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Article(id=1200147841520857449, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147837586604797, articleNumber=1001-2494(2024)10-0911-10, orderNo=null, doi=10.11669/cpj.2024.10.008, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1678204800000, receivedDateStr=2023-03-08, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1764067143087, onlineDateStr=2025-11-25, pubDate=1716307200000, pubDateStr=2024-05-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764067143087, onlineIssueDateStr=2025-11-25, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764067143087, creator=13701087609, updateTime=1764067143087, updator=13701087609, issue=Issue{id=1200147837586604797, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='10', pageStart='857', pageEnd='950', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764067142149, creator=13701087609, updateTime=1764067345188, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200148689244225889, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147837586604797, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200148689244225890, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147837586604797, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=911, endPage=920, ext={EN=ArticleExt(id=1200147841973842286, articleId=1200147841520857449, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Construction of Triptolide Prodrug Liposome Nanosystem and Evaluation of Its Anti-Pancreatic Cancer Activity, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To prepare triptolide lignoceric acid ester liposome and characterize it,investigate its therapeutic effect on pancreatic cancer. METHODS Firstly, triptolide lignoceric acid ester liposome was prepared by thin film dispersion method,the single factor test and Box-Behnken response surface method were used to optimize the formulation process. Secondly, liposome form was observed using transmission electron microscope, the particle size, the polydispersity index and Zeta potential of the liposome was observed using Malvin particle size instrument and the initial stability of the TPL-LA-lip was investigated. Finally, the anti-pancreatic activity of TPL-LA-lip in vivo was evaluated by Panc 02 tumor bearing mouse model. RESULTS Triptolide lignoceric acid ester liposome was prepared successfully, and the optimal process and prescription were determined. The liposome was prepared by thin film water method, phospholipid was selected PC-98T, the ratio of drug to phospholipid was 1∶10, cholesterol to phospholipid ratio was 1∶10, DSPE-mPEG2000 was 0.05%, and the preparation temperature was 55 ℃. The liposome was spherical in appearance, the encapsulation rate (EE%) was (98.30±0.32)%, the loading efficiency rate(LE%) was (8.33±0.24)%, the particle size was (105.60±0.01) nm, the Zeta potential was (-34.54±0.17) mV, and had good stability. In PBS medium containing 30% ethanol, the cumulative release of prodrug liposome was 40.35% at 24 h, and it showed good sustained-release effect. At the end of the pharmacokinetics experiment on day 15, the tumor bodies of mice in control, blank lip, TP solution, minnelide and TPL-LA-lip were (849.45±53.72)(880.45±121.45)(602.09±56.80) (265.67±23.12) (237.67±38.30) mm3, respectively. The change rates of body weight were 18.12%, 21.29%, -3.62%, 13.06% and 19.97%, respectively. Compared with the control and TP groups, the TPL-LA-lip group tumor volume was significantly different (P<0.05). In addition, there was no significant difference in body weight between the TPL-LA lip group and the negative control group, while the body weight and organs indexs of the mice treated with TP solution were significantly reduced, indicating the good biological safety of TPL-LA-lip. CONCLUSION The high lipophilic triptolide lignoceric acid ester prodrug greatly improved the formulation druggability of TP, and the liposome produced had high encapsulation rate and good stability. Prodrug technology combined with liposome carrier delivery of TP can significantly enhance the anti-pancreatic cancer effect of the drug, while reducing toxicity, providing a new idea and experimental basis for the development of triptolide prodrug nano drug delivery system.

, correspAuthors=Xin WU, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, 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=Mengmeng LIU, Hang CHEN, Jiecheng QIAN, Lanni FENG, Ruting WEI, Jianming CHEN, Xin WU), CN=ArticleExt(id=1200147843928388026, articleId=1200147841520857449, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=雷公藤甲素前药脂质体纳米递送系统的构建及抗胰腺癌活性评价, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 制备雷公藤甲素木蜡酸酯脂质体(triptolide lignoceric acid ester liposome,TPL-LA-lip),对其进行表征,并考察其对胰腺癌的治疗效果。方法 首先采用薄膜水合法制备TPL-LA-lip,以单因素试验与Box-Behnken 响应面法对处方工艺进行优化筛选;其次对脂质体的形态、粒径分布、Zeta电位及初步稳定性进行表征,并评价其在体外介质中的释放行为;最后采用鼠源胰腺癌细胞(Panc 02)荷瘤小鼠模型,评价TPL-LA-lip的体内抗胰腺癌活性。结果 制备出的TPL-LA-lip呈类球形,粒径分布均一,初步稳定性良好。平均粒径为(105.60±0.01)nm,Zeta电位为(-34.54±0.17)mV,包封率为(98.30±0.32)%,载药量为(8.33±0.24)%。在含有30%乙醇的磷酸盐缓冲液(PBS)介质中,24 h时前药脂质体的体外累积释放度为40.35%,显示出明显的缓释作用。第15天药效学实验结束时,阴性对照、空白脂质体、雷公藤甲素(triptolide,TP)溶液、Minnelide溶液和TPL-LA-lip各组的小鼠肿瘤体积分别为(849.45±53.72)(880.45±121.45)(602.09±56.80)(265.67±23.12)(237.67±38.30)mm3,体质量变化率分别是18.12%、21.29%、-3.62%、13.06%、和19.97%。与阴性对照、TP溶液两组相比,TPL-LA-lip组肿瘤体积具有显著统计学差异(P<0.05);此外,TPL-LA-lip组小鼠体质量及器官指数与阴性对照组无明显差异,而经TP溶液治疗后的小鼠体质量及器官指数明显降低,初步显示出TPL-LA-lip良好的生物安全性。结论 高脂溶性的雷公藤甲素木蜡酸酯前药,改善了TP的制剂成药性,制成的脂质体具有较高的包封率,且稳定性良好。前药技术结合脂质体载体递送TP,可以显著增强药物的抗胰腺癌作用,降低毒副作用,为TP前药纳米给药系统的开发提供新的思路与实验基础。

, correspAuthors=武鑫, authorNote=null, correspAuthorsNote=
*武鑫,男,硕士,高级工程师,硕士生导师 研究方向:纳米靶向给药系统及缓控释给药系统研究 Tel:(021)31198947
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刘梦梦,女,硕士研究生 研究方向:中药制剂与炮制

, authorsList=刘梦梦, 陈行, 钱洁成, 冯兰妮, 魏如婷, 陈建明, 武鑫)}, authors=[Author(id=1200147844603671001, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, 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=1200147844716917220, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, authorId=1200147844603671001, language=EN, stringName=Mengmeng LIU, firstName=Mengmeng, middleName=null, lastName=LIU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1 Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1200147844817580522, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, authorId=1200147844603671001, language=CN, stringName=刘梦梦, firstName=null, middleName=null, lastName=null, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=1, address=1 福建中医药大学, 福州 350122, bio={"content":"

刘梦梦,女,硕士研究生 研究方向:中药制剂与炮制

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刘梦梦,女,硕士研究生 研究方向:中药制剂与炮制

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A-blank liposome; B-TPL-LA solution; C-TPL-LA liposome.

