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Article(id=1195816327765078373, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195816324862624679, articleNumber=1001-2494(2024)24-2354-09, orderNo=null, doi=10.11669/cpj.2024.24.008, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1706976000000, receivedDateStr=2024-02-04, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1763034429732, onlineDateStr=2025-11-13, pubDate=1734796800000, pubDateStr=2024-12-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763034429732, onlineIssueDateStr=2025-11-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763034429732, creator=13701087609, updateTime=1763034429732, updator=13701087609, issue=Issue{id=1195816324862624679, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='24', pageStart='2299', pageEnd='2406', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763034429040, creator=13701087609, updateTime=1763034724390, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1195817563738390939, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195816324862624679, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1195817563738390940, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1195816324862624679, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2354, endPage=2362, ext={EN=ArticleExt(id=1195816328205480295, articleId=1195816327765078373, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Preparation and Pharmacodynamic Study of Dihydroartemisinin/Cetylamine Coupled Prodrug Self-Assembed Nanoparticles, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To design and release dihydroartemisinic(DHA) prodrug with long circulation ability in vivo by the stimulation of tumor cell microenvironment and improve drug accumulation in tumor site. METHODS DHA was covalently bonded to cetylamine (C16) carriers via disulfide (-SS-) and carbon-carbon bonds (-CC-) to synthesize two DHA/C16 coupled prodrugs of DHA-SS-C16 and DHA-CC-C16, which were formulated as self-assembled nanoparticles (DHA-SS-C16 NPs and DHA-CC-C16 NPs) by nanoprecipitation method. In vitro cellular studies were performed to assess the NPs' capacity in inhibiting the proliferation of 4T1 cells. Additionally, the pharmacokinetic behaviors in rats and the anti-tumor activity in 4T1 tumor bearing mice of NPs were also studied. RESULTS DHA-SS-C16 and DHA-CC-C16 were successfully synthesized. The particle size and Zeta potential of DHA-SS-C16 and DHA-CC-C16 NPs were (115.7±3.0) and (106.6±1.0) nm, (-34.5±0.4) and (-21.3±0.5 )mV, respectively. The average encapsulation efficiency and drug loading capacity of the two DHA/C16 coupled prodrugs were greater than 95% and 79% respectively, demonstrating good stability. NPs could inhibit the proliferation of 4T1 cells and reduce their migration ability. The pharmacokinetic studies showed that NPs prolonged the average retention time of DHA and enhanced the AUC of DHA to certain extent. The anti-tumor effect of DHA-SS-C16 NPs was better than that of DHA solution and DHA-CC-C16 NPs. CONCLUSION The self-assembled nano-drug delivery system designed in this paper, which utilizes disulfide bonds as connecting arm for DHA/C16-coupled prodrug, is capable of prolonging the retention time of drugs in the body, enhancing the accumulation of drugs at the tumor site, achieving responsive drug release in the tumor microenvironment, and improving anti-tumor effect. Furthermore, it also enhances the quality of life of mice. In conclusion, the nano-drug delivery system presents a promising long-acting and intelligent approach in drug delivery.

, correspAuthors=Shuqiu ZHANG, 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=Guolian REN, Rongrong WANG, Qiuyue JIN, Canqi PING, Ruili WANG, Shuqiu ZHANG), CN=ArticleExt(id=1195816657068274621, articleId=1195816327765078373, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=双氢青蒿素/十六胺偶联前药自组装纳米粒的制备及药效学研究, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 设计具有体内长循环能力和肿瘤细胞微环境刺激触发药物释放的双氢青蒿素(DHA)前药,提高肿瘤部位的药物蓄积,增强药物抗肿瘤疗效。方法 采用DHA为模型药物,十六胺(C16)为载体,二硫键(-SS-)和碳碳键(-CC-)为连接臂,合成2种DHA/C16偶联前药(DHA-SS-C16和DHA-CC-C16)。采用纳米沉淀法制备DHA/C16偶联前药自组装纳米粒(DHA-SS-C16 NPs和DHA-CC-C16 NPs)。体外细胞研究评价NPs对4T1细胞的增殖抑制能力;采用大鼠和小鼠分别研究NPs在大鼠体内的药动学特征及在4T1荷瘤小鼠体内的抗肿瘤活性。结果 成功合成了2种DHA/C16偶联前药,制备的DHA-SS-C16 NPs和DHA-CC-C16 NPs的粒径和Zeta电位分别为(115.7±3.0)(106.6±1.0) nm,(-34.5±0.4)(-21.3±0.5) mV,2种DHA/C16偶联前药的平均包封率和载药量分别大于95%和79%,稳定性良好。NPs可抑制4T1细胞的增殖,降低其迁移能力。药动学和药效学研究结果显示,NPs均不同程度地延长了DHA的平均滞留时间,提高了DHA的曲线下面积(AUC),对4T1荷瘤小鼠的肿瘤抑制效果远高于DHA溶液剂组,且DHA-SS-C16 NPs抗肿瘤效果优于DHA-CC-C16 NPs。。结论 本实验设计的以二硫键为连接臂的DHA/C16偶联前药自组装纳米递药系统DHA-SS-C16 NPs能够延长药物在体内的滞留时间,提高药物在肿瘤部位的蓄积能力,实现肿瘤部位微环境响应药物释放,增强了药物抗肿瘤能力,改善了小鼠的生存质量,使其有望成为一种有前景的长效智能纳米递药系统。

, correspAuthors=张淑秋, authorNote=null, correspAuthorsNote=
* 张淑秋,女,博士,教授,博士生导师 研究方向:药物新剂型与药物代谢动力学 Tel:(0351) 3985243
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任国莲,女,博士,副教授,硕士生导师 研究方向:新型纳米递药系统与药动学

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任国莲,女,博士,副教授,硕士生导师 研究方向:新型纳米递药系统与药动学

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任国莲,女,博士,副教授,硕士生导师 研究方向:新型纳米递药系统与药动学

