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Article(id=1198652612758303438, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2022-0997, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1660752000000, receivedDateStr=2022-08-18, revisedDate=1662393600000, revisedDateStr=2022-09-06, acceptedDate=null, acceptedDateStr=null, onlineDate=1763710652770, onlineDateStr=2025-11-21, pubDate=1691769600000, pubDateStr=2023-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763710652770, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763710652770, creator=13701087609, updateTime=1763710652770, updator=13701087609, issue=Issue{id=1198652605778985059, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='8', pageStart='0', pageEnd='2540', issueExtLink='null', onlineDate='null', pubDate='1691769600000', pubDateStr='2023-08-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763710651106, creator='13701087609', updateTime=1763710739504, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1198652976601596347, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198652976601596348, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2483, endPage=2493, ext={EN=ArticleExt(id=1198652614180172512, articleId=1198652612758303438, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Icaritin and pyropheophorbide-a self-assembled nanomedicine for enhanced the efficacy of photodynamic tumor therapy by increase the cell autophagy, columnId=null, journalTitle=Acta Pharmaceutica Sinica, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Autophagy often occurs after cells are attacked by oxidative stress, where damaged structures are phagocytic and degraded into nutrients, thereby reducing oxidative damage, promoting the survival of cancer cells and reducing the therapeutic effect of photodynamic therapy (PDT). However, excessive activation of autophagy can promote cell apoptosis. In this paper, the photosensitizer pyropheophorbide-a (Ppa) was used to produce a large amount of reactive oxygen species (ROS) to achieve the effect of killing cancer cells. At the same time, icaritin (Ica), an autophagy inducer, was used to over-activate autophagy, which transformed the protection of cancer cells into the promotion of cancer cell apoptosis, so as to improve the effect of photodynamic therapy. In this study, the interaction force between Ica and Ppa was exploited to successfully construct a self-assembled nanomedicine IP with good stability and high drug load. The synthesis method is simple, through using the drug itself as a carrier, and the loading capacity (LA) of Ica and Ppa can be increased to 83.53% and 16.45% without introducing potential biosafety risks of nanocarriers. Compared with free Ppa, self-assembled nanomedicine IP showed superior performance in cellular uptake and reactive oxygen species production. In addition, the self-assembled nanomedicine IP can reverse the protective autophagy induced by PDT by activating the autophagy of tumor cells, and facilitate apoptosis and antitumor coordination, which significantly improves the antitumor activity of PDT.

, authors=null, authorsList=Run-tian GUAN, Rong-rong ZHENG, Ni YANG, Xiao-na RAO, Shi-ying LI, authorCompany=null, correspAuthors=Shi-ying LI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1198652618756158417, articleId=1198652612758303438, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=淫羊藿素与焦脱镁叶绿酸-a自组装纳米药物通过诱导细胞自噬促进肿瘤光动力疗效的研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

自噬(autophagy) 经常发生在细胞遭受氧化应激(oxidative stress) 后, 通过吞噬受损结构并降解成营养物质, 从而降低氧化损伤, 促进癌细胞存活并降低光动力治疗(photodynamic therapy, PDT) 的治疗效果。然而过度激活自噬能促进细胞发生凋亡, 本研究使用光敏剂焦脱镁叶绿酸-a (pyropheophorbide-a, Ppa) 产生大量的活性氧(reactive oxygen species, ROS) 达到杀伤癌细胞的效果, 同时通过联用自噬诱导剂淫羊藿素(icaritin, Ica) 过度激活自噬, 使其对癌细胞的保护转变为促进癌细胞凋亡的作用, 进而达到提高PDT的效果。本研究利用Ica与Ppa间的相互作用力, 成功构建了具有稳定性好、载药量高等特点的自组装纳米药物IP。其中, 该纳米药物合成方法简单, 通过药物自身作为载体, 将Ica与Ppa的载药量(loading capacity, LA) 分别提升至83.53%和16.45%, 且不引入纳米载体潜在的生物安全性隐患。与游离Ppa相比, 自组装纳米药物IP在细胞摄取和ROS产生等方面展现出优越性能。此外, 自组装纳米药物IP能通过激活肿瘤细胞发生自噬, 进而逆转PDT诱发的保护性自噬并促进细胞凋亡和抗肿瘤协同, 显著提高PDT的抗肿瘤活性。

