胆酸

This study utilized monomethoxyl poly (ethylene glycol) 2000-poly (ε-caprolactone) 2000 (mPEG2K-PCL2K) and a self-synthesized functional carrier material, fructose-polyethylene glycol 2000-deoxycholic acid (Fru-PEG2K-DC), which targets the apical sodium-dependent bile acid transporter (ASBT) and glucose transporter 5 (GLUT5) on intestinal epithelial cells, to construct fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles/curcumin (FD-PMs/Cur) with the aim of improving drug transintestinal transport efficiency. First, Fru-PEG2K-DC was synthesized via an azide-alkyne click chemical reaction, and the structure of the synthesized product was confirmed by nuclear magnetic resonance (NMR) and infrared spectroscopy (IR). Subsequently, the film dispersion method was employed to prepare curcumin-loaded targeted micelles. The preparation process and formulation of the drug-loaded nanomicelles were optimized and screened based on evaluation indicators such as particle size, polymer dispersity index (PDI), encapsulation efficiency, and drug loading capacity. Finally, in vitro cell experiments were conducted to evaluate the cellular uptake of the constructed targeted formulation and lysosomal escape function. The prepared FD-PMs/Cur exhibited a near-spherical shape, uniform size, and good dispersibility, with an average particle size of 25.86 ± 0.160 4 nm, PDI of 0.169 ± 0.015, and surface charge of -5.74 ± 0.707 mV. The encapsulation efficiency and drug loading capacity were (92.31 ± 0.40)% and (7.69 ± 0.04)%, respectively. The micelles demonstrated slow release and high stability in gastrointestinal fluids. In vitro cell experiments revealed that the targeted micelles significantly enhanced cellular uptake compared to free drugs and non-targeted micelles, indicating excellent intestinal targeting ability and lysosomal escape function. The constructed FD-PMs/Cur exhibited good gastrointestinal stability, intestinal epithelial cell-targeting capability and lysosomal escape function, effectively enhancing transintestinal transport efficiency. This study provides a novel strategy for improving the oral bioavailability of lipophilic drugs.