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DOI:10.3390/pharmaceutics15010180., articleTitle=Gliadin nanoparticles containing doxorubicin hydrochloride: characterization and cytotoxicity, refAbstract=null)], funds=[Fund(id=1196081936604119413, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, awardId=82173767, language=CN, fundingSource=国家自然科学基金项目(82173767), fundOrder=null, country=null), Fund(id=1196081936675422582, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, awardId=20210302123310, language=CN, fundingSource=山西省应用基础研究项目(20210302123310), fundOrder=null, country=null), Fund(id=1196081936725754231, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, awardId=2021-089, language=CN, fundingSource=山西省省筹资金资助回国留学人员科研项目(2021-089), fundOrder=null, country=null), Fund(id=1196081936780280184, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, awardId=03201619, language=CN, fundingSource=山西医科大学博士启动基金(03201619), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1196081932250431799, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, xref=null, ext=[AuthorCompanyExt(id=1196081932258820408, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, companyId=1196081932250431799, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Pharmacy,Shanxi Medical University, Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Engineering Research Center of Characteristic Drug Development, Taiyuan 030001, China), AuthorCompanyExt(id=1196081932263014713, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, companyId=1196081932250431799, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山西医科大学药学院, 教育部慢性肾脏病医药基础研究创新中心,山西省药物合成与制剂新技术重点实验室,山西省特色药物研制工程研究中心, 太原 030001)])], figs=[ArticleFig(id=1196081934985118051, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Fig.1, caption=Synthesis routes and HR-MS spectra of dihydroartemisinin/cetylamine coupled prodrugs

A,C-DHA-SS-C16; B,D-DHA-CC-C16.

, figureFileSmall=Qu5Q3agxCowKLhYImFXZZw==, figureFileBig=t1ScMCMxB52iSjcTLlpADQ==, tableContent=null), ArticleFig(id=1196081935064809828, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=图1, caption=双氢青蒿素/十六胺偶联前药的合成路线和高分辨质谱图

A,C-二硫键为连接臂的双氢青蒿素/十六胺偶联自组装纳米粒(DHA-SS-C16); B,D-碳碳键为连接臂的双氢青蒿素/十六胺偶联自组装纳米粒(DHA-CC-C16)。

, figureFileSmall=Qu5Q3agxCowKLhYImFXZZw==, figureFileBig=t1ScMCMxB52iSjcTLlpADQ==, tableContent=null), ArticleFig(id=1196081935157084517, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Fig.2, caption=Appearance and TEM images of DHA-SS-C16 NPs and DHA-CC-C16 NPs (A, B); Changes of particle size distribution, size, and PDI of these two NPs after storage at 4 ℃ for 36 days (C,D,E,F); Changes of size and PDI of these two NPs after incubation with PBS and DMEM for 24 h (G, H). n=3,$\bar{x}±s$, figureFileSmall=gJiz2ulJXTKuOxTpe+GnIA==, figureFileBig=shhl3XhuREJwljDD6h+3Tg==, tableContent=null), ArticleFig(id=1196081935219999078, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=图2, caption=DHA-SS-C16 NPs、DHA-CC-C16 NPs溶液的外观与透射电镜图(A,B);4 ℃储存36 d后粒径分布和粒径与PDI变化(C,D,E,F)以及与PBS和DMEM孵育24 h后的粒径及PDI变化(G,H)。n=3,$\bar{x}±s$, figureFileSmall=gJiz2ulJXTKuOxTpe+GnIA==, figureFileBig=shhl3XhuREJwljDD6h+3Tg==, tableContent=null), ArticleFig(id=1196081935287107943, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Fig.3, caption=Inhibition ratios of DHA-sol (A), DHA-SS-C16 NPs (B), and DHA-CC-C16 NPs (C) on 4T1 cells after 48 and 72 h incubation.n=3,$\bar{x}±s$, figureFileSmall=mWWg13gxcpIg18ZF2KotlA==, figureFileBig=SvHME5CXTSZLPSaHo4MI2Q==, tableContent=null), ArticleFig(id=1196081935383576936, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=图3, caption=双氢青蒿素溶液剂(DHA-sol)(A),DHA-SS-C16 NPs(B)和DHA-CC-C16 NPs(C)与4T1细胞孵育的48 和72 h的抑制率。n=3,$\bar{x}±s$, figureFileSmall=mWWg13gxcpIg18ZF2KotlA==, figureFileBig=SvHME5CXTSZLPSaHo4MI2Q==, tableContent=null), ArticleFig(id=1196081935459074409, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Fig.4, caption=Effects of DHA-sol, DHA-SS-C16 NPs, and DHA-CC-C16 NPs on migration ability of 4T1 cells after 24 h incubation(×100), figureFileSmall=+FTw1iTfelkjHfiQXfQ4kQ==, figureFileBig=WSCPWyLysu1HxOfBswLcxQ==, tableContent=null), ArticleFig(id=1196081935513600362, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=图4, caption=DHA-sol,DHA-SS-C16 NPs和DHA-CC-C16 NPs与4T1细胞孵育24 h后对细胞迁移能力的影响(×100), figureFileSmall=+FTw1iTfelkjHfiQXfQ4kQ==, figureFileBig=WSCPWyLysu1HxOfBswLcxQ==, tableContent=null), ArticleFig(id=1196081935572320619, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Fig.5, caption=Mean concentration-time curves of DHA (A) and DHA coupled prodrug (B) in rat plasma after intravenous administration of DHA-sol, DHA-SS-C16 NPs, and DHA-CC-C16 NPs. n=3,$\bar{x}±s$, figureFileSmall=Em82zA4Y56ut4x9NsyjlDg==, figureFileBig=ikCWfv8WpO20NZok6YRL0w==, tableContent=null), ArticleFig(id=1196081935731704172, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=图5, caption=大鼠尾静脉注射DHA-sol,DHA-SS-C16 NPs和DHA-CC-C16 NPs后血浆中DHA(A)和DHA/C16偶联前药(B)的平均血药浓度与时间的曲线。n=3,$\bar{x}±s$, figureFileSmall=Em82zA4Y56ut4x9NsyjlDg==, figureFileBig=ikCWfv8WpO20NZok6YRL0w==, tableContent=null), ArticleFig(id=1196081935878504813, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Fig.6, caption=Changes of tumor volume (A), body weight (B), and HE staining(C) of different tissue sections of 4T1 tumor-bearing mice treated with DHA-sol, DHA-SS-C16 NPs, and DHA-CC-C16 NPs at 10 mg DHA·kg-1 via tail vein. n=6,$\bar{x}±s$, figureFileSmall=+UrKE7J91porSMm4m5UDLg==, figureFileBig=frTlujER7uX7ijgvjJjuPg==, tableContent=null), ArticleFig(id=1196081935995945326, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=图6, caption=4T1荷瘤小鼠尾静脉注射DHA-sol、DHA-SS-C16 NPs和DHA-CC-C16 NPs后肿瘤体积(A)、体质量(B)和不同组织切片的苏木精-伊红(HE)染色(C)变化。n=6,$\bar{x}±s$, figureFileSmall=+UrKE7J91porSMm4m5UDLg==, figureFileBig=frTlujER7uX7ijgvjJjuPg==, tableContent=null), ArticleFig(id=1196081936079831407, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Tab.1, caption=