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*李仕颖, Tel: 86-20-37103274, E-mail:
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ACS Nano, 2020, 14: 9711-9727., articleTitle=3-Bromopyruvate-conjugated nanoplatform-induced pro-death autophagy for enhanced photodynamic therapy against hypoxic tumor, refAbstract=null)], funds=[Fund(id=1198960120731370076, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, awardId=2021YFD1800600, language=CN, fundingSource=国家重点研发计划项目(2021YFD1800600), fundOrder=null, country=null), Fund(id=1198960120920113778, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, awardId=2021B1515020043, language=CN, fundingSource=广东省基础与应用基础项目(2021B1515020043), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1198960114309890999, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, xref=null, ext=[AuthorCompanyExt(id=1198960114322473914, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, companyId=1198960114309890999, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. School of Pharmacy, Guangzhou Medical University, Guangzhou 511436, China), AuthorCompanyExt(id=1198960114330862523, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, companyId=1198960114309890999, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.广州医科大学药学院, 广东 广州 511436)]), AuthorCompany(id=1198960114452497349, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, xref=null, ext=[AuthorCompanyExt(id=1198960114469274571, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, companyId=1198960114452497349, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China), AuthorCompanyExt(id=1198960114477663180, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, companyId=1198960114452497349, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.广东药科大学药学院, 广东 广州 510006)])], figs=[ArticleFig(id=1198960118760046996, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=EN, label=null, caption=null, figureFileSmall=+vMUwCVXB8tSMymUANrLtA==, figureFileBig=q59exbA6jJABcY5cM8urqQ==, tableContent=null), ArticleFig(id=1198960118902653348, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=CN, label=Figure 1, caption= Synthesis and characterization of nanomedicine IP. A: Transmission electron microscopy (TEM) images of nanomedicine prepared with free pyropheophorbide-a (Ppa), icaritin (Ica) and their different feed ratios. Scale bar: 1 000 nm; B-D: The hydrodynamic size of Ppa and Ica nanomedicine with various feed ratios; E-G: The hydrodynamic size changes and the polydispersity index (PDI) changes of the self-assembled nanomedicines formed with different feed ratio of Ppa and Ica in water within 7 days. Ppa∶Ica: 1∶1 (B, E), 1∶2 (C, F), 1∶3 (D, G). <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i> , figureFileSmall=+vMUwCVXB8tSMymUANrLtA==, figureFileBig=q59exbA6jJABcY5cM8urqQ==, tableContent=null), ArticleFig(id=1198960119062036922, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=EN, label=null, caption=null, figureFileSmall=PsYW8OnrmwT9Su/OlqiLYg==, figureFileBig=zPZQ4UXagWVKkBUuV1vZqw==, tableContent=null), ArticleFig(id=1198960119213031881, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=CN, label=Figure 2, caption= Characterization and drug loading of IP. A: The potential of IP; B: The ultraviolet-visible (UV-vis) absorbance of IP and Ppa in aqueous solution; C, D: The UV-vis absorbance (C) and the enlarged spectra (D) of IP, aggregated Ppa, and monomeric Ppa; E, F: The UV-vis absorbance (E) and the enlarged spectra (F) of IP after treatment with different concentrations of NaCl solutions; G: The UV-vis absorbance of IP in 0.2% sodium dodecyl sulfate (SDS) solutions; H, I: The regression curve of the peak area corresponding to the standard Ppa (H) and Ica (I) , figureFileSmall=PsYW8OnrmwT9Su/OlqiLYg==, figureFileBig=zPZQ4UXagWVKkBUuV1vZqw==, tableContent=null), ArticleFig(id=1198960119347249622, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=EN, label=null, caption=null, figureFileSmall=hOxul+o0cp+ltK79nzoW3w==, figureFileBig=ucm4gSvcPA69Qz+Dw7ETOA==, tableContent=null), ArticleFig(id=1198960119489855972, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=CN, label=Figure 3, caption= Cellular uptake of IP in 4T1 cells. A-D: Confocal laser scanning microscope (CLSM) images (A) and mean fluorescence intensity (MFI, C) of 4T1 cells treated with 2, 5, 8 μg·mL<sup>-1</sup> Ppa or IP for 12 h; CLSM images (B) and MFI (D) of 4T1 cells after treatment with 5 μg·mL<sup>-1</sup> Ppa or IP for 6, 12, or 18 h. Scale bar: 5 μm; E: Flow cytometry analysis of 4T1 cells after incubation with 2, 5, and 8 μg·mL<sup>-1</sup> Ppa or IP for 12 h; F: Flow cytometry analysis of 4T1 cells after incubation with 5 μg·mL<sup>-1</sup> Ppa or IP for 6, 12, or 18 h. <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i>. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001; ns: No significance , figureFileSmall=hOxul+o0cp+ltK79nzoW3w==, figureFileBig=ucm4gSvcPA69Qz+Dw7ETOA==, tableContent=null), ArticleFig(id=1198960119611490803, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=EN, label=null, caption=null, figureFileSmall=9DYWurBqTFgeUBg6F3qsOA==, figureFileBig=fWj68+TQVkWTzVr0o5S+Pg==, tableContent=null), ArticleFig(id=1198960119728931328, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=CN, label=Figure 4, caption= The production of reactive oxygen species (ROS) induced by IP light. A: With the increase of time, IP, Ica + Ppa, Ica and Ppa changed the fluorescence of singlet oxygen sensor green (SOSG) under light irradiation (20 s, 50 mW·cm<sup>-2</sup>) or no irradiation; B: CLSM images of 4T1 cells treated with IP, Ica + Ppa, Ica and Ppa (Ppa was 5 μg·mL<sup>-1</sup>) for 12 h and stained with 2, 7-dichlorodihydrofluorescein diacetate (DCFH-DA). Scale bar: 5 μm; C: CellROX<sup>TM</sup> Green under light irradiation (1 min) or no irradiation. Scale bar: 10 μm , figureFileSmall=9DYWurBqTFgeUBg6F3qsOA==, figureFileBig=fWj68+TQVkWTzVr0o5S+Pg==, tableContent=null), ArticleFig(id=1198960119829594637, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=EN, label=null, caption=null, figureFileSmall=EGcskUtp26gu6qZ8uyT5yQ==, figureFileBig=PmqptceXObIuVNyLCKr25A==, tableContent=null), ArticleFig(id=1198960120030921246, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=CN, label=Figure 5, caption= Autophagy induced by nanomedicine IP in 4T1 cells. A: CLSM images of mitochondria in 4T1 cells treated with 10, 20, and 40 μg·mL<sup>-1</sup> Ica for 12 h and stained with Rhodamine 123. Scale bar: 10 μm. The 4T1 cells were treated with each group of drugs (Ppa was 5 μg·mL<sup>-1</sup>) for 12 h and then incubated under light irradiation (30 s) or no irradiation for another 4 h; B, C: The levels of ATG5 (B) and LC3B (C) were determined by Western blot; D-F: Quantitative analysis of relative ATG5 (D), LC3B-I (E) and LC3B-II (F) expression. ATG5: Autophagy related protein 5; LC3B: Microtubule-associated protein 1 light chain 3 beta. <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i>. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=EGcskUtp26gu6qZ8uyT5yQ==, figureFileBig=PmqptceXObIuVNyLCKr25A==, tableContent=null), ArticleFig(id=1198960120320328243, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=EN, label=null, caption=null, figureFileSmall=+IonxW6OpnsEj5ILjL1/TQ==, figureFileBig=nm33PRQeRFYdM9bjHiFAkQ==, tableContent=null), ArticleFig(id=1198960120471323205, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652612758303438, language=CN, label=Figure 6, caption= Cytotoxicity of IP with or without light. A, B: The 4T1 cell viability was detected by methylthiazolyldiphenyl-tetrazolium bromide (MTT) method. 