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Article(id=1200500170715680931, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200500165426672625, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0858, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1689091200000, receivedDateStr=2023-07-12, revisedDate=1713369600000, revisedDateStr=2024-04-18, acceptedDate=null, acceptedDateStr=null, onlineDate=1764151144913, onlineDateStr=2025-11-26, pubDate=1718121600000, pubDateStr=2024-06-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764151144913, onlineIssueDateStr=2025-11-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764151144913, creator=13701087609, updateTime=1764151144913, updator=13701087609, issue=Issue{id=1200500165426672625, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='6', pageStart='1509', pageEnd='1896', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764151143651, creator=13701087609, updateTime=1764225143180, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200810542001680840, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200500165426672625, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200810542001680841, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200500165426672625, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1794, endPage=1803, ext={EN=ArticleExt(id=1200500172112384222, articleId=1200500170715680931, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Immunotherapy of pancreatic cancer with triptolide combined with ginsenoside Rg3, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Liposome was used as carrier to carry triptolide and ginsenoside Rg3 in the treatment of pancreatic cancer tumor mice. The effects of liposome on the levels of CD4+ and CD8+ microenvironmental immune factors of pancreatic cancer tumor were investigated, and the tumor inhibitory effect and safety were evaluated. In this study, Pan02 cells were used to construct a tumor-bearing C57BL/6 mouse model. After 14 days of treatment, the changes in tumor volume and body weight of tumor-bearing mice were observed. The results showed that the high and low doses of liposome had significant therapeutic effect on tumor volume in the model group (P < 0.01), and the tumor inhibition rate of high doses of liposome was significantly increased compared with triptolide group (P < 0.05). Immunohistochemistry showed that compared with the model group, the tumor inhibition rate of liposome was significantly increased. The high-dose liposome group can up-regulate the ratio of immune factor CD4+/CD8+, inhibit the expression of tumor proliferation factor and promote the expression of tumor apoptosis factor, and has a high safety after pathological hematoxylin and eosin staining of liver, spleen, lung and kidney and serum factor detection. Animal welfare and experimental procedures are in accordance with the regulations of the Experimental Animal Ethics Committee of Henan University of Chinese Medicine (approval No.: DWLL202103173). This study provides a new idea for the exploration of immunotherapy for pancreatic cancer.

, correspAuthors=Hua-hui ZENG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 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=Wen-wen ZHAO, Ting-ting JIANG, Zhi-rong WANG, Yun-yun WANG, Xiang-xiang WU, Hua-hui ZENG), CN=ArticleExt(id=1200500176998748665, articleId=1200500170715680931, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=雷公藤甲素联合人参皂苷Rg3免疫治疗胰腺癌研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本研究以脂质体作为载体包载雷公藤甲素与人参皂苷Rg3, 治疗胰腺癌荷瘤小鼠, 探讨脂质体对胰腺癌肿瘤微环境免疫因子CD4+、CD8+的水平影响, 并对抑瘤效果和安全性进行评价。研究采用Pan02细胞构建荷瘤C57BL/6小鼠模型, 经过14天治疗, 观测荷瘤小鼠肿瘤体积变化和体重变化。结果表明, 脂质体高、低剂量相对于模型组肿瘤体积有明显治疗效果(P < 0.01), 脂质体高剂量相对于雷公藤甲素组抑瘤率有明显提高(P < 0.05), 免疫组化表明, 与模型组相比, 脂质体高剂量组能上调免疫因子CD4+/CD8+比值, 且能抑制肿瘤增殖因子表达, 促进肿瘤凋亡因子表达, 经过肝、脾、肺、肾的病理苏木素-伊红染色和血清因子检测有较高的安全性。该实验方案已通过河南中医药大学实验动物伦理委员会审核批准(编号: DWLL202103173), 动物福利和实验过程均遵循河南中医药大学实验动物伦理委员会的规定。本研究为胰腺癌免疫治疗探索提供了一种新的思路。