Particle size, PDI, zeta potential, EE, and DL of DHA-SS-C16 NPs and DHA-CC-C16 NPs.n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Prodrug Size /nm PDI Zeta potential/mV EE/% DL/%
DHA-SS-C16 115.7±3.0 0.24±0.02 -34.5±0.4 96.1±1.2 80.1±1.0
DHA-CC-C16 106.6±1.0 0.14±0.03 -21.3±0.5 95.3±0.4 79.4±0.3
), ArticleFig(id=1196081936130163056, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=表1, caption=

DHA-SS-C16 NPs和DHA-CC-C16 NPs的粒径、多分散系数(PDI)、Zeta电位、包封率(EE)和载药量(DL)。n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Prodrug Size /nm PDI Zeta potential/mV EE/% DL/%
DHA-SS-C16 115.7±3.0 0.24±0.02 -34.5±0.4 96.1±1.2 80.1±1.0
DHA-CC-C16 106.6±1.0 0.14±0.03 -21.3±0.5 95.3±0.4 79.4±0.3
), ArticleFig(id=1196081936188883313, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Tab.2, caption=

IC50 of DHA-sol, DHA-SS-C16 NPs, and DHA-CC-C16 NPs in 4T1 cells after 48 and 72 h incubation.n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Formulations IC50(48 h)/μmol·L-1 IC50(72 h)/μmol·L-1
DHA-sol 2.60±0.22 1.25±0.04
DHA-SS-C16 NPs 2.78±0.12 1.80±0.17
DHA-CC-C16 NPs 3.04±0.11 2.09±0.05
), ArticleFig(id=1196081936260186482, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=表2, caption=

DHA-sol, DHA-SS-C16 NPs和DHA-CC-C16 NPs和4T1细胞孵育48和72 h后的半抑制浓度(IC50)。n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Formulations IC50(48 h)/μmol·L-1 IC50(72 h)/μmol·L-1
DHA-sol 2.60±0.22 1.25±0.04
DHA-SS-C16 NPs 2.78±0.12 1.80±0.17
DHA-CC-C16 NPs 3.04±0.11 2.09±0.05
), ArticleFig(id=1196081936323101043, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=EN, label=Tab.3, caption=

Pharmacokinetic parameters of DHA and DHA/C16 coupled prodrug in plasma of rat after 24 h intravenous administration of 6.3 mg DHA·kg-1 of DHA-sol, DHA-SS-C16 NPs, and DHA-CC-C16 NPs. n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Parameters DHA of
DHA-sol		 DHA of
DHA-SS-C16 NPs		 DHA of
DHA-CC-C16 NPs		 DHA-SS-C16 of
DHA-SS-C16 NPs		 DHA-CC-C16 of
DHA-CC-C16 NPs
AUC0-24/ng·h·L-1 857.59 ±103.74 6 196.56 ±1 388.80 18 206.48 ±4 435.52 76 981.85 ±20 199.58 5 175.46 ±3 849.09
AUC0-∞/ng·h·L-1 228.65 ±49.66 6 248.25 ±1 393.57 18 673.1 ±4 439.04 77 020.37 ±20 190.81 5 346.44 ±3 766.41
MRT/h 0.29 ±0.03 1.67 ±0.24 0.34 ±0.03 1.32 ±0.29 0.35 ±0.11
CL/L·h-1·kg-1 6.84 ±0.76 1.06 ±0.29 0.36 ±0.1 0.21 ±0.06 3.96 ±3.01
V/L·kg-1 2.27 ±0.19 1.39 ±0.55 0.12 ±0.03 1.77 ±1.18 0.16 ±0.06
t1/2/h 0.23 ±0.01 0.9 ±0.13 0.23 ±0.02 0.52 ±0.07 0.26 ±0.13
), ArticleFig(id=1196081936474095988, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1195816327765078373, language=CN, label=表3, caption=

大鼠尾静脉注射6.3 mg DHA·kg-1的DHA-sol,DHA-SS-C16 NPs和DHA-CC-C16 NPs 24 h后血浆中DHA和DHA/C16偶联前药的药动学参数。n=3,$\bar{x}±s$