4T1 cells are treated by the gradient concentration of different drugs (the highest concentration is Ppa was 10 μg·mL<sup>-1</sup>) for 12 h, and under no irradiation (A) or light (10 s) irradiation (B), continue to incubate for 12 h (<i>n</i> = 6); C, D: Apoptosis analysis and statistical charts of 4T1 cells after treatment for 12 h of different drugs (Ppa was 10 μg·mL<sup>-1</sup>), under no irradiation or light (30 s) irradiation (<i>n</i> = 3); E: Live/dead cell staining of 4T1 cells after treatment for 6 h with each group of drugs (Ppa was 10 μg·mL<sup>-1</sup>) under no irradiation or light (3 min) irradiation (<i>n</i> = 8). Scale bar: 50 μm. <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i>±<i>s</i>. <sup>***</sup><i>P</i> < 0.001. 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淫羊藿素与焦脱镁叶绿酸-a自组装纳米药物通过诱导细胞自噬促进肿瘤光动力疗效的研究
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关润钿 1 , 郑蓉蓉 1 , 杨妮 2 , 饶小娜 1 , 李仕颖 1, *
药学学报 | 研究论文 2023,58(8): 2483-2493
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药学学报 |研究论文 2023 , 58 (8) : 2483 -2493
淫羊藿素与焦脱镁叶绿酸-a自组装纳米药物通过诱导细胞自噬促进肿瘤光动力疗效的研究
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关润钿1, 郑蓉蓉1, 杨妮2, 饶小娜1, 李仕颖1, *
作者信息
  • 1.广州医科大学药学院, 广东 广州 511436
  • 2.广东药科大学药学院, 广东 广州 510006
通讯作者:
*李仕颖, Tel: 86-20-37103274, E-mail:
Icaritin and pyropheophorbide-a self-assembled nanomedicine for enhanced the efficacy of photodynamic tumor therapy by increase the cell autophagy
Run-tian GUAN1, Rong-rong ZHENG1, Ni YANG2, Xiao-na RAO1, Shi-ying LI1, *
Affiliations
  • 1. School of Pharmacy, Guangzhou Medical University, Guangzhou 511436, China
  • 2. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2022-0997
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摘要
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自噬(autophagy) 经常发生在细胞遭受氧化应激(oxidative stress) 后, 通过吞噬受损结构并降解成营养物质, 从而降低氧化损伤, 促进癌细胞存活并降低光动力治疗(photodynamic therapy, PDT) 的治疗效果。然而过度激活自噬能促进细胞发生凋亡, 本研究使用光敏剂焦脱镁叶绿酸-a (pyropheophorbide-a, Ppa) 产生大量的活性氧(reactive oxygen species, ROS) 达到杀伤癌细胞的效果, 同时通过联用自噬诱导剂淫羊藿素(icaritin, Ica) 过度激活自噬, 使其对癌细胞的保护转变为促进癌细胞凋亡的作用, 进而达到提高PDT的效果。本研究利用Ica与Ppa间的相互作用力, 成功构建了具有稳定性好、载药量高等特点的自组装纳米药物IP。其中, 该纳米药物合成方法简单, 通过药物自身作为载体, 将Ica与Ppa的载药量(loading capacity, LA) 分别提升至83.53%和16.45%, 且不引入纳米载体潜在的生物安全性隐患。与游离Ppa相比, 自组装纳米药物IP在细胞摄取和ROS产生等方面展现出优越性能。此外, 自组装纳米药物IP能通过激活肿瘤细胞发生自噬, 进而逆转PDT诱发的保护性自噬并促进细胞凋亡和抗肿瘤协同, 显著提高PDT的抗肿瘤活性。

光动力治疗  /  自噬  /  自组装  /  纳米药物  /  癌症

Autophagy often occurs after cells are attacked by oxidative stress, where damaged structures are phagocytic and degraded into nutrients, thereby reducing oxidative damage, promoting the survival of cancer cells and reducing the therapeutic effect of photodynamic therapy (PDT). However, excessive activation of autophagy can promote cell apoptosis. In this paper, the photosensitizer pyropheophorbide-a (Ppa) was used to produce a large amount of reactive oxygen species (ROS) to achieve the effect of killing cancer cells. At the same time, icaritin (Ica), an autophagy inducer, was used to over-activate autophagy, which transformed the protection of cancer cells into the promotion of cancer cell apoptosis, so as to improve the effect of photodynamic therapy. In this study, the interaction force between Ica and Ppa was exploited to successfully construct a self-assembled nanomedicine IP with good stability and high drug load. The synthesis method is simple, through using the drug itself as a carrier, and the loading capacity (LA) of Ica and Ppa can be increased to 83.53% and 16.45% without introducing potential biosafety risks of nanocarriers. Compared with free Ppa, self-assembled nanomedicine IP showed superior performance in cellular uptake and reactive oxygen species production. In addition, the self-assembled nanomedicine IP can reverse the protective autophagy induced by PDT by activating the autophagy of tumor cells, and facilitate apoptosis and antitumor coordination, which significantly improves the antitumor activity of PDT.