, correspAuthors=曾华辉, authorNote=null, correspAuthorsNote=
*曾华辉, Tel: 86-371-86566286, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2024, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=rrQ3wtyXkqecx7Cqn4FgWw==, magXml=LzDrRJiiywc8OK4JBT69Og==, pdfUrl=null, pdf=lqHXAWxslSb8wQHUYqNhnA==, pdfFileSize=5986793, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=mIu4kgnBn3GJjwG8Ecg7wA==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=mExVJjS0RTcDW/yytYiFtw==, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=赵文文, 江婷婷, 王志荣, 汪云云, 武香香, 曾华辉)}, authors=[Author(id=1201118421283992528, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200500170715680931, 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=1201118421447570393, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200500170715680931, authorId=1201118421283992528, language=EN, stringName=Wen-wen ZHAO, firstName=Wen-wen, middleName=null, lastName=ZHAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1. 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Immunol J (免疫学杂志), 2022, 38: 1030-1037., articleTitle=null, refAbstract=null), Reference(id=1201118439386608512, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200500170715680931, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[35], rfOrder=34, authorNames=null, journalName=null, refType=null, unstructuredReference=Gao S, Fang CC, Wang TC, et al. The effect of ginsenoside Rg3 combined with chemotherapy on immune function in non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials [J]. 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A: BUN; B: CRE; C: AST; D: ALT. <i>n</i> = 5, <span class="mag-xml-inline-formula"><tex-math id="M9">$ \overline{x} $</tex-math></span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05. BUN: Blood urea nitrogen; CRE: Creatinine; AST: Glutamic oxaloacetic transaminase; ALT: Alanine aminotransferase , figureFileSmall=wvBJgehvqzemNZE5VRahJg==, figureFileBig=QUtmSNaBhFNNtbFrE5L3ng==, tableContent=null), ArticleFig(id=1201118431031554625, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200500170715680931, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
CompoundLinear equationCoefficient of associationLinearity range /μg·mL-1
TriptolideY = 23 269 x + 52 1910.999 71-500
Ginsenoside Rg3Y = 2 607.7 x + 6 135.90.999 85-500
), ArticleFig(id=1201118431165772363, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200500170715680931, language=CN, label=Table 1, caption=

Regression equations, correlation coefficients and linear ranges of each chemistry

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CompoundLinear equationCoefficient of associationLinearity range /μg·mL-1
TriptolideY = 23 269 x + 52 1910.999 71-500
Ginsenoside Rg3Y = 2 607.7 x + 6 135.90.999 85-500
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Drug loading ratioParticle size /nmPDIZeta electric potential/mVEncapsulation efficiency/% (TP)Drug loading capacity/% (TP)Encapsulation efficiency/% (Rg3)Drug loading capacity/% (Rg3)
5∶1123.93 ± 0.160.20 ± 0.01-14.87 ± 3.0628.62 ± 0.750.15 ± 0.1154.80 ± 1.8911.85 ± 4.89
10∶1135.87 ± 0.310.20 ± 0.01-18.59 ± 2.4158.70 ± 3.130.32 ± 0.0633.90 ± 2.008.63 ± 0.10
30∶1168.90 ± 0.870.22 ± 0.02-20.68 ± 0.8066.00 ± 5.230.23 ± 0.0271.52 ± 5.2023.88 ± 0.21
50∶1119.42 ± 0.620.23 ± 0.01-18.99 ± 2.3290.11 ± 3.070.02 ± 0.0146.81 ± 8.4512.11 ± 2.08
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Lipid-drug ratio in liposomes and including triptolide and ginsenosides Rg3. n = 3, $ \overline{x} $ ± s. PDI: Polymer dispersity index

, figureFileSmall=null, figureFileBig=null, tableContent=
Drug loading ratioParticle size /nmPDIZeta electric potential/mVEncapsulation efficiency/% (TP)Drug loading capacity/% (TP)Encapsulation efficiency/% (Rg3)Drug loading capacity/% (Rg3)
5∶1123.93 ± 0.160.20 ± 0.01-14.87 ± 3.0628.62 ± 0.750.15 ± 0.1154.80 ± 1.8911.85 ± 4.89
10∶1135.87 ± 0.310.20 ± 0.01-18.59 ± 2.4158.70 ± 3.130.32 ± 0.0633.90 ± 2.008.63 ± 0.10