, figureFileSmall=null, figureFileBig=null, tableContent=
Parameters DHA of
DHA-sol		 DHA of
DHA-SS-C16 NPs		 DHA of
DHA-CC-C16 NPs		 DHA-SS-C16 of
DHA-SS-C16 NPs		 DHA-CC-C16 of
DHA-CC-C16 NPs
AUC0-24/ng·h·L-1 857.59 ±103.74 6 196.56 ±1 388.80 18 206.48 ±4 435.52 76 981.85 ±20 199.58 5 175.46 ±3 849.09
AUC0-∞/ng·h·L-1 228.65 ±49.66 6 248.25 ±1 393.57 18 673.1 ±4 439.04 77 020.37 ±20 190.81 5 346.44 ±3 766.41
MRT/h 0.29 ±0.03 1.67 ±0.24 0.34 ±0.03 1.32 ±0.29 0.35 ±0.11
CL/L·h-1·kg-1 6.84 ±0.76 1.06 ±0.29 0.36 ±0.1 0.21 ±0.06 3.96 ±3.01
V/L·kg-1 2.27 ±0.19 1.39 ±0.55 0.12 ±0.03 1.77 ±1.18 0.16 ±0.06
t1/2/h 0.23 ±0.01 0.9 ±0.13 0.23 ±0.02 0.52 ±0.07 0.26 ±0.13
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双氢青蒿素/十六胺偶联前药自组装纳米粒的制备及药效学研究
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任国莲 , 王蓉蓉 , 靳秋月 , 平灿锜 , 王锐利 , 张淑秋 *
中国药学杂志 | 论著 2024,59(24): 2354-2362
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中国药学杂志 | 论著 2024, 59(24): 2354-2362
双氢青蒿素/十六胺偶联前药自组装纳米粒的制备及药效学研究
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任国莲, 王蓉蓉, 靳秋月, 平灿锜, 王锐利, 张淑秋*
作者信息
  • 山西医科大学药学院, 教育部慢性肾脏病医药基础研究创新中心,山西省药物合成与制剂新技术重点实验室,山西省特色药物研制工程研究中心, 太原 030001

    • 任国莲,女,博士,副教授,硕士生导师 研究方向:新型纳米递药系统与药动学

通讯作者:

* 张淑秋,女,博士,教授,博士生导师 研究方向:药物新剂型与药物代谢动力学 Tel:(0351) 3985243
Preparation and Pharmacodynamic Study of Dihydroartemisinin/Cetylamine Coupled Prodrug Self-Assembed Nanoparticles
Guolian REN, Rongrong WANG, Qiuyue JIN, Canqi PING, Ruili WANG, Shuqiu ZHANG*
Affiliations
  • School of Pharmacy,Shanxi Medical University, Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Engineering Research Center of Characteristic Drug Development, Taiyuan 030001, China
出版时间: 2024-12-22 doi: 10.11669/cpj.2024.24.008
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摘要
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目的 设计具有体内长循环能力和肿瘤细胞微环境刺激触发药物释放的双氢青蒿素(DHA)前药,提高肿瘤部位的药物蓄积,增强药物抗肿瘤疗效。方法 采用DHA为模型药物,十六胺(C16)为载体,二硫键(-SS-)和碳碳键(-CC-)为连接臂,合成2种DHA/C16偶联前药(DHA-SS-C16和DHA-CC-C16)。采用纳米沉淀法制备DHA/C16偶联前药自组装纳米粒(DHA-SS-C16 NPs和DHA-CC-C16 NPs)。体外细胞研究评价NPs对4T1细胞的增殖抑制能力;采用大鼠和小鼠分别研究NPs在大鼠体内的药动学特征及在4T1荷瘤小鼠体内的抗肿瘤活性。结果 成功合成了2种DHA/C16偶联前药,制备的DHA-SS-C16 NPs和DHA-CC-C16 NPs的粒径和Zeta电位分别为(115.7±3.0)(106.6±1.0) nm,(-34.5±0.4)(-21.3±0.5) mV,2种DHA/C16偶联前药的平均包封率和载药量分别大于95%和79%,稳定性良好。NPs可抑制4T1细胞的增殖,降低其迁移能力。药动学和药效学研究结果显示,NPs均不同程度地延长了DHA的平均滞留时间,提高了DHA的曲线下面积(AUC),对4T1荷瘤小鼠的肿瘤抑制效果远高于DHA溶液剂组,且DHA-SS-C16 NPs抗肿瘤效果优于DHA-CC-C16 NPs。。结论 本实验设计的以二硫键为连接臂的DHA/C16偶联前药自组装纳米递药系统DHA-SS-C16 NPs能够延长药物在体内的滞留时间,提高药物在肿瘤部位的蓄积能力,实现肿瘤部位微环境响应药物释放,增强了药物抗肿瘤能力,改善了小鼠的生存质量,使其有望成为一种有前景的长效智能纳米递药系统。

双氢青蒿素  /  十六胺  /  前药  /  自组装纳米粒  /  抗肿瘤

OBJECTIVE To design and release dihydroartemisinic(DHA) prodrug with long circulation ability in vivo by the stimulation of tumor cell microenvironment and improve drug accumulation in tumor site. METHODS DHA was covalently bonded to cetylamine (C16) carriers via disulfide (-SS-) and carbon-carbon bonds (-CC-) to synthesize two DHA/C16 coupled prodrugs of DHA-SS-C16 and DHA-CC-C16, which were formulated as self-assembled nanoparticles (DHA-SS-C16 NPs and DHA-CC-C16 NPs) by nanoprecipitation method. In vitro cellular studies were performed to assess the NPs' capacity in inhibiting the proliferation of 4T1 cells. Additionally, the pharmacokinetic behaviors in rats and the anti-tumor activity in 4T1 tumor bearing mice of NPs were also studied. RESULTS DHA-SS-C16 and DHA-CC-C16 were successfully synthesized. The particle size and Zeta potential of DHA-SS-C16 and DHA-CC-C16 NPs were (115.7±3.0) and (106.6±1.0) nm, (-34.5±0.4) and (-21.3±0.5 )mV, respectively. The average encapsulation efficiency and drug loading capacity of the two DHA/C16 coupled prodrugs were greater than 95% and 79% respectively, demonstrating good stability. NPs could inhibit the proliferation of 4T1 cells and reduce their migration ability. The pharmacokinetic studies showed that NPs prolonged the average retention time of DHA and enhanced the AUC of DHA to certain extent. The anti-tumor effect of DHA-SS-C16 NPs was better than that of DHA solution and DHA-CC-C16 NPs. CONCLUSION The self-assembled nano-drug delivery system designed in this paper, which utilizes disulfide bonds as connecting arm for DHA/C16-coupled prodrug, is capable of prolonging the retention time of drugs in the body, enhancing the accumulation of drugs at the tumor site, achieving responsive drug release in the tumor microenvironment, and improving anti-tumor effect. Furthermore, it also enhances the quality of life of mice. In conclusion, the nano-drug delivery system presents a promising long-acting and intelligent approach in drug delivery.