photodynamic therapy  /  autophagy  /  self-assembly  /  nanomedicine  /  cancer
关润钿, 郑蓉蓉, 杨妮, 饶小娜, 李仕颖. 淫羊藿素与焦脱镁叶绿酸-a自组装纳米药物通过诱导细胞自噬促进肿瘤光动力疗效的研究. 药学学报, 2023 , 58 (8) : 2483 -2493 . DOI: 10.16438/j.0513-4870.2022-0997
Run-tian GUAN, Rong-rong ZHENG, Ni YANG, Xiao-na RAO, Shi-ying LI. Icaritin and pyropheophorbide-a self-assembled nanomedicine for enhanced the efficacy of photodynamic tumor therapy by increase the cell autophagy[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2483 -2493 . DOI: 10.16438/j.0513-4870.2022-0997
正文
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光动力治疗(photodynamic therapy, PDT) 作为广泛应用的抗肿瘤治疗手段, 由于其高效性、非侵入性、无耐药性等优势, 是近年来研究的热点[1]。在光照条件下, 摄取进入癌细胞的光敏剂能把细胞内O2转化为具有强氧化活性和细胞毒性的活性氧(reactive oxygen species, ROS), 从而氧化细胞内蛋白、脂质和DNA, 达到抑制细胞增殖和抗肿瘤的目的[2]。
自噬(autophagy) 是一种细胞内重要的物质分解过程, 通过把细胞内受损的细胞器或细胞质包裹后形成自噬体, 并递送到溶酶体中降解成可重新利用的营养物质[3]。PDT过程中产生的ROS可诱发肿瘤细胞自噬行为, 通过吞噬损伤的细胞部位并降解为基础营养物质以继续存活, 从而降低PDT带来的细胞毒性[4]。自噬的发生依赖于一些相关蛋白进行调控, 而这些蛋白也可作为自噬发生的标志[5]。在自噬体延伸过程中, 自噬相关蛋白5 (autophagy related protein 5, ATG5) 是必不可少的[6]。ATG5复合物定位在自噬体的膜上后, 膜向着背对ATG5的方向发生弯曲和延伸[7]。ATG5复合物与自噬体膜的结合后, 还会募集微管相关蛋白1轻链3β (microtubule-associated protein 1 light chain 3 beta, LC3B)[8]。在自噬过程中, LC3B最后会从LC3B-I脂质化成LC3B-II, LC3B-II的表达与自噬的发生呈正相关[9]。受损的胞质经自噬体递送到溶酶体并降解成对细胞有益的营养物质[10], 起到促进癌细胞的作用。然而自噬也是一把双刃剑, 过度激活的自噬会导致细胞死亡[11, 12]。研究表明[13], 尽管PDT过程中产生的ROS激活促进癌细胞存活的自噬, 但使用自噬诱导剂能将PDT中自噬的促存活作用逆转成促凋亡。
据文献[14]报道, 淫羊藿素(icaritin, Ica) 是从淫羊藿中提取的一种异戊二烯类黄酮衍生物, 对多种癌症都有治疗效果。Ica能通过诱导线粒体发生自噬, 使肝癌细胞发生凋亡[15]。而焦脱镁叶绿酸-a (pyropheophorbide-a, Ppa) 是一种常用的光敏剂, 具有较强的PDT效果, 目前已有大量相关研究[16]。但这两种药物较差的水溶性限制了细胞摄取, 通过构建纳米药物递送载体能有效提升其摄取能力。其中, 在PDT中, 光敏剂一般通过制备成纳米药物实现细胞递送[17], 如使用脂质体包载后递送[18], 或使用多肽修饰后进行递送[19]。然而, 它们的设计和合成复杂, 且载药量较低, 在实际条件中难以实现广泛应用。最近, 一种可实现药物与药物间自组装的自递送系统得以被设计, 其通过药物与药物间的分子间相互作用力自组装形成纳米药物, 具有良好的药物稳定性和较高的载药量, 且具有无需载体或其他物质进行修饰, 合成过程简单等优势[20]。然而, 基于光敏剂和自噬调节剂的自传递纳米药物未见相关报道。
本研究将自噬诱导剂Ica与光敏剂Ppa通过分子间相互作用力自组装形成纳米药物, 构建了一种自递送的纳米药物(简称IP)。由于药物自身作为载体, 纳米药物IP具有较高的载药量, 形成的纳米药物改善了单一药物的疏水性, 能在水相中表现出良好的稳定性, 并且增强了药物在细胞中的摄取。在光照条件下, 纳米药物IP中的光敏剂生成的活性氧可引发细胞凋亡, 自噬诱导剂Ica可进一步诱导肿瘤细胞过度自噬, 不仅可促凋亡, 还能逆转PDT中自噬的抗凋亡作用, 进而促进PDT效果。