curcumin  /  micelle  /  intestinal transport  /  fructose  /  deoxycholic acid
刘雨菲, 焦煜雯, 杨千年, 刘雪梅, 王金铃. 肠上皮细胞靶向姜黄素胶束的构建与评价. 药学学报, 2026 , 61 (6) : 2266 -2274 . DOI: 10.16438/j.0513-4870.2025-0906
Yu-fei LIU, Yu-wen JIAO, Qian-nian YANG, Xue-mei LIU, Jin-ling WANG. Preparation and evaluation of intestinal epithelial cell-targeting curcumin micelles[J]. Acta Pharmaceutica Sinica, 2026 , 61 (6) : 2266 -2274 . DOI: 10.16438/j.0513-4870.2025-0906
正文
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口服给药(oral administration) 作为一种非侵入性且便捷的给药方式, 患者依从性高, 一直是治疗的首选途径。纳米药物递送系统作为药物载体, 可以通过增加药物的溶解性、稳定性、控制药物释放等特性, 提高药物的口服生物利用度和治疗效果[1]。小肠是药物口服吸收的主要部位, 而纳米给药系统口服给药后, 需要穿过肠上皮细胞并以完整的形式进入血液循环, 进而发挥药物治疗疾病的潜能[2]。但是, 纳米制剂在胃肠道的吸收转运过程中, 严重受限于肠上皮细胞屏障, 而纳米制剂要实现有效的跨肠上皮吸收转运需要突破三重细胞屏障, 即顶端内吞、细胞内转运和基底侧胞吐[3]。
近年来, 利用特定配体对纳米制剂进行靶向性修饰已被广泛研究, 修饰后的纳米制剂通过配体-受体结合后, 可以经过特定的途径胞吞入胞、胞吐出胞, 增加纳米制剂的肠上皮细胞摄取与转运, 进而克服肠上皮细胞的顶侧内吞屏障及基底侧胞吐屏障[4]。另外, 纳米制剂进入肠细胞后, 易被细胞内的溶酶体捕获破坏(即胞内转运屏障), 使载药纳米制剂难以顺利到达细胞基底侧膜、胞吐入血液循环而降低疗效[5], 但通过特定途径克服胞内溶酶体屏障、实现溶酶体逃逸, 能显著提高口服疗效。
肠细胞顶侧和基底侧分布很多转运蛋白, 在药物与相关制剂的吸收与转运中起重要作用。肠上皮细胞顶侧的摄取型转运蛋白, 包括葡萄糖转运蛋白5 (glucose transporter 5, GLUT5)、顶端钠依赖性胆汁酸转运蛋白(apical sodium-dependent bile acid transporter, ASBT)、寡肽转运蛋白1 (oligopeptide transporter 1, PEPT1) 等, 可以有效增加药物与相关制剂的细胞摄取; 位于肠上皮细胞基底侧的外排转运蛋白, 主要包括多药耐药转运蛋白3 (multidrug resistance-associated protein 3, MRP3)、多药耐药转运蛋白1 (multidrug resistance-associated protein 1, MRP1)、有机溶质转运蛋白α/β异二聚体(organic solute transporter alpha/beta, OSTα/OSTβ)、葡萄糖转运蛋白2 (glucose transporter 2, GLUT2) 等, 可以将胞内的物质从基底侧胞吐至血液, 增加跨膜转运效率[6-9]。
其中, GLUT5主要负责果糖的肠上皮细胞顶侧的摄取[10]; 而GLUT2负责将肠细胞内的葡萄糖、果糖等单糖从基底侧胞吐至血液循环, 因而果糖修饰纳米制剂表面, 可以通过GLUT5和GLUT2协同增加纳米制剂的肠上皮细胞顶侧摄取及基底侧胞吐。ASBT是一种回肠钠依赖性转运蛋白, 在回肠上皮细胞顶侧表达, 负责将胆汁酸(如胆酸、熊去氧胆酸等) 摄取入肠上皮细胞; 随后胆汁酸通过回肠胆汁酸结合蛋白(ileum bile acid binding protein, IBABP) 被转运至基底侧, 产生溶酶体逃逸; 最后, 胞内的胆汁酸再经由基底侧膜上的OSTα/OSTβ转运出胞[11]。因而, 胆酸修饰可经顶侧ASBT摄取、IBABP转运至基底侧、OSTα/OSTβ转运出胞。