, figureFileSmall=Jqq6H2xNUx3T30gWtEdyJA==, figureFileBig=Kp0K9e6ol46HSR4dvTvdgg==, tableContent=null), ArticleFig(id=1200147849339040369, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=图1, caption=雷公藤甲素木蜡酸酯(TPL-LA)的高效液相色谱(HPLC)专属性色谱图

A-空白脂质体;B-TPL-LA溶液;C-TPL-LA脂质体。

, figureFileSmall=Jqq6H2xNUx3T30gWtEdyJA==, figureFileBig=Kp0K9e6ol46HSR4dvTvdgg==, tableContent=null), ArticleFig(id=1200147849599087223, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Fig.2, caption=The effect of various influencing factors on the EE of TPL-LA-lip. n=3, $\bar{x}±s$

A-the effect of phospholipid types on the EE of TPL-LA-lip; B-the effect of drug and phospholipid ratio on the EE of TPL-LA-lip; C-the effect of cholesterol to phospholipid ratio on the EE of TPL-LA-lip; D-the effect of DSPE-mPEG2000 dosage on the EE of TPL-LA-lip; E-the effect of preparation temperature on the EE of TPL-LA-lip.

, figureFileSmall=7tPOSN3zvN5aMDzxbCK+5A==, figureFileBig=lJZYpdAq8ocoPXebfTUZiw==, tableContent=null), ArticleFig(id=1200147849771053689, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=图2, caption=各影响因素对雷公藤甲素木蜡酸酯脂质体(TPL-LA-lip)包封率的影响. n=3, $\bar{x}±s$

A-磷脂种类对制备TPL-LA-lip包封率的影响;B-不同药脂比例对制备TPL-LA-lip包封率的影响;C-不同胆固醇与磷脂比例对制备TPL-LA-lip包封率的影响;D-不同DSPE-mPEG2000用量对制备TPL-LA-lip包封率的影响;E-不同温度对制备TPL-LA-lip脂质体包封率的影响。

, figureFileSmall=7tPOSN3zvN5aMDzxbCK+5A==, figureFileBig=lJZYpdAq8ocoPXebfTUZiw==, tableContent=null), ArticleFig(id=1200147849913660029, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Fig.3, caption=The response surface of EE as the function of levels and factors of TPL-LA-lip prescription, figureFileSmall=K5SvhZfHPOcFvmbYDwbevA==, figureFileBig=KQNfXaqxaoc06Z6JgT+rAg==, tableContent=null), ArticleFig(id=1200147850085626497, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=图3, caption=TPL-LA-lip处方的各因素相互关系及包封率的三维响应面和等高线图, figureFileSmall=K5SvhZfHPOcFvmbYDwbevA==, figureFileBig=KQNfXaqxaoc06Z6JgT+rAg==, tableContent=null), ArticleFig(id=1200147850245010052, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Fig.4, caption=Particles size distribution(A) and Zeta potential map of TPL-LA-lip(B), figureFileSmall=2TWAuw6axYyFhzX35lpXWw==, figureFileBig=sIivQW7QVTUPnx7mXsB3Mg==, tableContent=null), ArticleFig(id=1200147850354061960, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=图4, caption=TPL-LA-Lip的粒径分布(A)与Zeta电位(B)图, figureFileSmall=2TWAuw6axYyFhzX35lpXWw==, figureFileBig=sIivQW7QVTUPnx7mXsB3Mg==, tableContent=null), ArticleFig(id=1200147850446336652, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Fig.5, caption=TPL-LA-lip in vitro release study. n=3, $\bar{x}±s$, figureFileSmall=Nv5EzdX/wOq4rgPELEU/xg==, figureFileBig=CcZk164vlyOZt7X7bgV97A==, tableContent=null), ArticleFig(id=1200147850567971472, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=图5, caption=TPL-LA-lip体外释放研究. n=3, $\bar{x}±s$, figureFileSmall=Nv5EzdX/wOq4rgPELEU/xg==, figureFileBig=CcZk164vlyOZt7X7bgV97A==, tableContent=null), ArticleFig(id=1200147850672829074, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Fig.6, caption=Panc 02 pancreatic cancer model-antitumor effect evaluation in vivo(×20). n=6, $\bar{x}±s$

A-tumor volume in each group of mice growth curve; B-tumor mass of each group mice; C-survival curves of remaining tumor-bearing mice in each group; D-organs mass of each group; E-organs indexs of each group; F-body mass growth curves of mice in each group; G-representative images of tumor tissues in each group; H-HE of tumor tissues of mice in control group; I-HE of tumor tissues of mice in blank lip group; J-HE of tumor tissues of mice in TP group; K-HE of tumor tissues of mice in minnelide group; L-HE of tumor tissues of mice in TPL-LA-lip group; 1)P<0.05, there were significant differences between groups; 2)P<0.01, there are very significant differences between groups.

, figureFileSmall=ldCkgG7qBzP8sztesE1g4Q==, figureFileBig=0Q1jc7w9gvo3JoPAfU4O7Q==, tableContent=null), ArticleFig(id=1200147850769298071, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=图6, caption=小鼠Panc 02胰腺癌模型-体内抗肿瘤效果评价(×20). n=6, $\bar{x}±s$

A-各组小鼠肿瘤体积变化曲线;B-各组小鼠肿瘤质量;C-剩余荷瘤小鼠生存曲线;D-各组小鼠脏器质量;E-各组小鼠器官指数;F-各组小鼠体质量生长曲线;G-各组小鼠肿瘤组织的代表图;H-生理盐水组肿瘤组织HE;I-空白脂质体组肿瘤组织HE;J-TP组肿瘤组织HE;K-Minnelide组肿瘤组织HE;L-TPL-LA-lip组肿瘤组织HE;组间有显著性差异,1)P<0.05;组间有极显著差异,2)P<0.01。

, figureFileSmall=ldCkgG7qBzP8sztesE1g4Q==, figureFileBig=0Q1jc7w9gvo3JoPAfU4O7Q==, tableContent=null), ArticleFig(id=1200147850882544280, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Tab.1, caption=