30∶1168.90 ± 0.870.22 ± 0.02-20.68 ± 0.8066.00 ± 5.230.23 ± 0.0271.52 ± 5.2023.88 ± 0.21
50∶1119.42 ± 0.620.23 ± 0.01-18.99 ± 2.3290.11 ± 3.070.02 ± 0.0146.81 ± 8.4512.11 ± 2.08
), ArticleFig(id=1201118431551648356, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200500170715680931, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Time/dayLeakage rate (TP)/%Leakage rate (Rg3)/%
13.19 ± 2.441.20 ± 1.05
34.66 ± 2.354.20 ± 1.33
55.88 ± 3.235.06 ± 2.08
78.03 ± 3.067.97 ± 4.94
1412.74 ± 0.2120.38 ± 8.19
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Leakage rates of TP and Rg3 in liposomes at different time periods. n = 3, $ \overline{x} $ ± s

, figureFileSmall=null, figureFileBig=null, tableContent=
Time/dayLeakage rate (TP)/%Leakage rate (Rg3)/%
13.19 ± 2.441.20 ± 1.05
34.66 ± 2.354.20 ± 1.33
55.88 ± 3.235.06 ± 2.08
78.03 ± 3.067.97 ± 4.94
1412.74 ± 0.2120.38 ± 8.19
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雷公藤甲素联合人参皂苷Rg3免疫治疗胰腺癌研究
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赵文文 1 , 江婷婷 1 , 王志荣 2 , 汪云云 2 , 武香香 2 , 曾华辉 2, *
药学学报 | 研究论文 2024,59(6): 1794-1803
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药学学报 | 研究论文 2024, 59(6): 1794-1803
雷公藤甲素联合人参皂苷Rg3免疫治疗胰腺癌研究
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赵文文1, 江婷婷1, 王志荣2, 汪云云2, 武香香2, 曾华辉2, *
作者信息
  • 1.河南中医药大学药学院, 河南 郑州 450046
  • 2.河南中医药大学中医药科学院, 河南 郑州 450046

通讯作者:

*曾华辉, Tel: 86-371-86566286, E-mail:
Immunotherapy of pancreatic cancer with triptolide combined with ginsenoside Rg3
Wen-wen ZHAO1, Ting-ting JIANG1, Zhi-rong WANG2, Yun-yun WANG2, Xiang-xiang WU2, Hua-hui ZENG2, *
Affiliations
  • 1. College of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou 450046, China
  • 2. College of Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China
出版时间: 2024-06-12 doi: 10.16438/j.0513-4870.2023-0858
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摘要
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本研究以脂质体作为载体包载雷公藤甲素与人参皂苷Rg3, 治疗胰腺癌荷瘤小鼠, 探讨脂质体对胰腺癌肿瘤微环境免疫因子CD4+、CD8+的水平影响, 并对抑瘤效果和安全性进行评价。研究采用Pan02细胞构建荷瘤C57BL/6小鼠模型, 经过14天治疗, 观测荷瘤小鼠肿瘤体积变化和体重变化。结果表明, 脂质体高、低剂量相对于模型组肿瘤体积有明显治疗效果(P < 0.01), 脂质体高剂量相对于雷公藤甲素组抑瘤率有明显提高(P < 0.05), 免疫组化表明, 与模型组相比, 脂质体高剂量组能上调免疫因子CD4+/CD8+比值, 且能抑制肿瘤增殖因子表达, 促进肿瘤凋亡因子表达, 经过肝、脾、肺、肾的病理苏木素-伊红染色和血清因子检测有较高的安全性。该实验方案已通过河南中医药大学实验动物伦理委员会审核批准(编号: DWLL202103173), 动物福利和实验过程均遵循河南中医药大学实验动物伦理委员会的规定。本研究为胰腺癌免疫治疗探索提供了一种新的思路。

脂质体  /  雷公藤甲素  /  人参皂苷Rg3  /  胰腺癌  /  免疫治疗  /  T细胞

Liposome was used as carrier to carry triptolide and ginsenoside Rg3 in the treatment of pancreatic cancer tumor mice. The effects of liposome on the levels of CD4+ and CD8+ microenvironmental immune factors of pancreatic cancer tumor were investigated, and the tumor inhibitory effect and safety were evaluated. In this study, Pan02 cells were used to construct a tumor-bearing C57BL/6 mouse model. After 14 days of treatment, the changes in tumor volume and body weight of tumor-bearing mice were observed. The results showed that the high and low doses of liposome had significant therapeutic effect on tumor volume in the model group (P < 0.01), and the tumor inhibition rate of high doses of liposome was significantly increased compared with triptolide group (P < 0.05). Immunohistochemistry showed that compared with the model group, the tumor inhibition rate of liposome was significantly increased. The high-dose liposome group can up-regulate the ratio of immune factor CD4+/CD8+, inhibit the expression of tumor proliferation factor and promote the expression of tumor apoptosis factor, and has a high safety after pathological hematoxylin and eosin staining of liver, spleen, lung and kidney and serum factor detection. Animal welfare and experimental procedures are in accordance with the regulations of the Experimental Animal Ethics Committee of Henan University of Chinese Medicine (approval No.: DWLL202103173). This study provides a new idea for the exploration of immunotherapy for pancreatic cancer.