因此, 为了克服纳米制剂的肠上皮细胞屏障, 在纳米制剂进行果糖和胆酸的双重修饰, 可以通过多重转运蛋白介导而增加纳米制剂的肠上皮细胞摄取、胞内运输及跨胞转运, 以提高药物的口服吸收。
姜黄素(curcumin, Cur) 是从姜科和天南星科部分植物根茎中提取的二酮类化合物, 具有抗炎[12]、抗氧化[13]、抗肿瘤[14]等作用, 虽然Cur的药效得到了国内外认可, 但Cur水溶性差、生物利用度低等问题, 限制了其临床应用。综上, 本研究首先合成了兼具肠上皮细胞顶侧ASBT和GLUT5靶向、溶酶体逃逸的果糖-聚乙二醇-脱氧胆酸(fructose-polyethylene glycol 2000-deoxycholic acid, Fru-PEG2K-DC) 的转运体靶向聚合物材料, 然后以Fru-PEG2K-DC和甲氧基聚乙二醇-聚己内酯[monomethoxyl poly (ethylene glycol) 2000-poly (ε-caprolactone) 2000, mPEG2K-PCL2K] 为载体材料, 以Cur为模型药物, 构建肠上皮细胞靶向纳米胶束, 进一步从细胞水平上对所构建胶束的细胞摄取、溶酶体逃逸进行评价。本研究旨在通过转运体靶向纳米制剂, 克服肠上皮细胞屏障, 提高药物的肠上皮细胞摄取、跨肠转运效率, 进而提高药物的口服生物利用度。
材料与方法
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仪器  万分之一电子天平(ME204)、十万分之一电子天平(XS105) 购自梅特勒-托利多仪器(上海) 有限公司; 集热式恒温磁力搅拌器(DF-101S, 巩义市予华仪器有限责任公司); 旋转蒸发仪(R-200, 瑞士步琦有限公司); 核磁共振仪(ARX-300, 美国Varian技术有限公司); 傅里叶变换红外光谱仪(Thermo IS5, 美国赛默飞世尔科技公司); 高分辨透射电子显微镜(JEM-2100, 日本电子株式会社); 冷冻干燥机(Alpha2-4LDplus, 德国Christ公司); 真空干燥箱(DZF-6090, 上海申贤恒温设备厂); 多功能酶标仪(TECAN M1000, 瑞士帝肯集团公司); 激光共聚焦显微镜(Zeiss LSM 800, 北京欧波同光学技术有限公司); Eppendorf高速离心机[德国艾本德(上海) 国际贸易有限公司]; 高效液相色谱仪(LC-20ADXR, 日本岛津公司); 超声破碎仪(CPX500, 北京中科科尔仪器有限公司); 马尔文纳米激光粒度分析仪(Zetasizer Nano ZEN3690, Malvern公司)。
药品与试剂  炔基化果糖、叠氮-聚乙二醇-脱氧胆酸(RM0222101、RF0222829, 西安瑞禧生物科技有限公司); 溴化亚铜(H2121176, 上海阿拉丁生化科技股份有限公司); 抗坏血酸钠(D031S234044)、香豆素6 (coumarin 6, C6, D19HS204500, 纯度≥ 95%) 购自上海源叶生物科技有限公司; Cur [SLBD8415V, 西格玛奥德里奇(上海) 贸易有限公司]; 甲氧基聚乙二醇-聚己内酯(济南岱罡生物工程有限公司); 二甲基亚砜(20230206)、Hoechst 33342 (20250225)、透析袋(20211122, 截留分子质量14 kDa) 购自北京百瑞极生物科技有限公司; 4′, 6-二脒基-2-苯基吲哚(DAPI)、Lyso-Tracker Red (072723240412、A230250505, 上海碧云天生物技术有限公司); CCK-8试剂盒、4%多聚甲醛(K001032551、4500061441, 北京兰博利德商贸有限公司); 胎牛血清(F103-01, 南京诺唯赞生物科技股份有限公司); DMEM高糖培养基(G4511, 武汉赛维尔生物科技有限公司)。
细胞  人结直肠腺癌细胞Caco-2购于南京科佰生物科技有限公司。
Fru-PEG2K-DC的合成  称取适量叠氮-聚乙二醇-脱氧胆酸、炔基化果糖、抗坏血酸钠置于茄形瓶中, 加入5 mL纯水搅拌使其溶解后, 将适量溴化亚铜溶解于DMSO后加入茄形瓶中, 氮气保护, 室温搅拌反应12 h。将溶液转至透析袋(MWCO = 3 500 Da) 中, 于足量超纯水中进行透析, 72 h后将溶液进行真空冷冻干燥, 即得Fru-PEG2K-DC粉末(叠氮-聚乙二醇-脱氧胆酸∶炔基化果糖∶抗坏血酸钠∶溴化亚铜= 1∶1.5∶3∶1, 摩尔比)。
Fru-PEG2K-DC的结构验证