Intra-day precision and inter-day precision results of TPL-LA. n=5, $\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Theoretical concentration
/μg·mL-1		 Intra-day precision Inter-day precision
Actual concentration/μg·mL-1 RSD/% Actual concentration/μg·mL-1 RSD/%
5.0 5.05±0.03 0.59 5.16±0.05 0.97
50.0 50.11±0.07 0.14 50.25±0.16 0.32
100.0 100.67±0.81 0.79 100.33±1.17 1.17
), ArticleFig(id=1200147850953847449, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=表1, caption=

TPL-LA日内精密度和日间精密度结果. n=5, $\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Theoretical concentration
/μg·mL-1		 Intra-day precision Inter-day precision
Actual concentration/μg·mL-1 RSD/% Actual concentration/μg·mL-1 RSD/%
5.0 5.05±0.03 0.59 5.16±0.05 0.97
50.0 50.11±0.07 0.14 50.25±0.16 0.32
100.0 100.67±0.81 0.79 100.33±1.17 1.17
), ArticleFig(id=1200147851054510746, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Tab.2, caption=

Results of average recovery of TPL-LA. n=5, $\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Theoretical
concentration
/μg·mL-1		 Actual
concentration
/μg·mL-1		 Recovery
/%		 RSD
/%
5.0 5.12±0.10 101.79±1.95 1.92
50.0 50.39±0.36 100.66±0.73 0.73
100.0 100.17±0.11 100.08±0.11 0.11
), ArticleFig(id=1200147851155174046, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=表2, caption=

TPL-LA的平均回收率. n=5, $\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Theoretical
concentration
/μg·mL-1		 Actual
concentration
/μg·mL-1		 Recovery
/%		 RSD
/%
5.0 5.12±0.10 101.79±1.95 1.92
50.0 50.39±0.36 100.66±0.73 0.73
100.0 100.17±0.11 100.08±0.11 0.11
), ArticleFig(id=1200147851264225954, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Tab.3, caption=

Box-Behnken factors and levels of TPL-LA-lip prescription

, figureFileSmall=null, figureFileBig=null, tableContent=
Levels Factors
X1 X2 X3
-1 1∶5 1∶5 0
0 1∶10 1∶10 0.05
1 1∶20 1∶15 0.2
), ArticleFig(id=1200147851473941156, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=表3, caption=

TPL-LA-lip处方的Box-Behnken设计因素及水平

, figureFileSmall=null, figureFileBig=null, tableContent=
Levels Factors
X1 X2 X3
-1 1∶5 1∶5 0
0 1∶10 1∶10 0.05
1 1∶20 1∶15 0.2
), ArticleFig(id=1200147851608158889, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Tab.4, caption=

Box-Behnken effect surface method test design and corresponding results of TPL-LA-lip prescription

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Factors EE
/%
X1 X2 X3
1 -1 -1 0 76.15
2 1 -1 0 93.70
3 -1 1 0 72.31
4 1 1 0 91.56
5 -1 0 -1 76.40
6 1 0 -1 94.87
7 -1 0 1 76.40
8 1 0 1 95.60
9 0 -1 -1 92.50
10 0 1 -1 88.65
11 0 -1 1 90.52
12 0 1 1 88.62
13 0 0 0 98.56
14 0 0 0 96.12
15 0 0 0 96.45
16 0 0 0 94.90
17 0 0 0 95.60
), ArticleFig(id=1200147851687850667, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=表4, caption=

TPL-LA-lip处方的Box-Behnken响应面试验设计及相应结果表

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Factors EE
/%
X1 X2 X3
1 -1 -1 0 76.15
2 1 -1 0 93.70
3 -1 1 0 72.31
4 1 1 0 91.56
5 -1 0 -1 76.40
6 1 0 -1 94.87
7 -1 0 1 76.40
8 1 0 1 95.60
9 0 -1 -1 92.50
10 0 1 -1 88.65
11 0 -1 1 90.52
12 0 1 1 88.62
13 0 0 0 98.56
14 0 0 0 96.12
15 0 0 0 96.45
16 0 0 0 94.90
17 0 0 0 95.60
), ArticleFig(id=1200147851771736750, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Tab.5, caption=

Results of regression variance analysis of Box-Behnken design-response surface methodology of TPL-LA-lip prescription

, figureFileSmall=null, figureFileBig=null, tableContent=
Source Sum of Squares df Mean Square F P
Model 1 145.35 9 127.26 102.17 <0.000 1
X1 687.65 1 687.65 552.06 <0.000 1
X2 16.33 1 16.33 13.11 0.008 5
X3 0.20 1 0.20 0.16 0.697 2
X1X2 1.00 1 1.00 0.80 0.400 0
X1X3 0.13 1 0.13 0.11 0.753 2
X2X3 0.95 1 0.95 0.76 0.411 3
X12 312.35 1 312.35 250.76 <0.000 1
X22 79.97 1 79.97 64.20 <0.000 1
X32 15.13 1 15.13 12.15 0.010 2
Residual 8.72 7 1.25
Lack of Fit 1.11 3 0.37 0.19 0.895 1
Pure Error 7.61 4 1.90
Cor Total 1 154.07 16
), ArticleFig(id=1200147851901760179, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=表5, caption=

TPL-LA-lip处方的Box-Behnken设计-响应面方法的回归方差分析结果

, figureFileSmall=null, figureFileBig=null, tableContent=
Source Sum of Squares df Mean Square F P
Model 1 145.35 9 127.26 102.17 <0.000 1
X1 687.65 1 687.65 552.06 <0.000 1
X2 16.33 1 16.33 13.11 0.008 5
X3 0.20 1 0.20 0.16 0.697 2
X1X2 1.00 1 1.00 0.80 0.400 0
X1X3 0.13 1 0.13 0.11 0.753 2
X2X3 0.95 1 0.95 0.76 0.411 3
X12 312.35 1 312.35 250.76 <0.000 1
X22 79.97 1 79.97 64.20 <0.000 1
X32 15.13 1 15.13 12.15 0.010 2
Residual 8.72 7 1.25
Lack of Fit 1.11 3 0.37 0.19 0.895 1
Pure Error 7.61 4 1.90
Cor Total 1 154.07 16
), ArticleFig(id=1200147851998229171, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Tab.6, caption=