liposome  /  triptolide  /  ginsenoside Rg3  /  pancreatic cancer  /  immunotherapy  /  T cell
赵文文, 江婷婷, 王志荣, 汪云云, 武香香, 曾华辉. 雷公藤甲素联合人参皂苷Rg3免疫治疗胰腺癌研究. 药学学报, 2024 , 59 (6) : 1794 -1803 . DOI: 10.16438/j.0513-4870.2023-0858
Wen-wen ZHAO, Ting-ting JIANG, Zhi-rong WANG, Yun-yun WANG, Xiang-xiang WU, Hua-hui ZENG. Immunotherapy of pancreatic cancer with triptolide combined with ginsenoside Rg3[J]. Acta Pharmaceutica Sinica, 2024 , 59 (6) : 1794 -1803 . DOI: 10.16438/j.0513-4870.2023-0858
正文
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癌症一直是全人类面临的共同难题, 其中胰腺癌是致命的恶性肿瘤之一。目前手术切除是胰腺癌的主要治疗手段[1], 但由于胰腺癌被发现时多为中晚期, 导致术后生存率极低, 因此使得新的治疗手段策略不断涌现, 通过改善肿瘤微环境实现肿瘤免疫治疗就是其中之一[2]。胰腺癌的肿瘤微环境存在着多种具有不同功能的免疫细胞[3, 4], 如具有抗肿瘤效应的CD4+、CD8+效应T细胞、自然杀伤NK细胞等。T细胞根据细胞表面分化抗原(cluster of differentiation, CD) 的不同主要分为2个亚组: CD4+和CD8+T细胞。CD4+和CD8+T细胞在抗肿瘤免疫中都起着关键作用, CD4+T细胞可以通过招募CD8+T细胞, 增加其增殖, 并通过干扰素-γ依赖的趋化因子和白介素-2的产生来增强其效应功能[5-7]; 而CD8+T细胞的主要功能亚群是一类毒性T细胞可产生直接杀死肿瘤细胞的作用效果。雷公藤是卫矛科雷公藤属植物, 其入药部位为木制藤本的干燥根[8-10], 有活血通络、消肿定痛的功效[11, 12]。雷公藤甲素(triptolide, TP) 则是由中药雷公藤提取的具有生物活性的三氧化二萜化合物[13, 14]。近代研究发现, TP有良好的抑制肿瘤细胞增殖的作用, 抑制多种肿瘤组织的生长, 包括乳腺癌、肺癌和各种胃肠道肿瘤、胰腺癌等[15-20]。
人参为五加科植物人参的干燥根或根茎[21], 人参皂苷Rg3 (ginsenoside Rg3, Rg3) 是人参中的主要活性成分, 属于四环三菇类人参二醇型皂苷单体[22, 23], 研究发现其具有抗肿瘤[24, 25]、增强免疫功能[26-28]等广泛药理作用。现代研究表明, 人参皂苷Rg3具有多种功效, 如刺激淋巴细胞表达CD4+、提高CD4+T淋巴细胞的活性、促进干扰素-γ (interferon-γ, INF-γ)、肿瘤坏死因子-β (tumor necrosis factor-β, TNF-β) 等抗肿瘤细胞因子的分泌[29]、上调CD4+T/CD8+T比值、增强机体免疫功能[30, 31]等, 可在一定程度上改善肿瘤抑制的免疫微环境, 增强免疫细胞的浸润, 极有可能助力胰腺癌的临床治疗。
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; 通过包载雷公藤甲素与人参皂苷Rg3可促进化药治疗和免疫治疗的治疗效果, 从而实现增效减毒的目的。本研究通过构建一种脂质体, 在动物水平探讨两种药物联用对肿瘤组织的抑制作用和促进T细胞的免疫调节作用, 为其临床应用提供初步依据[32]。
材料与方法
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仪器  AL204精密电子秤(梅特勒-托利多仪器上海有限公司); FreeZone2.5冷冻干燥机(美国Labconco公司); LC-2030C3D Plus高效液相色谱仪(岛津企业管理(中国) 有限公司); HE8433手动挤压器(Genizer公司); KQ3200E超声波清洗机(昆山市超声仪器有限公司); Brookhaven Instruments纳米粒度与zeta电位仪(美国布鲁克海文仪器公司); JEM-1230 (HC) 透射电子显微镜(transmission electron microscope, TEM, 日本电子株式会社)。