核磁共振光谱法  将适量的Fru-PEG2K-DC放入真空干燥箱内去除样品中的水分, 用氘代氯仿溶解产物并转移至核磁管内, 通过核磁共振氢谱法(600 MHz) 对所合成聚合物的结构进行验证。
红外光谱法  将适量的Fru-PEG2K-DC溶解于甲醇中, 吸取适量溶液均匀地滴在溴化钾窗片上, 并在红外灯下烘干, 在4 000~400 cm-1于红外光谱仪进行测定。
肠上皮细胞靶向Cur胶束的制备
胶束的制备  称取适量的Cur、mPEG2K-PCL2K和Fru-PEG2K-DC, 甲醇溶解后, 转移至100 mL的茄形瓶中, 37 ℃旋转蒸发除去有机溶剂, 向茄形瓶内加入5 mL PBS溶液, 水浴超声5 min, 冰浴下探头超声4 min (200 W, 工作2 s, 间歇2 s), 上清液过0.22 μm滤膜, 即得肠上皮细胞靶向Cur胶束(fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles/curcumin, FD-PMs/Cur)。采用相同方法制备不含Cur的空白纳米胶束(fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles, FD-PMs)。
处方工艺优化  按照上述的制备方法, 以包封率(encapsulation efficiency, EE)、粒径及多分散系数(polydispersity index, PDI) 为指标, 调控胶束制备中Cur的投入量(mPEG2K-PCL2K∶Cur = 15∶1、10∶1、5∶1)、水化温度(25、37、50 ℃)、水化时间(5、10、15 min)、探头超声时间(3、4、5 min), 以优化制备工艺; 同时, 固定mPEG2K-PCL2K与Cur的质量比为10∶1, 调节靶向载体材料Fru-PEG2K-DC与mPEG2K-PCL2K的质量比(1∶20、1∶10、1∶5), 通过细胞摄取实验, 确定靶向材料的比例, 具体操作如下: C6代替Cur加入处方, 制备得到靶向材料修饰不同比例的荧光纳米胶束, 将上述不同靶向比例的荧光胶束与Caco-2细胞共孵育2 h后, 利用酶标仪检测不同组别细胞内摄取的荧光强度。最终, 确定胶束的最优处方和工艺。
非靶向胶束  仅不加入靶向材料Fru-PEG2K-DC, 采用靶向胶束相同的方法制备非靶向Cur胶束(polymeric micelles/curcumin, PMs/Cur)、空白非靶向胶束(polymeric micelles, PMs)。
荧光标记胶束  选用C6作为荧光探针替代Cur, 采用相同方法制备荧光标记的肠上皮细胞靶向胶束(fructose-polyethylene glycol 2000-deoxycholic acid-polymeric micelles/coumarin 6, FD-PMs/C6); 荧光标记的非靶向胶束(polymeric micelles/coumarin 6, PMs/C6), 用于细胞摄取实验。
制剂学评价
粒径分布和电位  制备所得FD-PMs/Cur用PBS作适当稀释后, 混匀加入比色皿中, 利用马尔文纳米激光粒度分析仪测定粒径、PDI和zeta电位。
形态观察  采用透射电镜磷钨酸负染色法观察胶束的形态, 首先将少量的纳米胶束溶液滴加在铜网上, 将铜网放置在烘箱中在37 ℃下烘干30 min, 磷钨酸负染30 s, 自然晾干后, 采用透射电镜(transmission electron microscope, TEM) 观察FD-PMs/Cur的形态。
包封率与载药量的测定  采用高效液相色谱法(high performance liquid chromatography, HPLC) 测定Cur的含量。HPLC色谱方法: 色谱柱为InertSustain C18柱(250 mm × 4.6 mm, 5 µm); 流动相为乙腈-0.3%冰醋酸(60∶40); 柱温为30 ℃; 检测波长430 nm; 流速为1.0 mL·min-1; 进样体积为10 µL。根据公式(1) 和(2) 分别计算EE (%) 和载药量(DL):
$\mathrm{EE}(\%)=\mathrm{Cur} \text { 的包载质量/Cur的投入量 × } 100 \%$
$\begin{aligned}\mathrm{DL}(\%)= & \text { 纳米胶束中药物的含量/纳米胶束的总 } \\& \text { 重量 × } 100 \%\end{aligned}$