Preliminary stability of TPL-LA-lip at normal temperature and pressure. n=3, $\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Days Appearance Particle size/nm PDI EE/%
0 Transparent 109.34±1.32 0.15±0.01 98.73±0.97
30 Transparent 109.07±0.55 0.14±0.01 98.62±0.91
90 Transparent 108.63±1.82 0.15±0.01 96.99±0.94
), ArticleFig(id=1200147852119863990, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=表6, caption=

TPL-LA-lip在常温常压下的初步稳定性实验结果. n=3, $\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Days Appearance Particle size/nm PDI EE/%
0 Transparent 109.34±1.32 0.15±0.01 98.73±0.97
30 Transparent 109.07±0.55 0.14±0.01 98.62±0.91
90 Transparent 108.63±1.82 0.15±0.01 96.99±0.94
), ArticleFig(id=1200147852207944378, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=EN, label=Tab.7, caption=

Antitumor effect on Panc 02 pancreatic cancer model of ICR mouse

, figureFileSmall=null, figureFileBig=null, tableContent=
Group ICR mouse beginning/end Mass change/% m(Tumor)/g Tumor inhibition rate/% Relative tumor growth rate(T/C)/%
Control 6/6 18.12 0.52±0.230 - -
Blank lip 6/6 21.29 0.49±0.210 - -
TP 6/6 -3.62 0.28±0.145 46.15 75.91
Minnelide 6/6 13.06 0.11±0.034 77.55 42.23
TPL-LA-lip 6/6 19.97 0.08±0.0461),2) 83.671),2) 36.52
), ArticleFig(id=1200147852526711485, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841520857449, language=CN, label=表7, caption=

对ICR小鼠Panc 02胰腺癌模型的抗肿瘤作用

, figureFileSmall=null, figureFileBig=null, tableContent=
Group ICR mouse beginning/end Mass change/% m(Tumor)/g Tumor inhibition rate/% Relative tumor growth rate(T/C)/%
Control 6/6 18.12 0.52±0.230 - -
Blank lip 6/6 21.29 0.49±0.210 - -
TP 6/6 -3.62 0.28±0.145 46.15 75.91
Minnelide 6/6 13.06 0.11±0.034 77.55 42.23
TPL-LA-lip 6/6 19.97 0.08±0.0461),2) 83.671),2) 36.52
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雷公藤甲素前药脂质体纳米递送系统的构建及抗胰腺癌活性评价
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刘梦梦 1 , 陈行 1, 2 , 钱洁成 1 , 冯兰妮 1 , 魏如婷 1 , 陈建明 1 , 武鑫 1, 2, *
中国药学杂志 | 论著 2024,59(10): 911-920
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中国药学杂志 | 论著 2024, 59(10): 911-920
雷公藤甲素前药脂质体纳米递送系统的构建及抗胰腺癌活性评价
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刘梦梦1, 陈行1, 2, 钱洁成1, 冯兰妮1, 魏如婷1, 陈建明1, 武鑫1, 2, *
作者信息
  • 1 福建中医药大学, 福州 350122
  • 2 上海维洱实验室, 上海 201712

    • 刘梦梦,女,硕士研究生 研究方向:中药制剂与炮制

通讯作者:

*武鑫,男,硕士,高级工程师,硕士生导师 研究方向:纳米靶向给药系统及缓控释给药系统研究 Tel:(021)31198947
Construction of Triptolide Prodrug Liposome Nanosystem and Evaluation of Its Anti-Pancreatic Cancer Activity
Mengmeng LIU1, Hang CHEN1, 2, Jiecheng QIAN1, Lanni FENG1, Ruting WEI1, Jianming CHEN1, Xin WU1, 2, *
Affiliations
  • 1 Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
  • 2 Shanghai Wei Er Lab, Shanghai 201712, China
出版时间: 2024-05-22 doi: 10.11669/cpj.2024.10.008
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摘要
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目的 制备雷公藤甲素木蜡酸酯脂质体(triptolide lignoceric acid ester liposome,TPL-LA-lip),对其进行表征,并考察其对胰腺癌的治疗效果。方法 首先采用薄膜水合法制备TPL-LA-lip,以单因素试验与Box-Behnken 响应面法对处方工艺进行优化筛选;其次对脂质体的形态、粒径分布、Zeta电位及初步稳定性进行表征,并评价其在体外介质中的释放行为;最后采用鼠源胰腺癌细胞(Panc 02)荷瘤小鼠模型,评价TPL-LA-lip的体内抗胰腺癌活性。结果 制备出的TPL-LA-lip呈类球形,粒径分布均一,初步稳定性良好。平均粒径为(105.60±0.01)nm,Zeta电位为(-34.54±0.17)mV,包封率为(98.30±0.32)%,载药量为(8.33±0.24)%。在含有30%乙醇的磷酸盐缓冲液(PBS)介质中,24 h时前药脂质体的体外累积释放度为40.35%,显示出明显的缓释作用。第15天药效学实验结束时,阴性对照、空白脂质体、雷公藤甲素(triptolide,TP)溶液、Minnelide溶液和TPL-LA-lip各组的小鼠肿瘤体积分别为(849.45±53.72)(880.45±121.45)(602.09±56.80)(265.67±23.12)(237.67±38.30)mm3,体质量变化率分别是18.12%、21.29%、-3.62%、13.06%、和19.97%。与阴性对照、TP溶液两组相比,TPL-LA-lip组肿瘤体积具有显著统计学差异(P<0.05);此外,TPL-LA-lip组小鼠体质量及器官指数与阴性对照组无明显差异,而经TP溶液治疗后的小鼠体质量及器官指数明显降低,初步显示出TPL-LA-lip良好的生物安全性。结论 高脂溶性的雷公藤甲素木蜡酸酯前药,改善了TP的制剂成药性,制成的脂质体具有较高的包封率,且稳定性良好。前药技术结合脂质体载体递送TP,可以显著增强药物的抗胰腺癌作用,降低毒副作用,为TP前药纳米给药系统的开发提供新的思路与实验基础。