dihydroartemisinin  /  cetylamine  /  prodrug  /  self-assembled nanoparticle  /  anti-tumor
任国莲, 王蓉蓉, 靳秋月, 平灿锜, 王锐利, 张淑秋. 双氢青蒿素/十六胺偶联前药自组装纳米粒的制备及药效学研究. 中国药学杂志, 2024 , 59 (24) : 2354 -2362 . DOI: 10.11669/cpj.2024.24.008
Guolian REN, Rongrong WANG, Qiuyue JIN, Canqi PING, Ruili WANG, Shuqiu ZHANG. Preparation and Pharmacodynamic Study of Dihydroartemisinin/Cetylamine Coupled Prodrug Self-Assembed Nanoparticles[J]. Chinese Pharmaceutical Journal, 2024 , 59 (24) : 2354 -2362 . DOI: 10.11669/cpj.2024.24.008
正文
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双氢青蒿素(dihydroartemisinin,DHA)是我国创新药物青蒿素(artemisinin,ART)衍生物,在保留ART特殊骨架结构和过氧桥活性基团的同时,具有更好的抗疟疗效和生物安全性[1-2]。近年来研究发现,DHA亦可抑制恶性肿瘤的生长,主要通过阻断细胞周期、诱导细胞凋亡、抑制肿瘤血管生成和增强抗肿瘤免疫等途径发挥抗肿瘤作用[3-4]。然而,DHA溶解度差、生物半衰期短、生物利用度低等缺点在一定程度上限制了肿瘤的治疗[5]。如何提高DHA的抗肿瘤疗效,降低对正常组织脏器的损伤,是DHA面临的挑战。
近年来,自组装纳米粒(NPs)成为制备纳米药物递送系统的一种新策略。这种自组装策略通常采用共价结合方法使药物与载体制备成偶联前体药物(前药),偶联前药成为自形成和自释放的单组分纳米药物,具有制备简单,重现性好,提高药物稳定性、延迟释放等优点[6-8]。同时,肿瘤血管的异常导致高渗透性长滞留效应(enhanced permeability and retention effect,EPR)增强,前药纳米制剂可实现肿瘤内被动蓄积,从而提高疗效、降低毒性[9-10]。本课题组前期合成并制备了十二醇修饰的DHA前药[11]、十四胺修饰的DHA前药[12]、十八胺修饰的DHA前药[13]等,并制备成NPs,制备过程简单方便、快速,包封率和载药量高,显著降低了制剂中辅料的应用,减少了制剂毒性,治疗效果较佳。
因此,本研究在前期研究的基础之上,以十六胺(cetylamine,C16)作为载体,与DHA共价结合,并选择二硫键为DHA与C16之间的连接臂,利用肿瘤细胞内高浓度的谷胱甘肽(glutathione,GSH)的优势,设计GSH还原响应断裂的二硫键为连接臂的DHA/C16偶联前药[14-16]。本研究设计的前药,一方面有C16的引入,可增加DHA的脂溶性,改善药物的膜通透性,延长药物在体内的循环时间,提高生物利用度;另一方面前药中的二硫键与GSH发生化学反应,实现药物在肿瘤细胞中的选择性释放,由于较多的DHA释放在肿瘤细胞,降低对正常细胞的细胞毒性,抑制肿瘤生长。
基于上述策略,本研究成功设计并合成了以二硫键(-SS-)和碳碳键(-CC-)为连接臂的2种DHA/C16偶联前药,并将其制备成NPs(DHA-SS-C16 NPs和DHA-CC-C16 NPs),对制剂学、抑制肿瘤细胞增殖能力、大鼠体内药动学特征和体内药效学等方面进行了评价,综合研究其抗肿瘤效果,为偶联前药纳米递药系统的开发提供依据。
1 材料
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1.1 仪器
BT25S型电子天平(德国Sartorius公司);Nano-ZS90型粒度分析仪(英国马尔文仪器有限公司);KDC-140HR型高速冷冻离心机(安徽中佳科学仪器有限公司);TDL-5-A型低速台式离心机(上海安亭科学仪器厂);HA-BA型气浴恒温振荡器(荣华仪器制造有限公司);RE-52AA型旋转蒸发仪(上海亚荣生化仪器厂);ZF-7型暗箱三用紫外分析仪(上海嘉鹏科技有限公司);LC-2030型高效液相色谱仪(日本岛津制作所)。
1.2 材料
DHA和青蒿琥酯(重庆武陵山制药有限公司);C16和3,3'-二硫代二丙酸(阿拉丁生物科技有限公司);4-二甲氨基吡啶、N-羟基琥珀酰亚胺和N,N'-二环己基碳二亚胺(国药化学试剂有限公司);DSPE-MPEG2000(上海艾伟特医药科技有限公司);RPMI 1640培养基、DMEM高糖培养基、胰蛋白酶、青霉素、链霉素和胎牛血清(武汉博士德生物工程有限公司);四甲基偶氮唑蓝(北京索莱宝科技有限公司);其余试剂均为分析纯。
健康Balb/c小鼠(20±2 g),雄性Sprague Dawley(SD)大鼠18只(180~220 g),均由山西医科大学实验动物中心提供。动物实验伦理批准文件编号(2021-240)。
2 方法
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2.1 DHA/C16偶联前药的合成
2.1.1 DHA-SS-C16的合成