Cur标准曲线的绘制  精密称取5.0 mg Cur于10 mL棕色量瓶中, 乙腈溶解并定容至刻度线, 配制成0.5 mg·mL-1的Cur储备液。分别吸取Cur储备液20、40、80、200、1 000、1 600、2 000 µL置于10 mL棕色量瓶内, 加入乙腈稀释定容, 摇匀, 分别制备成1、2、4、10、50、80、100 mg·mL-1的标准溶液。精密吸取10 µL样品注入高效液相色谱仪, 记录峰面积, 以峰面积(y) 为纵坐标, 质量浓度(x) 为横坐标, 以峰面积对质量浓度进行线性回归, 得回归方程为y = 88 505x + 64 696, r = 0.999 1。
人工胃液(simulated gastric fluid, SGF) 的配制  分别称取氯化钠粉末2 g, 胃蛋白酶2 g, 加入1 000 mL去离子水, 磁力搅拌30 min使粉末充分溶解, 然后使用pH计缓慢滴加稀盐酸溶液调节pH至1.2, 即得SGF。
人工肠液(simulated intestinal fluid, SIF) 的配制  分别称取磷酸二氢钾粉末6.8 g, 胰蛋白酶10 g, 加入1 000 mL去离子水, 磁力搅拌30 min使粉末充分溶解, 然后使用pH计缓慢滴加氢氧化钠溶液调节pH至6.8, 即得SIF。
稳定性考察  将一定体积的FD-PMs/Cur分别置于SGF 2 h和SIF 8 h中, 不同时间点测定其粒径, 以评价所制备的靶向胶束FD-PMs/Cur在人工胃肠液中的稳定性。
体外释放  取一定体积的FD-PMs/Cur于透析袋(MWCO = 14 kDa) 中, 然后将透析袋置于SGF中2 h后, 再放入SIF中直至24 h, 室温不断振摇, 分别于0.5、1、2、4、8、12、24 h时间点吸取1 mL释放介质, 并补充等体积对应的新鲜释放介质。同时将各时间点的样品加入10倍体积的甲醇破乳, 按照包封率与载药量的测定项下HPLC色谱方法测定Cur的含量, 根据公式(3) 计算Cur的累积释放百分率(Qa):
$\mathrm{Qa}(\%)=M_n / M \times 100 \%$
其中, Mn为不同时间点释放介质中Cur的累积释放量; M为FD-PMs/Cur中Cur的总质量。
靶向材料Fru-PEG2K-DC和靶向空白胶束FD-PMs的细胞毒性评价  将Caco-2细胞以每孔1×104个细胞的密度接种于96孔板, 24 h后待细胞长至80%, 分别加入靶向材料Fru-PEG2K-DC (5、10、20、30、40、50 μg·mL-1) 及靶向空白胶束FD-PMs (55、110、220、330、440、550 μg·mL-1, 按所对应的Fru-PEG2K-DC的浓度折合成的胶束的质量浓度), 每个浓度设3个复孔, 继续培养24 h后, 吸除药液并每孔加入10 µL CCK-8溶液孵育1 h后, 于酶标仪450 nm处测定细胞的光密度(optical density, OD) 值, 并计算细胞存活率。
FD-PMs/Cur与Caco-2细胞共定位及细胞摄取定量考察  以Caco-2细胞为模型, 分别采用共聚焦显微镜和多功能酶标仪对靶向与非靶向胶束的细胞摄取进行定性和定量的考察。以C6替代Cur, 按照FD-PMs/Cur的制备方法制备得到C6标记的靶向纳米胶束FD-PMs/C6与C6标记的非靶向纳米胶束PMs/C6。激光共聚焦定性考察具体如下: 将Caco-2细胞以每孔5×104个接种于激光共聚焦皿中, 培养24 h后, FD-PMs/C6和PMs/C6与Caco-2细胞共孵育2 h后, 去除药液, PBS洗两次, 4%多聚甲醛固定细胞10 min后, PBS冲洗细胞2次, 加入DAPI培养30 min后, 于共聚焦显微镜下观察FD-PMs/C6和PMs/C6与Caco-2细胞的共定位情况。酶标仪定量考察具体如下: 将Caco-2细胞以每孔5×104个接种于12孔板中, 培养24 h后, 加入FD-PMs/C6和PMs/C6与Caco-2细胞培养2 h后, 去除药液, PBS洗细胞2次后, 多功能酶标仪定量测定细胞摄取情况。
细胞摄取与制剂浓度依赖性评价  采用酶标仪对不同浓度的靶向与非靶向胶束的细胞摄取进行定量考察, 以评价制剂的摄取浓度依赖性。以Caco-2细胞为模型, 将细胞以每孔5×104个接种于12孔板中, 培养24 h后, 去除培养液, 将FD-PMs/C6和PMs/C6 (1、2、5 g·mL-1) 与Caco-2细胞共孵育2 h后, 去除药液, PBS洗细胞两次, 多功能酶标仪测定细胞内FD-PMs/C6和PMs/C6的荧光强度。
细胞摄取与摄取时间依赖性评价  以Caco-2细胞为模型, 定量考察靶向和非靶向胶束与细胞孵育不同时间的细胞摄取情况。Caco-2细胞以每孔5×104个接种于12孔板中, 培养24 h后, 去除培养液, 分别将FD-PMs/C6和PMs/C6与Caco-2细胞共孵育0.5、1和2 h后, 去除药液, PBS洗细胞两次, 多功能酶标仪对细胞内摄取的FD-PMs/C6和PMs/C6荧光强度进行定量。