雷公藤甲素  /  脂质体  /  Box-Behnken 响应面法  /  胰腺癌

OBJECTIVE To prepare triptolide lignoceric acid ester liposome and characterize it,investigate its therapeutic effect on pancreatic cancer. METHODS Firstly, triptolide lignoceric acid ester liposome was prepared by thin film dispersion method,the single factor test and Box-Behnken response surface method were used to optimize the formulation process. Secondly, liposome form was observed using transmission electron microscope, the particle size, the polydispersity index and Zeta potential of the liposome was observed using Malvin particle size instrument and the initial stability of the TPL-LA-lip was investigated. Finally, the anti-pancreatic activity of TPL-LA-lip in vivo was evaluated by Panc 02 tumor bearing mouse model. RESULTS Triptolide lignoceric acid ester liposome was prepared successfully, and the optimal process and prescription were determined. The liposome was prepared by thin film water method, phospholipid was selected PC-98T, the ratio of drug to phospholipid was 1∶10, cholesterol to phospholipid ratio was 1∶10, DSPE-mPEG2000 was 0.05%, and the preparation temperature was 55 ℃. The liposome was spherical in appearance, the encapsulation rate (EE%) was (98.30±0.32)%, the loading efficiency rate(LE%) was (8.33±0.24)%, the particle size was (105.60±0.01) nm, the Zeta potential was (-34.54±0.17) mV, and had good stability. In PBS medium containing 30% ethanol, the cumulative release of prodrug liposome was 40.35% at 24 h, and it showed good sustained-release effect. At the end of the pharmacokinetics experiment on day 15, the tumor bodies of mice in control, blank lip, TP solution, minnelide and TPL-LA-lip were (849.45±53.72)(880.45±121.45)(602.09±56.80) (265.67±23.12) (237.67±38.30) mm3, respectively. The change rates of body weight were 18.12%, 21.29%, -3.62%, 13.06% and 19.97%, respectively. Compared with the control and TP groups, the TPL-LA-lip group tumor volume was significantly different (P<0.05). In addition, there was no significant difference in body weight between the TPL-LA lip group and the negative control group, while the body weight and organs indexs of the mice treated with TP solution were significantly reduced, indicating the good biological safety of TPL-LA-lip. CONCLUSION The high lipophilic triptolide lignoceric acid ester prodrug greatly improved the formulation druggability of TP, and the liposome produced had high encapsulation rate and good stability. Prodrug technology combined with liposome carrier delivery of TP can significantly enhance the anti-pancreatic cancer effect of the drug, while reducing toxicity, providing a new idea and experimental basis for the development of triptolide prodrug nano drug delivery system.