药品试剂  雷公藤甲素(HX190617010, 含量≥ 98%, 西安昊轩生物科技有限公司); 人参皂苷Rg3 (MUST-22033111, 含量99.15%, 成都曼思特生物科技有限公司); 大豆卵磷脂(B1504087, 含量 > 98%, 阿拉丁)、聚乙二醇(25322683, 2 kDa) (阿拉丁); 小鼠肌酐(creatinine, CRE) 测定试剂盒(C011-2-1)、小鼠尿素氮(blood urea nitrogen, BUN) 测试盒(C013-1-1)、小鼠(alanine aminotransferase, ALT) 试剂盒(C009-2-1)、小鼠(glutamic oxaloacetic transaminase, AST) 试剂盒(C010-2-1) (南京建成生物工程研究所)。
实验细胞  鼠源胰腺癌细胞(Pan02) 购买于武汉普诺赛生命科技有限公司。
实验动物  健康C57BL/6小鼠100只, 本研究所用动物为SPF级小鼠, 雌性, 体重质量为(20 ± 2) g, 动物生产许可证号为SCXK (豫) 2019-0002, 该实验方案已通过河南中医药大学实验动物伦理委员会审核批准(编号: DWLL202103173)。
脂质体制备  将卵磷脂、聚乙二醇、Rg3和TP按质量比例18∶6∶6∶1在甲醇完全溶解搅拌12 h后, 置于旋转蒸发仪上(30 ℃, 100 r·min-1) 蒸发除去甲醇, 真空干燥箱内干燥12 h, 加入4.0 mL的去离子水, 室温下800 r·min-1磁力搅拌2 h促进薄膜水合, 250 W下超声10 min促进粒子分散, 挤压通过0.22 μm的水系滤头, 放置于超滤离心管(截留分子质量为3 kDa), 冷冻离心机6 000 r·min-1离心20 min, 分离出溶液中游离的TP和Rg3, 即得载药的脂质体(liposomes containing triptolide saponin and ginsenoside Rg3, Rg3-TP-LPs)。
脂质体的粒径分布及zeta电位的测定  将500 µL的脂质体溶液用去离子水稀释至2.0 mL, 使用粒径电位仪的动态光散射法(dynamic light scattering, DLS) 测定脂质体的粒径分布及zeta电位。在90°散射角下测定3次, 得到粒径分布及zeta电位。
脂质体的透射电子显微镜研究  取15 µL的脂质体放置在TEM铜网上。30 min后滤去样品滴, 然后将新配制的1.0%磷酸钨溶液放在透射电镜铜网上15 µL。1 min后, 除去磷酸钨溶液, 用15 μL的去离子水洗涤样品3次。样品在漏斗下清洁的无尘表面上干燥过夜, 用TEM观察并拍摄图像。
包封率和载药量的测定
TP标准曲线的建立  采用高效液相色谱法(high performance liquid chromatography, HPLC) 测定TP的含量, 采用ZORBAX SB-C18色谱柱(4.6 mm × 250 mm, 5 μm); 流动相为乙腈/水(33∶67, v/v); 流动相流速为1.0 mL·min-1; 检测波长为218 nm; 色谱柱温度为25 ℃; 进样量10 μL。配置质量浓度为1、5、10、25、50、80、100、250和500 μg·mL-1的TP标准溶液, 采用HPLC测定不同质量浓度梯度的TP含量。
Rg3标准曲线的建立  采用HPLC测定Rg3的含量, 色谱柱同上; 流动相流速为1.0 mL·min-1; 流动相为乙腈/水(50∶50, v/v); 色谱柱温度为25 ℃; 检测波长为203 nm; 进样量10 μL。配置质量浓度为5、10、20、50、80、100、250和500 μg·mL-1的Rg3标准溶液, 采用HPLC测定不同质量浓度梯度的Rg3含量。
取0.2 mL Rg3-TP-LPs加入1.0 mL无水甲醇, 超声5 min破坏脂质体结构, 通过高效液相色谱法检测其中TP和Rg3的含量。取1 mL脂质体冷冻干燥24 h后称量干燥后剩余固体的质量。分别使用公式(1) 和(2) 计算脂质体包封率和载药量:
$\quad 包封率 = 脂质体内包裹的药物质量 / (脂质体内包\\裹的药物质量 + 未包裹的游离药物质量) × 100\%$
$\quad 载药量 = 脂质体内的药物质量/脂质体的质量 × \\100\%$
载体与药物的投料比考察  根据预实验的结果, 固定卵磷脂/PEG/Rg3比为3∶1∶1, 室温水化和水化时间24 h, 选取载体(卵磷脂、PEG和Rg3) 与TP不同的投料比为5∶1、10∶1、30∶1和50∶1。制备方法如上, 并且以载药量、包封率、粒径为考察因素。