溶酶体逃逸  以Caco-2细胞为模型, 定性考察靶向胶束溶酶体逃逸情况。操作如下: Caco-2细胞以每孔5×104个接种于激光共聚焦培养皿中, 培养24 h后, 去除培养液, 分别将FD-PMs/C6和PMs/C6与Caco-2细胞共孵育2 h后, 去除药液, PBS洗细胞3次, 于37 ℃条件下, 以100 nmol·L-1 Lyso-Tracker Red染溶酶体(红色) 30 min, Hoechst 33342染细胞核(蓝色) 15 min, 再采用激光共聚焦显微镜观察C6进入Caco-2细胞后, 在细胞内与溶酶体的共定位情况。
数据分析和处理  本研究数据以平均值±标准差的形式来展示。采用GraphPad Prism 9.5进行单因素方差分析和t检验进行数据差异性检验, 对数据进行分析及图表绘制。P < 0.05表示差异具有统计学意义。
结果
收起
1　靶向材料验证
1.1　核磁图谱
Fru-PEG2K-DC与N3-PEG2K-DC的核磁氢谱结果如图1B所示, Fru-PEG2K-DC图谱, δH 2.04~2.60是果糖的信号峰, δH 3.62为PEG的-CH2-信号峰, δH 5.10处为N-CH2单峰信号峰, δH 7.84出现三氮唑环上不饱和氢的单峰信号。将Fru-PEG2K-DC与N3-PEG2K-DC的核磁氢谱进行对比, Fru-PEG2K-DC不仅显示了N3-PEG2K-DC中PEG中亚甲基的质子氢信号峰, 包含了果糖中的质子氢信号峰, 而且出现了Fru-PEG2K-DC中的三氮唑环上不饱和氢的信号峰。上述结果表明, 果糖衍生物与叠氮-聚乙二醇-脱氧胆酸通过化学连接而成功合成了聚合物Fru-PEG2K-DC。
1.2　红外光谱
Fru-PEG2K-DC与炔基化果糖的红外光谱图如图1C所示, 3 356、2 114 cm-1处的吸收振动峰归属于炔基化果糖中果糖的C-H伸缩振动和炔基CC的伸缩振动峰; 而Fru-PEG2K-DC的红外光谱图中, 3 355 cm-1为果糖的C-H伸缩峰(图1C), 但炔基的吸收振动峰消失, 同时1 655 cm-1处的吸收振动峰归属于N3-PEG2K-DC中酰胺基的C=O伸缩振动峰增强。表明炔基化果糖与叠氮-聚乙二醇-脱氧胆酸化学连接成功。
2　FD-PMs/Cur的制备与表征
2.1　FD-PMs/Cur的制备工艺参数优化
采用薄膜分散法制备Cur靶向胶束FD-PMs/Cur, 分别对制备时处方中Cur的投入量、水化温度、水化时间、探头超声时间进行考察, 以优化制备工艺。结果如表1所示, 当mPEG2K-PCL2K∶Cur = 10∶1、水化温度为37 ℃、水化时间为10 min、探头超声时间为4 min时, 制备所得FD-PMs/Cur的EE较高, 且粒径及PDI较小。同时, 通过细胞摄取实验, 优化靶向材料Fru-PEG2K-DC的修饰比例, 当Fru-PEG2K-DC与mPEG2K-PCL2K的质量比为1∶10和1∶5时, 细胞摄取量较高, 且二者没有显著性差异, 最终选择Fru-PEG2K-DC与mPEG2K-PCL2K的质量比为1∶10作为制备靶向纳米胶束的比例。
根据上述实验结果, 靶向Cur胶束的最优处方如下: 称取1 mg Cur、10 mg mPEG2K-PCL2K和1 mg Fru-PEG2K-DC溶解于甲醇后, 于37 ℃旋转蒸发除去有机溶剂, 加入PBS溶液, 水浴超声5 min后, 冰浴下探头超声4 min (200 W, 工作2 s, 间歇2 s), 上清液过0.22 μm滤膜, 即得肠上皮细胞靶向Cur胶束(FD-PMs/Cur)。
2.2　FD-PMs/Cur制剂学性质表征
以最优处方工艺制备靶向Cur胶束FD-PMs/Cur, 其粒径均一、表面呈近电中性, 粒径为25.86 ± 0.16 nm、PDI为0.169 ± 0.015, zeta电位为-5.74 ± 0.707 mV。TEM结果显示, FD-PMs/Cur为近球形, 且粒径较均一(图2A)。
采用透析法, 考察所构建的肠上皮细胞靶向Cur胶束FD-PMs/Cur与非靶向Cur胶束PMs/Cur在模拟胃肠液环境中Cur的释放情况, 以评价制剂在胃肠液中的稳定。结果如图2B所示, PMs/Cur和FD-PMs/Cur在胃肠液中24 h内累计释放量分别为23.48%和17.58%, 二者并无显著性差异, 且两种载药胶束都表现出一定的缓释效果, 表明所构建的胶束在胃肠液中的稳定性较高, 制剂在胃肠液中大部分仍以完整胶束的形式存在, 不但增加了药物的稳定性, 而且能以胶束形式增加药物的摄取、提高药物的口服生物利用度。