triptolide  /  liposome  /  Box-Behnken response surface methodology  /  pancreatic cancer
刘梦梦, 陈行, 钱洁成, 冯兰妮, 魏如婷, 陈建明, 武鑫. 雷公藤甲素前药脂质体纳米递送系统的构建及抗胰腺癌活性评价. 中国药学杂志, 2024 , 59 (10) : 911 -920 . DOI: 10.11669/cpj.2024.10.008
Mengmeng LIU, Hang CHEN, Jiecheng QIAN, Lanni FENG, Ruting WEI, Jianming CHEN, Xin WU. Construction of Triptolide Prodrug Liposome Nanosystem and Evaluation of Its Anti-Pancreatic Cancer Activity[J]. Chinese Pharmaceutical Journal, 2024 , 59 (10) : 911 -920 . DOI: 10.11669/cpj.2024.10.008
正文
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雷公藤甲素(triptolide, TP)是从卫矛科植物雷公藤(Tripterygium wilfordii Hook. f. )的根、叶、花及果实中提取的一种环氧二萜内酯化合物,具有抗炎、抗类风湿、免疫抑制及抗癌作用[1-3]。大量研究证明,TP对多种癌症如胰腺癌、肺癌以及白血病等有卓越的抗肿瘤活性,是极具潜力的候选药物[4-5]。然而,TP溶解性与制剂成药性差,治疗窗窄、毒副作用大,限制了其在临床上的应用[6]。
随着前药工程研究的深入及纳米药物递送技术的发展,越来越多的难溶性药物纳米给药系统被开发出来应用于抗肿瘤药物递送领域[7-8]。前药技术一方面改善药物的制剂成药性,一方面可延长体内半衰期,降低毒副作用[9]。纳米载体可在体内稳定转运,改善药物分布,通过增强渗透滞留(EPR)效应靶向至肿瘤组织发挥高效治疗作用,减少游离药物对健康组织的直接暴露,提高用药安全性[10]。脂质体作为一种传递系统,早在1985年便已进入了临床研究阶段。从1995年第一个被美国食品药品监督管理局(FDA)批准的脂质体制剂Doxil[11]上市以来,约有20种脂质体制剂相继被批准上市,其中AmBisome和Doxil每年有着数亿的销售额,这些都充分体现了脂质体制剂的应用前景。目前已有不少抗肿瘤药物脂质体相继应用于临床,如紫杉醇脂质体、伊立替康脂质体[12]、阿糖胞苷脂质体[13]等,这为TP脂质体制剂的开发提供了重要的参考。
本研究采用脂质体技术将高度亲脂的雷公藤甲素木蜡酸酯 (TPL-LA)制备成TP前药脂质体纳米递送系统,在优选的处方工艺基础上,评价了其对Panc 02胰腺癌小鼠模型的抗肿瘤效果,为TP前药脂质体的开发提供方法参考与实验基础。
1 仪器与材料
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1.1 仪器
千分之一分析天平(型号:JA103,上海海康电子仪器厂);十万分之一分析天平(型号:XPR205/AC,Mettler-Toledo);水浴超声仪(SK5210HP型,上海KUDOS公司);高效液相色谱系统(型号:Agilent 1260Ⅱ)、色谱柱(型号:ZORBAX Eclipse Plus C18)(美国Agilent公司);涡旋仪(型号:MX-S,美国SCILOGEX公司);电热恒温调速振荡器(型号:SYC-A,上海CIMO公司);旋转蒸发仪(型号:ZX 98-1,上海LOOYE公司);微射流均质机(型号:Nano DeBEE,美国DeBEE公司);过滤挤出器(型号:NanoAble-150,美国PhD公司);Zetasizer分析仪(型号:NANO-ZS 90,英国Malvern公司);透射电子显微镜(型号:JEM-1400,日本电子株式会社);气套式CO2培养箱(型号:Forma 311气套式,Thermo Fisher Scientific公司);超净台(型号:SW-CJ-2D,苏州净化设备公司)。
1.2 药品与试剂
TPL-LA(纯度≥95%,自制);TP(纯度≥98%,Aktin Chemicals);Minnelide(纯度≥96%,广州优瓦科技有限公司);甲醇(MeOH)为色谱纯,正辛醇为分析纯,葡聚糖凝胶(Sephadex G-50,Pharmacia);蛋黄卵磷脂(注射级,艾伟拓医药科技有限公司);二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-mPEG2000)(分析纯,德国Lipoid公司);胆固醇(分析纯,国药集团化学试剂有限公司);胎牛血清、DMEM培养基、双抗溶液(郑州九龙生物制品有限公司);Panc 02(中国科学院细胞库)
1.3 实验动物
实验动物由福建中医药大学动物实验伦理委员会批准,并严格遵守实验动物在医学研究过程中应该遵守的所有伦理原则,选取ICR小鼠50只,♂,4周龄,体质量(20±2) g,由上海雷根生物科技有限公司提供[许可证号:SCXK(苏)2018-006],实验前动物于环境内适应性饲养2~3 d,室温26 ℃,相对湿度50%~60%。
2 方法与结果
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2.1 TP脂质体的制备[14-15]
采用薄膜水合法进行脂质体的制备,称取适量TPL-LA、大豆卵磷脂、胆固醇至圆底烧瓶中,加入适量二氯甲烷溶解,旋转蒸发除去有机溶剂,形成均匀的脂质薄膜,再加入50 mL磷酸盐缓冲液(PBS)振荡水化,置于挤出器中挤出3次,0.22 μm滤膜过滤后,4 ℃冷藏备用。同法制备空白脂质体。
2.2 方法学考察
2.2.1 色谱条件
采用色谱柱:Agilent ZORBAX Eclipse Plus C18柱(4.6 mm×250 mm,5 μm),流动相:100% MeOH,柱温:30 ℃,流速:1.0 mL·min-1,进样量:20 μL,检测波长:218 nm的色谱条件检测样品。
2.2.2 样品溶液的配制
对照品储备液:精密称取10.0 mg TPL-LA至10 mL量瓶中,加入适量MeOH超声溶解,并以MeOH定容至刻度,涡旋混匀,得1.0 mg·mL-1的储备液,于4 ℃保存备用。
供试品溶液:精密吸取500 μL TPL-LA-lip至5 mL量瓶中,加入适量MeOH超声5 min至破乳,定容至刻度,涡旋混匀,即得。
空白脂质体溶液:精密吸取空白脂质体至量瓶中,按供试品溶液相同方法进行配制。
2.2.3 专属性考察
分别取“2.2.2”项下各溶液20 μL注入HPLC,按“2.2.1”项下色谱条件进行分析,结果见图1。由图1可知,在该色谱条件下,TPL-LA峰形良好,保留时间为15.720 min,溶剂及脂质成分不会对TPL-LA的检测产生干扰,表明该方法专属性良好。
2.2.4 线性关系
精密吸取不同体积的对照品储备液,分别稀释得质量浓度为5.0、10.0、25.0、50.0、100.0、250.0和500.0 μg·mL-1的系列溶液。各吸取20 μL注入高效液相色谱仪,按“2.2.1”项下色谱条件进行分析。以质量浓度ρ(μg·mL-1)为横坐标,峰面积A为纵坐标,进行线性回归,建立TPL-LA的标准曲线。
结果可知,TPL-LA溶液经HPLC法测定后,计算TPL-LA的线性回归方程分别为:y=7.009 2x+62.039 0(r2=0.999 9)。结果表明,TPL-LA在5.0~500.0 μg·mL-1内线性关系良好。
2.2.5 精密度考察
分别配制质量浓度为5.0、50.0和100.0 μg·mL-1的TPL-LA溶液各5份,按“2.2.1”项下色谱条件,于1 d内连续进样5次,记录色谱峰面积,计算日内精密度;连续进样5 d,计算日间精密度。实验结果见表1,低、中、高3个质量浓度下,日内精密度相对标准偏差(RSD)分别为0.59%、0.14%、0.79%;日间精密度RSD分别为0.97%,0.32%、1.17%。日内、日间精密度良好,该方法能满足测定需求。