体外稳定性考察  用动态光散射考察了纳米粒子在4 ℃和37 ℃下的稳定性。将600 µL的Rg3-TP-LPs溶液分别用去离子水、PBS和含有10%胎牛血清的DMEM细胞培养基稀释至3.0 mL, 分别放置于4 ℃ (冰箱)、37 ℃ (培养箱) 环境中30天和48 h, 在预定的时间点通过粒径电位仪测定其粒径分布和zeta电位。
脂质体的渗漏率  制备脂质体在4 ℃进行保存, 分别在1、3、5、7、14天时取出脂质体重新测定经过贮藏后的脂质体包封率, 通过公式(3) 计算脂质体的渗漏率:
$\quad 脂质体的渗漏率 = (初始脂质体的包封率 - 贮藏后\\脂质体的包封率)/初始脂质体的包封率 × 100\%$
体外释放  取Rg3-TP-LPs和TP、Rg3溶液各1.0 mL装入(截留分子质量为2 kDa) 透析袋中, 用夹子密封透析袋的两端。取40 mL含有0.5% (v/v) Tween 80的PBS缓冲液(pH = 7.4) 中, 置于37 ℃恒温摇床中, 将缓冲液预热30 min后, 将装有样品的透析袋浸入缓冲溶液中。按照预定的时间点, 再放入0.5、1、2、4、6、8、12、24、36、48 h吸取1 mL缓冲溶液, 同时补充相同体积的新鲜缓冲溶液。
细胞培养  鼠源Pan02细胞使用含有10%胎牛血清、90% DMEM高糖培养基培养, 在显微镜下观察细胞覆盖培养皿底部80%左右进行细胞传代。取对数生长期细胞, 制备瘤细胞悬液, 调整细胞密度为每毫升1×107个。
动物模型制备  收集Pan02细胞并稀释成浓度为每毫升1×107个, 取0.1 mL的细胞悬液注射在小鼠右侧腋下, 构建荷瘤小鼠模型。当肿瘤体积大小生长到80~100 cm3为造模成功标志。游标卡尺测量瘤体的长径和短径, 通过公式(4) 计算瘤体体积:
$体积 = (长径 × 短径^2) / 2$
动物药效学  将造模成功的小鼠随机分为模型组、雷公藤甲素组、人参皂苷Rg3组、雷公藤甲素+人参皂苷Rg3组、脂质体高剂量组、脂质体低剂量组, 随机分组每组5只, 给药剂量为低剂量雷公藤甲素0.2 mg·kg-1, 人参皂苷Rg3为1.2 mg·kg-1; 高剂量为0.4 mg·kg-1, 人参皂苷Rg3为2.4 mg·kg-1, 除人参皂苷Rg3和人参皂苷Rg3+TP采用灌胃给药, 其余组均为尾静脉给药。每两天给药1次, 给药7次, 第15天, 处死小鼠, 剥离肿瘤组织、称重, 并进行苏木素-伊红(hematoxylin and eosin, H&E)、CD4+、CD8+、TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay)、Ki67 (flex monoclonal mouse anti-human Ki67 antigen labeling assay) 免疫组化染色。同时取肝、脾、肺、肾组织, 进行H&E染色, 考察各给药组的生物安全性, 通过公式(5) 计算抑瘤率:
$\quad 抑瘤率 = (对照组平均质量-实验组平均质量) / 对\\照组平均质量 × 100%$
统计学方法  实验数据用均值±标准差($ \overline{x} $ ± s) 表示, 采用统计学软件SPSS2.1.0进行数据分析, 组间比较采用单因素方差分析。
结果
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1 Rg3-TP-LPs的形态、粒径及表面电荷
通过DLS测定Rg3-TP-LPs的粒径分布和zeta电位。Rg3-TP-LPs的粒径为168.90 ± 0.87 nm (图 1A), 分散系数(polymer dispersity index, PDI) 为0.22 ± 0.02, zeta电位为-20.68 ± 0.80 mV (图 1B)。通过透射电镜观察(从左到右为×100 000、×200 000) Rg3-TP-LPs分散呈球形, 可见脂质体典型的环状类指纹结构, 粒径与测定的大小相一致(图 1C、D)。
2 药物测定方法学
测定雷公藤甲素、人参皂苷Rg3的标准工作曲线, 两条标准曲线的相关系数均大于0.999 (表 1), 说明建立了良好的HPLC方法学。
3 载体与药物投料比
可根据制备的粒径、PDI、电位值, 筛选出最佳脂质与雷公藤甲素比例30∶1, 粒径小、分散性良好、负电荷的脂质体(Rg3-TP-LPs), 且包封率、载药量良好(表 2)。测定最佳比例脂质体雷公藤甲素的载药量为0.23% ± 0.02%, 人参皂苷的载药23.88% ± 0.21%, 粒径168.90 ± 0.87 nm, PDI为0.22 ± 0.02, 电位为-20.68 ± 0.80 mV。
4 脂质体稳定性