①将3,3'-二硫代二丙酸(0.95 mmol)与3 mL乙酸酐混匀,30 ℃反应3.5 h,甲苯除去乙酸酐,得到二硫代二丙酸酐,产物直接与DHA(0.32 mmol)、4-二甲氨基吡啶(DMAP,0.03 mmol)在二氯甲烷中35 ℃下反应36 h,混合液采用薄层大板分离纯化,即得中间产物DHA-SS-COOH。②取DHA-SS-COOH(0.21 mmol)、N-羟基琥珀酰亚胺(NHS,0.25 mmol)和N,N'-二环己基碳二亚胺(DCC,0.25 mmol),溶于适量的二氯甲烷溶液中,混合液于0 ℃反应4 h后,室温继续反应20 h。③将上述②的反应液,滴加至C16(0.25 mmol)的二氯甲烷溶液中,室温反应48 h,采用薄层大板分离纯化即得最终产品(DHA-SS-C16),以高分辨质谱(HR-MS)进行相对分子质量鉴定。
2.1.2 DHA-CC-C16的合成
①取青蒿琥酯(AS,0.39 mmol)、NHS(0.78 mmol)和DCC(0.78 mmol)溶于适量的二氯甲烷溶液中,0 ℃反应4 h后,室温继续反应20 h。②取C16(0.47 mmol)的二氯甲烷溶液滴加至第一步的反应液中,室温下反应36 h。采用薄层大板分离纯化即得最终产品(DHA-CC-C16),以HR-MS进行相对分子质量鉴定。
2.2 DHA/C16偶联前药自组装纳米粒的制备及表征
采用纳米沉淀法制备DHA/C16偶联前药NPs,取适量DHA/C16偶联前药溶于含DSPE-MPEG2000的无水乙醇溶液中,以一定的搅拌速度和制备温度注入纯化水中,即得自组装的纳米粒溶液(DHA-SS-C16 NPs和DHA-CC-C16 NPs)。采用Nano-ZS90粒度分析仪测定样品的粒径、多分散指数(PDI)和Zeta电位,透射电子显微镜观察NPs的形状和大小。
2.3 包封率和载药量的测定
采用低速离心法测定DHA/C16偶联前药NPs的包封率(EE)和载药量(DL)。具体操作如下:取1 mL DHA/C16偶联前药NPs于3 500 r·min-1的速度下离心20 min,分别取离心后的上清液及未离心的DHA/C16偶联前药NPs各0.8 mL,置于5 mL量瓶中,甲醇稀释定容,涡旋5 min,超声5 min,0.22 μm有机滤膜过滤,采用反相高效液相柱后衍生法测定DHA/C16偶联前药的EE和DL(公式1~2)。
EE(%)= m 1 m×100%
DL(%)= m 1 m 2×100%
式中,m1为NPs中DHA/C16偶联前药的质量;m2为制备NPs时使用的DHA/C16偶联前药的总质量;m2为NPs中DHA/C16偶联前药和稳定剂的总质量。
2.4 初步稳定性研究
取优化处方制备的DHA-SS-C16 NPs和DHA-CC-C16 NPs适量,采用纯化水稀释一定倍数,4 ℃储存条件下储存36 d;并采用pH 7.4磷酸盐缓冲液(PBS)和DMEM高糖培养液稀释一定倍数,于37 ℃恒温震荡24 h,在不同时间点取样,以粒径和PDI为评价指标,考察2种NPs的初步稳定性。
2.5 体外细胞毒研究
将4T1细胞株置于RPMI 1640培养基(含10%胎牛血清、100 U·mL-1青霉素和链霉素)中,于37 ℃、相对湿度90%、含体积分数5% CO2的无菌培养箱中培养。采用MTT法检测DHA溶液剂(DHA-sol)、DHA-SS-C16 NPs和DHA-CC-C16 NPs对4T1细胞增殖抑制力的影响。首先将4T1细胞以每孔8 000个的比例接种于96孔板,贴壁24 h后,弃去旧的培养液,加入100 μL不同浓度的DHA-sol、DHA-SS-C16 NPs和DHA-CC-C16 NPs进行孵育,未处理的细胞为对照组,每个浓度设置3个重复孔。孵育48和72 h后,每孔加入20 μL MTT溶液(5 mg·mL-1),孵育4 h后弃去上清液,加入二甲亚砜150 μL,室温震荡15 min,采用酶标仪490 nm测定每孔的吸光度(A),按公式3计算细胞抑制率。
细胞抑制率(%)= A 对 照 组 吸 光 度 - A 样 品 组 吸 光 度 A 对 照 组 吸 光 度×100%
2.6 细胞迁移研究
采用细胞划痕试验考察DHA-sol、DHA-SS-C16 NPs和DHA-CC-C16 NPs对4T1细胞迁移能力的影响。将4T1细胞以每孔1×105个接种于6孔板,孵育24 h后,采用200 μL无菌枪头制备划痕,并做好标记,每孔分别加入100 μL的DHA-sol、DHA-SS-C16 NPs和DHA-CC-C16 NPs(2.6 μmol·L-1 DHA),与细胞孵育0和24 h时,在显微镜下观察并拍照,测量划痕面积。
2.7 大鼠体内药动学研究
采用健康雄性SD大鼠研究不同制剂在大鼠体内药动学行为特征。18只大鼠,自由饮水,禁食12 h,随机分DHA-sol(DHA-sol由本课题组前期研究提供[12])、DHA-SS-C16 NPs和DHA-CC-C16 NPs 3组,每组6只,给药剂量为6.3 mg DHA·kg-1。尾静脉注射不同制剂后,于0.083、0.166、0.25、0.5、0.75、1、2、4、6、8、12、24 h,取血0.5 mL,在14 000 r·min-1的条件下,离心10 min,取血浆,-20 ℃保存备用。
采用液液萃取法提取大鼠血浆中DHA及DHA/C16偶联前体药物,以液相色谱-串联质谱法(LC-MS/MS)测定大鼠血浆中DHA和DHA/C16偶联前药的含量,采用统计矩分析计算相关药动学参数。
2.8 小鼠体内药效学研究
以皮下接种4T1细胞的Balb/c雌性小鼠为模型动物,考察不同制剂在小鼠体内抗肿瘤疗效。首先取0.2 mL的4T1细胞悬液(每毫升2×106个)注射于Balb/c小鼠第4对乳房右侧皮下组织处,建立肿瘤模型,选取肿瘤体积60~100 mm3进行药效学实验。