2.2.6 回收率
分别配制质量浓度为5.0、50.0和100.0 μg·mL-1的TPL-LA溶液各5份,按“2.2.1”项下色谱条件分别进样,记录色谱峰面积,代入标准曲线计算浓度,与实际浓度进行比较,计算回收率。实验结果见表2。3个浓度下的平均回收率均分布在100.0%~ 102.0%之间(RSD<2%),该方法可以满足测定需求,用于药物的含量测定。
2.3 脂质体包封率(EE)及载药量(LE)的测定[16]
精密吸取0.2 mLTPL-LA-lip加入制备好的凝胶柱,1 000 r·min-1离心3 min后,收集洗脱液。另精密吸取0.2 mL超纯水,相同条件离心洗涤3次,2次重复操作后分别收集洗脱液于量瓶中,用MeOH溶液稀释并定容,照HPLC含量测定方法测得TPL-LA的浓度,得TPL-LA的游离药物质量浓度ρ游和游离药物质量m游;另精密吸取0.2 mL TPL-LA-lip至相同体积的量瓶中,用MeOH溶液稀释并定容,得TPL-LA的总质量浓度ρ总和总质量m总。取TPL-LA-lip溶液1 mL直接冻干,取冻干粉体称重,即m,TPL-LA-lip的EE与LE的计算见公式1~2。
EE(%)=(ρ总-ρ游)/ρ总×100%
LE(%)=(m总-m游)/m×100%
2.4 单因素考察
2.4.1 磷脂种类的筛选
根据确定的制备工艺,用固定处方:磷脂10.0 mg·mL-1、胆固醇1.0 mg·mL-1、DSPE-mPEG2000 1.0 mg·mL-1、药物含量1.0 mg·mL-1,考察不同种类磷脂如蛋黄卵磷脂(PL-100M)、蛋黄卵磷脂(PC-98T)、氢化大豆磷脂(HSPC)、高纯蛋黄卵磷脂(EPCS)对脂质体EE的影响。实验结果见图2A,PC-98T磷脂对药物具有高包封率,且脂质体粒径与PDI均较小,故优选其作为制备脂质体的磷脂。
2.4.2 药脂比例筛选
根据相同的制备条件,用固定处方:磷脂10.0 mg·mL-1;胆固醇1.0 mg·mL-1;DSPE-mPEG2000 1.0 mg·mL-1;药物含量1.0 mg·mL-1,考察药物/磷脂质量比为1∶5、1∶10、1∶20、1∶30条件对脂质体粒径分布及EE的影响,结果见图2B。随着药脂比的增大,EE具有明显的提升,当药脂比达到1∶10时,脂质体粒径分布窄、EE高,且基本趋于稳定。故选择药脂比为1∶10作为处方量。
2.4.3 胆固醇与磷脂的比例筛选
根据相同的制备条件,用固定处方:磷脂10.0 mg·mL-1;胆固醇1.0 mg·mL-1;DSPE-mPEG2000 1.0 mg·mL-1;药物含量1.0 mg·mL-1,考察胆固醇/磷脂质量比为1∶2、1∶5、1∶10、1∶20、1∶50条件对脂质体粒径分布及EE的影响,结果见图2C。当脂质体加入胆固醇/磷脂比例为1∶10时,EE更高,粒径分布较窄,并且随着胆固醇与磷脂比例的减少,EE、粒径、多分散系数(PDI)趋于稳定。故优选胆固醇/磷脂比例为1∶10作为处方量。
2.4.4 DSPE-mPEG2000的用量筛选
根据相同的制备条件,用固定处方:磷脂10.0 mg·mL-1;胆固醇1.0 mg·mL-1;药物含量1.0 mg·mL-1;DSPE-mPEG2000为0、0.2、0.5、2.0、4.0 mg·mL-1条件对脂质体粒径分布及EE的影响。由图2D结果可知,随着DSPE-mPEG2000用量的增加,脂质体EE呈先上升后下降的趋势。且在制备过程中发现,当加入一定DSPE-mPEG2000时,增加了脂质体过膜的顺畅性。而DSPE-mPEG2000用量为0.5 mg·mL-1时,EE更高,粒径分布更窄,因此0.5 mg·mL-1 DSPE-mPEG2000用量为优选用量。
2.4.5 制备温度的筛选
根据相同的制备条件,用固定处方:磷脂10.0 mg·mL-1;胆固醇1.0 mg·mL-1;DSPE-mPEG2000 0.5 mg·mL-1;药物含量1.0 mg·mL-1,考察脂质体制备温度为40、45、55、60 ℃对脂质体粒径分布及EE的影响,结果见图2E。当制备温度较低时,TPL-LA-lip的粒径和PDI偏大,溶液出现浑浊,透明度低;随着温度的上升,TPL-LA-lip粒径分布和EE均较为稳定且符合脂质体制备工艺的要求。但考虑到温度过高可能会造成前药的降解,故选择55℃作为脂质体的最佳制备温度。
2.5 Box-Behnken响应面法优化制剂
2.5.1 因素与水平
在脂质体处方工艺的单因素考察基础上,采用Box-Behnken效应面法对处方进一步考察优化。固定药物含量(1.0 mg·mL-1),以药脂比(X1)、胆固醇与磷脂比例(X2)和DSPE-mPEG2000用量(X3)对脂质体粒径分布及EE影响较大的3个因素,并以EE为评价指标,对TPL-LA-lip处方进行三因素三水平的试验设计,试验设计见表3,结果见表4~5。
2.5.2 模型的建立及其显著性检验
根据Design-expert软件绘制的相应三维响应面和二维等高线图(图3)可以看出,药脂比(X1)对TPL-LA-lip脂质体的EE影响最为显著,随着X1的增加EE明显升高;而胆固醇/磷脂的比例(X2)和DSPE-mPEG2000含量(X3)对TPL-LA-lip脂质体的EE影响相对较小。
2.5.3 最佳工艺的确定和验证
(利用软件中Optimization的Numerical功能,以最高EE%为出发点,拟合确定最佳处方为药脂比为12.67,胆固醇/磷脂为9.79,DSPE-mPEG2000用量为0.15。根据预测所得最佳处方进行脂质体的制备,测得脂质体包封率为(98.30±0.32)%(n=3)与预测值98.90%接近),载药量为(8.33±0.24)%,模型建立可靠。
2.6 脂质体表征
2.6.1 外观及透射电镜(TEM)观察结果
移取适量TPL-LA-lip滴在喷碳铜网表面,使脂质体沉降到铜网中,再用2%磷钨酸负染3 min,自然晾干后在高分辨透射电子显微镜下观察TPL-LA-lip的形态,结果见图4A。由图4A可见,制备得到的TPL-LA-lip为均一、稳定的具淡蓝色乳光的半透明至透明的液体。可观察到TPL-LA-lip外观呈球形或类球形。
2.6.2 粒径及电位的测定
利用马尔文粒度仪测定TPL-LA-lip的粒径和Zeta电位。测定方法为移取100 μL TPL-LA-lip至比色皿中,加入1 mL纯化水稀释后重复测定3次,记录测得粒径、PDI以及Zeta电位结果,结果见图4B。TPL-LA-lip的粒径为(105.60±0.01 )nm(n=3),呈单峰,PDI为(0.10±0.02)(n=3),Zeta电位为(-34.54±0.17) mV(n=3)。
3 TPL-LA-lip的初步稳定性研究
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对新制备的 TPL-LA-lip 溶液置于常温常压下的稳定性进行了探究,分别于第0、30、90天取出,分别测定粒径、PDI和EE,通过外观、粒径、PDI和EE的变化初步考察TPL-LA-lip 的稳定性,结果见表6。实验表明,90 d内TPL-LA-lip 初步稳定性良好。
4 TPL-LA-lip的体外累积释放度研究
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通过药物释放试验,定量检测了TPL-LA-lip的体外释放动力学。采用含30%乙醇的PBS作为释放介质,向200 mL溶出杯中加入100 mL释放介质,(37±0.5)℃,搅拌速度为100 r·min-1,投药前预先使释放介质受热并搅拌均匀,随后用移液器移取脂质体样品(1 mL)置于盛有适量体积释放介质的溶出杯中,恒温匀速搅拌,分别于0.5、1、2、4、6、8、12、24 h各时间点取样2 mL,并立即补充新鲜释放介质。随后样品用0.22 μm尼龙滤膜过滤。精密吸取100 μL供试品溶液于5 mL量瓶中,用甲醇稀释并定容,涡旋混合1 min后,20 μL进样量进行含量测定。体外累积释放率(cr)的计算见公式3。