为考察Rg3-TP-LPs的体外稳定性, 作者将脂质体加入去离子水中并存放在4 ℃的冰箱中, 考察脂质体的储存稳定性。同时将脂质体分别加入PBS和含有10%胎牛血清的DMEM中, 并存放在37 ℃的培养箱中, 模拟细胞培养环境。结果如图 2所示, 在PBS中, 30天内粒径、PDI变化不大; 脂质体在37 ℃ PBS中PDI和zeta可能是受PBS缓冲液中离子的影响, 电位有下降, 但还是相对稳定; 脂质体在10%胎牛血清的DMEM中粒径可能是受其中部分蛋白的影响, 在12 h后有所增加, PDI基本稳定, zeta电位保持稳定, 说明制备的脂质体贮存稳定性良好, 且在模拟环境内能保持基本形态。
5 脂质体的渗漏率
脂质体的渗漏率是评价脂质体储藏稳定性的重要指标之一。脂质体经过一段时间的储藏后, 两种药物的渗漏率如表 3所示, 脂质体在4 ℃条件下随时间的延长, 渗漏率逐步增加, 14天内脂质体的TP的渗漏率均小于15%, Rg3的渗漏率小于30%, 说明脂质体在4 ℃条件下贮藏良好。
6 药物释放
通过HPLC测定样品中的TP、Rg3的含量, 计算TP、Rg3体外累计释放百分率。结果显示, TP呈快速释放的趋势(图 3A), 8 h内已累计释放90%左右, 而脂质体均呈缓慢地释放, 直到24 h时累计释放率才达到顶峰, Rg3的释放远大于脂质体的释放(图 3B), 且脂质体释放速度缓慢, 说明表现出较好的缓释性能。
7 脂质体药效学评价
经过14天内的治疗结果如图 4所示, 与模型组相比, 给药组肿瘤体积都有一定的抑制作用, 其中最后一天Rg3-TP-LPs-L、Rg3-TP-LPs-H的肿瘤体积与模型组相比肿瘤体积抑制率(P < 0.001); 与TP组相比抑制率明显提高(P < 0.05)。
8 小鼠肿瘤H&E组织染色
H&E染色结果如图 5所示, 模型组的肿瘤组织的细胞结构完整、排列整齐、细胞核的染色清晰; TP、TP+Rg3组的肿瘤细胞形态变得膨胀、排列混乱, Rg3-TP-LPs-L组肿瘤细胞核消失; Rg3-TP-LPs-H组肿瘤细胞结构基本受损、细胞排列基本完全混乱。
9 肿瘤免疫组化分析
与模型组相比, TP+Rg3、Rg3-TP-LPs-H、Rg3-TP-LPs-L组的染色结果呈现较强的阳性效果, TP组呈现阴性效果(图 5), 说明脂质体组和混合给药组能够促进肿瘤组织的CD4+的表达。
与模型组相比, TP+Rg3组、脂质体Rg3-TP-LPs-L组、Rg3-TP-LPs-H组呈现阴性结果(图 5), 说明TP+Rg3和脂质体能够抑制肿瘤CD8+的免疫应答, 但是脂质体与两种药物混合组相比对肿瘤组织CD8+的免疫应答抑制效果更明显, 可能与脂质体的生物利用度或药效更高有关。
TUNEL检测结果可见, 与模型组相比, Rg3、Rg3-TP-LPs-L、Rg3-TP-LPs-H组肿瘤细胞被大量染色(图 5), 说明给药后肿瘤凋亡因子大量表达。
模型组肿瘤细胞Ki67染色呈现阳性结果, 说明模型组细胞增殖旺盛。与模型组相比, Rg3-TP-LPs-H、Rg3-TP-LPs-L、TP+Rg3组呈现阴性表达(图 5), 说明给药后肿瘤细胞增殖受到抑制。
10 免疫组化半定量分析
CD4+、CD8+、TUNEL、Ki67, 采用Image J软件对免疫组化进行半定量分析, 结果如图 6所示。雷公藤甲素一定程度地抑制了CD4+和CD8+的表达水平, 人参皂苷Rg3能显著促进CD4+和CD8+因子的表达, 低浓度脂质体能上调CD4+因子水平和下调CD8+因子水平, 而且脂质体组比混合组的CD4+/CD8+比值高, 这可能与脂质体能延缓药物的作用时间有关(图 6A、B)。另外, 值得注意的是两种药物在治疗胰腺癌时, 都能抑制肿瘤细胞增殖, 促进肿瘤凋亡(图 6C、D)。
11 体内安全性评价
11.1 小鼠体重变化
毒性是雷公藤甲素在临床应用中的障碍之一。通过绘制抗癌疗法期间小鼠体重的曲线以评估全身毒性(图 7), 与模型组相比均无明显降低趋势, 说明给药剂量合理, 对小鼠体重无明显影响。
11.2 小鼠组织形态学结果
生物安全性是给药系统评价的重要补充, 对主要脏器的H&E染色结果如图 8所示, 可观测到雷公藤甲素对小鼠肝脏、肾脏和脾脏有一定的损伤, 主要表现为肝细胞索排列紊乱, 肾小管球毛细血管内皮细胞肿胀等, 脾脏红髓与白髓界限模糊, 髓窦扩张, 充有大量的红细胞等, 与模型组相比, Rg3、TP+Rg3、Rg3-TP-LPs-L、Rg3-TP-LPs-H等各组在脾脏、肝脏、肾脏、肺等器官组织无明显的病理损伤, 说明两种药物联合能降低雷公藤甲素对肝脏、脾脏、肾脏的损伤。
11.3 小鼠血清因子测定
BUN、CRE、AST和ALT4项指标(图 9) 异常则表示肝脏和肾脏的功能受损。与模型组相比, TP组的CRE、AST含量显著增加, 说明TP对肾脏和肝脏有一定的损伤; 其他给药组无明显变化趋势, 这些结果与H&E病理结果相符。以上结果证明, 两种药物联用可以有效降低TP对肝脏的毒性。