将4T1荷瘤小鼠随机分为4组,每组10只,尾静脉分别注射生理盐水、DHA-sol、DHA-SS-C16 NPs和DHA-CC-C16 NPs,给药剂量为10 mg DHA·kg-1,隔1 d给药1次,连续给药5次。观察并记录小鼠体质量和肿瘤体积,给药结束后第8天处死小鼠,将心、肝、脾、肺、肾及肿瘤于多聚甲醛固定,石蜡包埋,切片,苏木精-伊红(HE)染色,评价不同制剂的毒性。
2.9 统计学分析
所有实验均重复3次,数据以平均值±SD表示,采用t检验进行统计学分析,以P<0.05为差异有统计学意义。
3 结果与讨论
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3.1 DHA/C16偶联前药的合成与表征
DHA-SS-C16和DHA-CC-C16的合成路线见图1A和1B,高分辨质谱结果见图1C和1D。DHA-SS-C16和DHA-CC-C16的质荷比分别为699.41和607.47,图1C和1D高分辨质谱结果中质荷比为722.41的化合物组成为[C37H65NO7NaS2]+,630.43的化合物组成为[C35H61NO7Na]+,与实际分子式结果一致,证明合成的DHA-SS-C16和DHA-CC-C16相对分子质量正确。
3.2 DHA/C16偶联前药自组装纳米粒的制备与表征
采用纳米沉淀法成功制备了DHA-SS-C16 NPs和DHA-CC-C16 NPs。NPs显示出淡蓝色乳光,透射电镜结果显示NPs均为球形,外观呈圆形(图2A和2B)。DHA-SS-C16 NPs和DHA-CC-C16 NPs的粒径、PDI、Zeta电位、EE和DL见表1。由表1可知,制备的NPs具有较高的载药能力,主要是由于DHA/C16偶联前药本身既是载体又是药物,可显著提高药物的递送效率,同时本研究设计的NPs,仅含有一种DSPE-MPEG2000辅料,可降低制剂中添加的赋形剂引发的不良反应。此外,Zeta电位的测量可以表明纳米体系的稳定性,本实验制备的NPs带有负电位,具有较好的抗聚集稳定性。
3.3 初步稳定性研究
制备的2种DHA-SS-C16 NPs和DHA-CC-C16 NPs在4 ℃放置36 d粒径和PDI分布见图2C~2F。DHA-SS-C16 NPs在储存期间较为稳定,DHA-CC-C16 NPs的粒径分布略有增加(图2D)。研究结果表明,DHA-SS-C16 NPs粒径第36天时[(109.2±0.214)nm]与第1天的粒径[(108.6±1.193)nm]没有统计学差异(P>0.05),而DHA-CC-C16 NPs粒径第36天时[(123.2±7.824)nm]比第1天的粒径[(101.9±1.38)nm]显著增加(P<0.05),DHA-SS-C16 NPs的Zeta电位绝对值高于DHA-CC-C16 NPs(表1),本研究结果提示,DHA-CC-C16 NPs稳定性没有DHA-SS-C16 NPs好,DHA-SS-C16纳米粒具有较好的稳定性有利于药物在肿瘤部位的蓄积,发挥抗肿瘤作用。2种DHA/C16偶联前药NPs在PBS和DMEM高糖培养基中保存24 h后,粒径均小于200 nm,无明显变化(图2G和2H)。初步稳定性研究结果表明,2种DHA/C16偶联前药NPs在研究条件下,均能稳定保存,具有良好的长期储存稳定性和物理稳定性。分析原因是制剂中DSPE-MPEG2000含有亲水性的PEG,能显著增加制剂的稳定性,有利于后续药动学和药效学实验[17]。
3.4 体外细胞毒研究
DHA-sol、DHA-SS-C16 NPs和DHA-CC-C16 NPs对4T1细胞的增殖抑制能力呈浓度依赖性和时间依赖性(图3)。与DHA-sol相比,DHA-SS-C16 NPs和DHA-CC-C16 NPs的半抑制浓度(IC50)值均小于DHA-sol,表明NPs抑制肿瘤细胞增殖的效果低于溶液剂组,这可能是由于DHA/C16偶联前药NPs中的DHA的释放需要一定的时间,延缓了DHA的释放(表2)[18]。此外,以二硫键为连接臂的DHA-SS-C16 NPs的IC50值优于DHA-CC-C16 NPs。这是因为在肿瘤细胞内高浓度的GSH可与二硫键发生相互作用,加速二硫键的断裂,释放更多的DHA,促进肿瘤细胞凋亡[19]。
3.5 细胞迁移研究
细胞划痕实验成本低、操作简便,通过计算细胞的迁移面积可初步反映不同制剂在4T1细胞中的迁移抗性(图4)。与4T1细胞孵育24 h后,各组细胞划痕面积均减小,DHA-sol、DHA-SS-C16 NPs和DHA-CC-C16 NPs划痕愈合率分别为(47.43±0.58)%、(48.55±1.32)%和(53.80±1.32)%。与空白对照组比较,差异有统计学意义(P<0.01),结果表明不同制剂组均可抑制4T1细胞的迁移,其中DHA-SS-C16 NPs抑制细胞迁移的能力优于DHA-CC-C16 NPs,结果表明-SS-为连接臂的DHA前药比-CC-为连接臂的DHA前药易于被肿瘤细胞内高浓度的GSH响应释放DHA而发挥抗细胞迁移的作用。
3.6 大鼠体内药动学研究
大鼠尾静脉注射DHA-sol,DHA-SS-C16 NPs和DHA-CC-C16 NPs后的体内血浆中DHA和DHA/C16偶联前药的平均血药浓度-时间曲线分别见图5A和5B,药动学参数见表3。由表3可知,2种DHA/C16偶联前药NPs在血液中的滞留时间显著延长,DHA-SS-C16 NPs组DHA/C16偶联前药的AUC0-t是DHA-CC-C16 NPs组的15倍,相应的,DHA-SS-C16 NPs组体内DHA的AUC0-t低于DHA-CC-C16 NPs组(P<0.05)。DHA-CC-C16 NPs在大鼠血浆中的DHA含量大于DHA-SS-C16 NPs,可能是由于以碳碳键为连接臂的DHA前药结构稳定性差,纳米结构易于破坏,故DHA释放较多,表现出DHA血药浓度高,而DHA-CC-C16前药的浓度低[20]。本研究设计合成的DHA-SS-C16是基于肿瘤细胞中高浓度的谷胱甘肽还原相应的二硫键为连接臂进行设计,希望药物在血液中稳定,达到长循环的目的,将更多的药物递送至肿瘤部位,发挥抗肿瘤作用,而血液中的谷胱甘肽含量远低于肿瘤细胞,因此DHA-SS-C16 NPs血液中的DHA浓度较低,DHA-SS-C16前药的浓度高[21]。同时DHA-SS-C16的MRT是DHA-CC-C16的3.77倍,显著延长了前药在体内的滞留时间,因此血液中的DHA释放缓慢,血药浓度时间曲线平缓,具有较长的长循环特征,可利用肿瘤组织增强的高通透和滞留效应(EPR)效应提升药物在肿瘤中的蓄积能力,显著增加其抗肿瘤效果。