考察PMs/Cur和FD-PMs/Cur在胃肠液中的稳定性(图3), PMs/Cur在SGF 2 h内, 胶束粒径变化较小, FD-PMs/Cur在SGF 2 h内, 胶束粒径略微减小, 但整体仍保持在稳定范围内, 说明两种胶束在胃部酸性环境及酶系作用下, 2 h内可稳定存在; 在SIF 8 h内, PMs/Cur和FD-PMs/Cur粒径均先减小后保持稳定, 未出现明显聚集或粒径骤变的情况, 表明两种胶束在肠道中性/弱碱性环境、胰酶体系中, 8 h内仍能维持结构稳定性。综上说明PMs/Cur和FD-PMs/Cur在胃肠液中8 h内能够稳定存在, 具有较好的胃肠道稳定性。
3　靶向材料Fru-PEG2K-DC和靶向空白胶束FD-PMs的细胞毒性评价
采用CCK8法评价靶向材料Fru-PEG2K-DC和FD-PMs对Caco-2细胞的安全性, 如图4A、B所示, 靶向材料Fru-PEG2K-DC及靶向空白胶束FD-PMs (以内含有的靶向材料的浓度计算) 在5~50 μg·mL-1, 细胞相对存活率均高于95%, 表明在此质量浓度范围内Fru-PEG2K-DC和空白靶向胶束FD-PMs对Caco-2细胞无毒性, 具有良好的生物相容性, 可以用于后续的细胞实验。
4　FD-PMs/Cur与Caco-2细胞共定位及摄取定量考察
C6具有较强的荧光强度, 选择C6作为荧光探针替代Cur考察Caco-2细胞对载药纳米胶束的摄取。采用酶标仪测定C6的荧光强度并绘制C6的标准曲线。C6的标准曲线的回归方程为: y = 16 862x + 3 677.8, r = 0.994 8。结果表明, C6质量浓度在0.1~10 μg·mL-1, C6的浓度与荧光强度线性关系良好, 可用于后续细胞实验C6的定量测定。
通过细胞摄取实验分别定性和定量地考察FD-PMs/Cur的肠上皮细胞靶向能力。细胞摄取的定量结果如图4C所示, 相比于C6溶液剂, 靶向和非靶向胶束均显著提高了C6的细胞摄取; 且Caco-2细胞对FD-PMs/C6的摄取量是PMs/C6的1.26倍, 其主要是由于FD-PMs/C6制剂的表面修饰果糖, 能与Caco-2细胞表面的GLUT5转运蛋白结合, 进而增加FD-PMs/C6的细胞摄取, 证实果糖靶向修饰胶束具有更高效的肠上皮细胞靶向摄取能力。通过共聚焦显微镜定性观察Caco-2细胞对FD-PMs/C6和PMs/C6的摄取情况(图4D), FD-PMs/C6和PMs/C6均分布在细胞质内, 定性的摄取结果与定量结果一致, FD-PMs/C6的绿色荧光信号强于PMs/C6, 进一步证实了FD-PMs/C6具有肠上皮细胞GLUT5靶向性, 能显著提高药物及非靶向胶束的细胞摄取。
5　细胞摄取与制剂浓度依赖性评价
定量考察Caco-2细胞摄取量与制剂浓度的依赖性, 制剂的细胞摄取量随着药物浓度的增加而增加, 制剂的细胞摄取具有浓度依赖性, 且不同浓度下, FD-PMs/C6的细胞摄取量均大于PMs/C6 (图5A), 也进一步证实表明自制靶向载体材料Fru-PEG2K-DC修饰纳米胶束增加了胶束的细胞摄取。
6　细胞摄取与摄取时间依赖性评价
定量考察Caco-2细胞摄取量与制剂与细胞孵育时间的依赖性, Caco-2细胞分别与质量浓度为5 μg·mL-1的PMs/C6、FD-PMs/C6共孵育0.5、1、2 h后, 通过酶标仪对细胞内C6的荧光强度进行测定。Caco-2细胞对胶束的摄取量随着摄取时间的延长而增加, 胶束的细胞摄取具有时间依赖性(图5B)。且在不同摄取时间内, FD-PMs/C6的摄取量也显著高于PMs/C6, 上述研究结果表明, 靶向胶束FD-PMs/C6能通过肠上皮细胞表面转运蛋白GLUT5介导而增加细胞摄取。
7　溶酶体逃逸
采用激光共聚焦定性考察靶向纳米胶束FD-PMs/C6的溶酶体逃逸功能, 如果纳米胶束的绿色荧光与溶酶体的红色荧光重合, 表明胶束被溶酶体捕获, 而两者重合显示为黄色, 黄色越深, 表明溶酶体捕获越严重。由图5C清晰可见, 非靶向制剂PMs/C6组比靶向制剂FD-PMs/C6组中溶酶体的红色荧光更为清晰, 且PMs/C6的绿色荧光与溶酶体的红色荧光重合高于FD-PMs/C6, 主要是由于FD-PMs/C6内含有胆酸修饰, 脱氧胆酸可以通过改变膜微结构域来扰动膜结构, 随后与胞内的IBABP结合, 避免溶酶体捕获[15]。本研究证实了Fru-PEG2K-DC靶向材料的修饰使胶束具备溶酶体逃逸功能, 因而所构建的靶向胶束FD-PMs有助于克服溶酶体屏障, 避免制剂的胞内降解与破坏。
讨论