cr(%)= c n L / V 2 + ( c n - 1 + … + c 2 + c 1 ) V 1 L×100%
式中:cn为每个时间点的样品浓度;L为制剂标示量;V1为每个时间点的固定取样体积;V2为释放介质体积。实验结果见图5。采用含30%乙醇的PBS作为释放介质时,在8 h内TP释放达到90%以上;而TPL-LA-lip整体释放较慢,且24 h的累积释放度仅为40.35%,表明前药脂质体有良好的缓释作用。
5 TP脂质体药效学评价
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5.1 肿瘤细胞培养以及胰腺癌模型的构建[17]
复苏培养Panc 02胰腺癌细胞,培养一段时间后,选取对数生长期的肿瘤细胞,PBS冲洗2~3次,胰酶消化成单细胞悬液,1 000 r·min-1离心9 min后弃上清液,加入定量PBS重悬细胞后,调节细胞密度至1×107·mL-1。将Panc 02细胞接种于小鼠右侧腋窝,建立小鼠的胰腺癌模型。
5.2 分组给药
待肿瘤体积生长至100~150 mm3时,将小鼠按瘤体积分别随机分为5组。小鼠Panc 02胰腺癌模型中,每隔3 d分别静脉注射生理盐水、Blank lip、TP溶液、Minnelide和TPL-LA-lip,共计4次,各治疗组TP剂量均为0.30 mg·kg-1;治疗期间监测荷瘤动物的肿瘤体积[TV,TV(mm3)=a×b2/2,“a”和“b”分别表示肿瘤的长径和短径]和体质量,在最后一次给药3~5 d后,剖取各组小鼠重要器官与肿瘤并称重,最后计算各治疗组的肿瘤抑制率(TIR,公式4)以及相对肿瘤增殖率(T/C,公式5)。
TIR(%)=(mcontrol-mtreat)/mcontrol×100%
mcontrol和mtreat分别代表对照组和治疗组肿瘤的平均质量)。
T/C(%)=RTV(治疗组)/RTV(对照组)×100%
RTV为相对肿瘤体积;RTV=TVt/TV0,其中TV0为分组时测量的肿瘤体积,TVt代表每次测量时的肿瘤体积。器官指数=小鼠器官质量/小鼠质量。
5.3 苏木素-伊红(HE)染色
在最后一次给药后隔天处死小鼠,剖取各组肿瘤组织,并迅速以4%多聚甲醛固定液固定,进行石蜡包埋,切片,HE染色,于显微镜下观察各组肿瘤组织微观结构。
5.4 实验结果
如图6所示,与接受TP(0.30 mg·kg-1)的小鼠相比,TPL-LA-lip(0.59 mg·kg-1,与TP等剂量)可显著抑制小鼠Panc 02胰腺癌肿瘤的生长。值得注意的是,TPL-LA-lip组小鼠从治疗第4天开始便出现肿瘤消退现象,TPL-LA-lip对肿瘤生长的抑制作用更加显著。
此外,TPL-LA-lip在小鼠体内的耐受性良好,未出现有体质量减轻现象(图6F);图6D~E说明TPL-LA-lip组小鼠脏器质量与阴性对照无明显差异,而经TP溶液治疗后的小鼠体重及器官指数明显降低,显示出TPL-LA-lip良好的生物安全;从表7可知,等剂量条件下,TP溶液组肿瘤抑制率仅46.15%,而TPL-LA-lip组的抑瘤率可达到83.67%,组间差异具有统计学意义(P<0.05);TPL-LA-lip组与Minnelide组相比,其抑瘤率高于Minnelide,但并无统计学差异,说明与阳性药达到等效的作用,但经脂质体包载后,可以增加生物安全性同时提高了药物的抗肿瘤疗效。
TP组肿瘤组织切片显示局部有少量肿瘤细胞死亡,Minnelide也有大量肿瘤细胞凋亡,但其凋亡程度小于TPL-LA-lip,TPL-LA-lip导致了大量的瘤内凋亡,肿瘤细胞膜皱缩,细胞核增大或变形,肿瘤组织出现较多坏死;这也进一步体现了TPL-LA-lip更显著的抗肿瘤作用(图6L)。
另外,为了评估TPL-LA-lip对荷瘤小鼠长期的治疗作用,实验还记录了动物的总体存活时间。60 d为观察期限,结果显示,生理盐水组动物在30 d内全部死亡,接受TP的小鼠在第17天出现死亡,在观察期限内无小鼠存活。而接受TPL-LA-lip的小鼠60 d内均未出现死亡,期限内仅有2只小鼠死亡,由TPL-LA-lip治疗的荷瘤小鼠生存期得以显著延长(图6C)。
6 讨论
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本研究选择薄膜水合法制备脂质体,简单快速、条件温和、成功制备出了雷公藤甲素前药脂质体。将前药技术和脂质体递送技术相结合,不仅改善了TP成药性差的问题,还可以更好地发挥抗肿瘤疗效且降低毒副作用。
单因素考察筛选出对 TPL-LA-lip 的EE影响较大的3个因素,通过Box-Behnken 响应面法,可以减少试验次数,从而得到较优的处方工艺参数。根据最优工艺参数所制备的脂质体,实测值与预测值偏差较小,表明 Box-Behnken 响应面具有较好的预测性,可用于 TPL-LA-lip 的处方和制备工艺的优化设计。体外释放说明TPL-LA-lip具有缓释效果,在24 h内的累积释放率为40.35%。
肿瘤组织切片染色结果显示,TPL-LA-lip导致了大量的瘤内凋亡,肿瘤细胞膜皱缩,细胞核增大,肿瘤组织坏死,显示了良好的抗肿瘤效果;ICR小鼠肿瘤模型药效学研究表明,TPL-LA-lip组脂质体肿瘤体积并未增大且小鼠体质量并未下降,说明TPL-LA-lip能显著抑制肿瘤生长并显示出良好的生物安全性,表明针对TP,经饱和长链脂肪酸(木蜡酸)修饰制成前药,并与纳米药物递送技术相结合,可能更有效的延长了药物在体内的作用时间,从而使药物的抗肿瘤效果越好。
本试验成功制备了TPL-LA-lip,为TP前药脂质体的开发提供方法参考与实验基础,同时具有潜在的临床应用价值,为胰腺癌后期治疗研究奠定了重要基础。
基金
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  • 国家自然科学基金项目资助(81772749)
  • 福建中医药大学高层次人才科研启动资金项目资助(X2019006-人才)
  • 上海青浦区产学研合作发展资金项目资助(青产学研2021-7)
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2024年第59卷第10期
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doi: 10.11669/cpj.2024.10.008
  • 接收时间：2023-03-08
  • 首发时间：2025-11-25
  • 出版时间：2024-05-22
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  • 收稿日期：2023-03-08
基金
国家自然科学基金项目资助(81772749)
福建中医药大学高层次人才科研启动资金项目资助(X2019006-人才)
上海青浦区产学研合作发展资金项目资助(青产学研2021-7)
作者信息
    1 福建中医药大学, 福州 350122
    2 上海维洱实验室, 上海 201712

通讯作者:

*武鑫,男,硕士,高级工程师,硕士生导师 研究方向:纳米靶向给药系统及缓控释给药系统研究 Tel:(021)31198947
参考文献
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https://castjournals.cast.org.cn/joweb/zgyxzz/CN/10.11669/cpj.2024.10.008
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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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