讨论
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本研究成功构建了以卵磷脂为载体、人参皂苷Rg3代替胆固醇增加双层磷脂的流动性并包载雷公藤甲素的Rg3-TP-LPs脂质体。由于人参皂苷Rg3与胆固醇化学结构相似, 故人参皂苷Rg3代替胆固醇不会影响本脂质体的结构稳定性。本研究分别通过DLS和TEM测得Rg3-TP-LPs的粒径分布、zeta电位和形态结构均符合实验要求, 具有典型脂质体的基本特征。Rg3-TP-LPs脂质体分别在水、PBS和含血清的培养基中保持良好的稳定性, 而且Rg3-TP-LPs脂质体具有良好的缓释性能。因此制备的Rg3-TP-LPs脂质体符合本实验中动物实验的基本要求。
TP和人参皂苷Rg3均具有抗癌作用, 人参皂苷Rg3可以调控机体中CD4+和CD8+细胞因子的表达水平[26, 33], 而发挥抗肿瘤作用。研究结果表明, Rg3-TP-LPs脂质体在动物实验中上调CD4+/CD8+的表达, 调节肿瘤T淋巴细胞亚群比例, 改善肿瘤组织部位T淋巴细胞功能, 从而提高细胞免疫应答, 提高肿瘤部位T淋巴细胞的浸润及抗肿瘤活性, 且能有效抑制肿瘤的生长。TUNEL与Ki67免疫组化染色进一步证实Rg3-TP-LPs脂质体能抑制肿瘤细胞的增殖, 促进肿瘤细胞的凋亡。同时生物安全性考察显示Rg3-TP-LPs能显著改善由TP导致的肝脏、肾脏、脾脏毒性, 脂质体具有良好的生物安全性。综上所述, 人参皂苷Rg3与TP联用并制备脂质体实现了协同抗肿瘤效果, 表现出良好的免疫调节作用, 生物安全性好, 拥有良好的临床应用前景。
肿瘤的发生和发展是一系列复杂的生物学过程。胰腺癌肿瘤微环境中浸润的淋巴细胞以T淋巴细胞为主, 包括CD4+T淋巴细胞和CD8+T淋巴细胞等, 其中CD4+T淋巴细胞是辅助诱导T细胞, 激活后产生大量细胞因子, 增强肿瘤免疫效果, CD8+T淋巴细胞是具有病毒清除和黏附功能的细胞毒性T细胞[34, 35]。CD4+/CD8+的比值衡量机体的免疫状态, 该值越低, 说明细胞对肿瘤的免疫反应能力越差。而肿瘤患者常处于免疫失衡状态, CD4+T细胞减少, CD4+/CD8+降低, 细胞免疫功能紊乱, 因此上调CD4+T细胞/CD8+T细胞比值, 能提高患者的免疫功能, 发挥更强的抗肿瘤作用。
本研究对肿瘤组织样本进行了CD4+、CD8+免疫组化分析, 未对肿瘤微环境进行详细的炎症因子检测, 面对复杂的肿瘤微环境, 本研究仅是初步探索, 未来加快研究进展和扩大样本分析, 期望能够为临床治疗胰腺癌研究提供理论指导。
作者贡献: 曾华辉负责实验设计; 武香香负责对实验进行指导; 赵文文负责主要实验操作及文章的撰写; 江婷婷、王志荣和汪云云协助实验操作及数据分析。
利益冲突: 本文所有作者声明不存在利益冲突关系。
基金
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  • 河南省科技研发计划联合基金(优势学科培育类)-培育项目(222301420060)
  • 河南省优秀青年基金(212300410057)
  • 河南省自然科学基金面上项目(222300420482)
文献
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2024年第59卷第6期
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doi: 10.16438/j.0513-4870.2023-0858
  • 接收时间：2023-07-12
  • 首发时间：2025-11-26
  • 出版时间：2024-06-12
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  • 收稿日期：2023-07-12
  • 修回日期：2024-04-18
基金
河南省科技研发计划联合基金(优势学科培育类)-培育项目(222301420060)
河南省优秀青年基金(212300410057)
河南省自然科学基金面上项目(222300420482)
作者信息
    1.河南中医药大学药学院, 河南 郑州 450046
    2.河南中医药大学中医药科学院, 河南 郑州 450046

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2种不同金属材料的力学参数
科
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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