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口服给药具有方便安全、患者服从性高等优点, 但同时也面临诸多挑战, 如药物易受胃肠道pH、酶、菌群及肠黏膜结构的影响, 限制了其口服生物利用度[16]。纳米给药系统能提高药物在胃肠道中的稳定性, 增强药物在胃肠道内的吸收, 在提高药物口服吸收方面具有一定的优势, 但仍受肠上皮细胞屏障的限制, 药物口服吸收提高的程度受限。转运体靶向纳米制剂能通过受体-配体相互作用, 增加纳米制剂的肠上皮细胞摄取, 能一定程度克服肠上皮细胞屏障[17]。
目前, 基于肠上皮细胞表面高表达的转运蛋白, 构建的口服转运体靶向纳米制剂已有相关研究报道, Lei等[18]构建甘露糖-PEG-PLGA纳米粒, 通过甘露糖靶向到肠上皮细胞表面的GLUT1而增加肠吸收、克服肠上皮细胞屏障; 有研究[19]模拟生理果糖肠吸收途径, 制备果糖修饰纳米粒能靶向肠上皮细胞顶侧的GLUT5和基底侧的GLUT2, 促进了纳米制剂从顶侧到基底侧的单向跨上皮细胞转运, 显著提高药物的口服吸收; 缬氨酸修饰TPGS纳米胶束, 能靶向结合PEPT1而吸收、转运, 显著提高制剂的口服吸收效率[20]; 胆汁酸(熊去氧胆酸、脱氧胆酸等) 能与ASBT特异性结合, 甘胆酸[4]或熊去氧胆酸[21]等修饰的纳米制剂能靶向ASBT摄取、具有溶酶体逃逸能力而显著克服肠细胞屏障而提高跨肠转运效率; 另外, 肠上皮细胞表面和肝星状细胞表面均高表达的视黄醇结合蛋白, 能与维生素A特异性结合而提高其肠细胞摄取和肝靶向性, Yu等[22]设计了维生素A修饰的聚合物脂质纳米粒, 能同时靶向肠细胞增加跨肠吸收和靶向肝星状细胞递送, 有效治疗肝纤维化。
因而, 转运体靶向纳米制剂在克服肠细胞屏障、增加口服药物吸收方面具有显著优势。多转运体靶向纳米制剂能通过多种转运蛋白而改善纳米制剂的肠上皮细胞摄取及转运的生物途径和机制, 会更具优势, 但目前转运体靶向制剂的研究多以单一转运蛋白靶向为主要, 以两种或多种转运蛋白为靶点而设计纳米制剂的研究较少。
本研究以Cur为模型药物, 为提高其在胃肠道中的稳定性和口服吸收效率, 构建了果糖和胆酸双修饰的纳米胶束, 其不仅在人工胃肠液内8 h内粒径无明显变化, 24 h内药物释放低于30%, 显著提高药物的胃肠道稳定性; 靶向胶束具有更强的溶酶体逃逸功能, 主要是因为胆酸修饰胶束不仅可以与ASBT结合增加胶束的肠细胞摄取, 而且入胞后能与胞内的IBABP结合而避免被溶酶体捕获、破坏, 提高胶束的胞内稳定性; 同时体外细胞摄取结果显示, Caco-2细胞对FD-PMs/C6的摄取量是PMs/C6的1.26倍, 且具备浓度依赖性和时间依赖性, 主要是由于靶向制剂能够与肠上皮细胞顶侧GLUT5、ASBT受体结合。因而, 所构建的果糖和胆酸双修饰纳米胶束能通过多转运体靶向、溶酶体逃逸等作用而显著提高胶束的肠细胞摄取与转运。
综上所述, 本研究构建了一种肠上皮细胞多转运蛋白靶向的纳米胶束体系, 能有效提高药物的肠上皮细胞顶侧摄取、胞内转运, 为克服肠上皮细胞屏障和口服纳米给药系统的研究提供了新思路, 同时也为其他脂溶性中药成分的递送系统开发提供了参考, 具有较高的研究价值。

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2026年第61卷第6期
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doi: 10.16438/j.0513-4870.2025-0906
  • 接收时间：2025-08-03
  • 首发时间：2026-09-21
  • 出版时间：2026-06-12
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  • 收稿日期：2025-08-03
  • 修回日期：2025-10-29
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    1北京中医药大学, 北京中医药研究院, 中药现代研究中心, 北京 102488
    2北京中医药大学中药学院, 北京 102488

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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
species (%)
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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