3.7 小鼠体内药效学研究
4T1荷瘤小鼠尾静脉注射DHA-sol,DHA-SS-C16 NPs和DHA-CC-C16 NPs后,肿瘤体积、体质量和苏木精-伊红(H&E)染色结果见图6。生理盐水组肿瘤持续快速生长,第18天时平均肿瘤体积达到(1 244.82±237.62) mm3,其他3组肿瘤生长明显慢于生理盐水组。试验结束时DHA-sol,DHA-SS-C16 NPs和DHA-CC-C16 NPs肿瘤体积分别为(759.21±174.17) (516.6±148.84)和(893.13±98.945 79)mm3。2种DHA/C16偶联前药NPs组的小鼠肿瘤生长均明显被抑制,且以二硫键为连接臂的DHA/C16偶联前药NPs组的肿瘤体积比以碳碳键为连接臂的DHA/C16偶联前药NPs组肿瘤体积较小,抗肿瘤效果相对较好(图6A)。从给药开始至停药后8 d,各组小鼠体质量均无明显变化,说明NPs对小鼠的毒性较小(图6B)。不同组织的H&E染色结果见图6C,由图6C可知生理盐水组和DHA-sol组肾小球萎缩变形,肾小管增大,边缘模糊,肝窦周围细胞放射状排列不明显,肿瘤细胞密集分布;DHA/C16偶联前药NPs组小鼠心脏、肝脏、脾脏、肺脏、肾脏未见明显组织损伤,且DHA-SS-C16 NPs处理的小鼠肿瘤细胞坏死明显。
上述结果表明,2种DHA/C16偶联前药NPs治疗组的平均肿瘤体积更小,肿瘤生长速度更慢,体内抗肿瘤作用更强,这是由于所制备的NPs表面存在负电荷,保证了NPs良好的稳定性,使其在EPR作用下更容易在肿瘤内蓄积[22]。更重要的是,二硫键的存在使DHA-SS-C16 NPs具有更显著和相对持久的肿瘤组织药物蓄积的能力,提高了DHA的治疗指数,具有潜在的临床应用价值。
4 结论
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综上所述,本研究成功地开发了具有体内长循环能力兼具在肿瘤蓄积能力的DHA/C16偶联前药自组装纳米递药系统(DHA-SS-C16 NPs和DHA-CC-C16 NPs),2种DHA/C16偶联前药NPs均具有较小的粒径、较高的包封率与载药量。与对照组相比,2种纳米制剂均能显著抑制4T1细胞增殖,降低细胞迁移能力,促进细胞凋亡。一方面,2种纳米制剂在体内保留时间较长,且二硫键凸显出较好的优势。另一方面,两种纳米制剂对4T1荷瘤小鼠肿瘤生长表现出良好抑制作用。但是由于对氧化还原环境反应的敏感性不同,故以二硫键为连接臂的DHA/C16偶联前药NPs在体内抗肿瘤疗效方面优于以碳碳键为连接臂的DHA/C16偶联前药NPs。综上所述,这种制备方法简单、具备较高的载药量和高效的肿瘤微环境刺激响应释放的前药NPs的设计为智能纳米药物递送系统的开发提供了新的思路,并为DHA及其他药物共载和共递送的双协同治疗和递送提供了可能性。
基金
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  • 国家自然科学基金项目(82173767)
  • 山西省应用基础研究项目(20210302123310)
  • 山西省省筹资金资助回国留学人员科研项目(2021-089)
  • 山西医科大学博士启动基金(03201619)
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2024年第59卷第24期
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doi: 10.11669/cpj.2024.24.008
  • 接收时间：2024-02-04
  • 首发时间：2025-11-13
  • 出版时间：2024-12-22
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  • 收稿日期：2024-02-04
基金
国家自然科学基金项目(82173767)
山西省应用基础研究项目(20210302123310)
山西省省筹资金资助回国留学人员科研项目(2021-089)
山西医科大学博士启动基金(03201619)
作者信息
    山西医科大学药学院, 教育部慢性肾脏病医药基础研究创新中心,山西省药物合成与制剂新技术重点实验室,山西省特色药物研制工程研究中心, 太原 030001

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* 张淑秋,女,博士,教授,博士生导师 研究方向:药物新剂型与药物代谢动力学 Tel:(0351) 3985243
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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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