材料与方法
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主要仪器  纳米颗粒分析仪(MAL1175005, 英国马尔文仪器有限公司); 透射电子显微镜(JEM-1400 PLUS, 捷欧路科贸有限公司); 紫外分光光度计(UV-2600)、荧光分光光度计(RF-5301PC)、高效液相色谱仪(LC-20AT) (岛津仪器设备有限公司); 超高分辨率共聚焦显微镜(LSM 880, 德国卡尔蔡司有限公司); Amnis成像流式细胞仪(德国默克密理博公司); 630 nm LED光源(北京镭源科技有限公司); 精密电子天平(SQP, 赛多利斯科学仪器有限公司)。
主要试剂  Ica、Ppa (上海源叶生物科技有限公司); DCFH-DA (2, 7-dichlorodihydrofluorescein diacetate)、Hoechst 33342、Rhodamine 123、Annexin V-FITC细胞凋亡检测试剂盒、MTT (methylthiazolyldiphenyl-tetrazolium bromide)、SDS-PAGE凝胶配制试剂盒(上海碧云天生物技术有限公司); 单线态氧绿色荧光探针(singlet oxygen sensor green, SOSG, 大连美仑生物技术有限公司); CellROXTM Green试剂(美国英杰生命技术有限公司); 洗膜缓冲液TBST (Tris buffered saline Tween) 粉末(广州晶欣生物科技有限公司); RIPA (radio immunoprecipitation assay) 裂解和提取缓冲液、BCA (bicinchoninic acid) 试剂盒(赛默飞世尔科技公司); 聚偏二氟乙烯(polyvinylidene fluoride, PVDF) 膜(默克公司); 蛋白酶抑制剂、LC3B抗体、ATG5 (D5F5U) rabbit mAb (Cell Signaling公司); 辣根酶标记抗兔IgG、辣根酶标记抗鼠IgG (北京中杉金桥生物技术有限公司); 所有细胞培养相关试剂如磷酸盐缓冲液(phosphate buffer saline, PBS)、高糖DMEM、胎牛血清(FBS)、青霉素-链霉素(penicillin-streptomycin solution, PS) 混合液[赛默飞世尔生物化学制品(北京) 有限公司]。
纳米药物IP的制备  分别将Ica和Ppa溶解成10 mg·mL-1的DMSO溶液, Ica和Ppa的DMSO溶液按照摩尔比为3∶1 (108 μL∶53 μL) 的投料比在EP管中混匀后, 在超声中滴入到2 mL的超纯水中, 用移液枪吹打50次后, 继续超声15 min。收集超声后的溶液并用14 000 r·min-1的转速离心30 min, 以除去溶液中的游离Ica和Ppa。离心去除上清液后加入2 mL的超纯水进行重悬, 得到纳米药物IP。再以此方法分别制备Ica和Ppa的投料比为1∶1 (36 μL∶53 μL)、2∶1 (72 μL∶53 μL) 的纳米药物。
纳米药物IP的表征  采用超纯水把不同投料比的纳米药物稀释3倍, 在超声中使用移液枪吹打30下后得到纳米药物的稀释水溶液。使用动态光散射法(dynamic light scattering, DLS) 连续7天测量各比例纳米药物的粒径大小及多分散系数(polydispersity index, PDI), 并测量纳米药物的zeta电势。将纳米药物适当稀释后, 分别滴加在300目的普通碳支持膜正面上以制备电镜样品。样品自然阴干后通过透射电子显微镜观察纳米药物的微观形态。
纳米药物IP的载药量  首先根据纳米药物IP的投料量分别制备Ica和Ppa的标准溶液, 并使用高效液相色谱仪制作药物的标准曲线。在纳米药物IP的合成中, Ica的投料浓度为0.54 mg·mL-1, 由于提纯后药物的量会有所损耗, 所以样品在稀释10倍后Ica会少于54 μg。故Ica标准溶液的浓度设置为10、15、20、25、30、40、50 μg·mL-1。同样地, Ppa的投料浓度为0.265 mg·mL-1, 故Ppa标准溶液的浓度设置为2、5、10、15、20、25、30 μg·mL-1。合成纳米药物IP的平行样品3个, 使用DMSO稀释10倍后加入到色谱瓶中, 超声1 min, 使用高效液相色谱仪测定峰面积, 其中紫外可见吸收检测器作为检测器。色谱条件如下: 流动相A为0.1%三氟乙酸水溶液; 流动相B为乙腈。使用二元高压梯度洗脱, 保留时间与流动相比例为: 0~9 min, A∶B (40~60); 9~30 min, A∶B (5~95); 30~45 min, A∶B (0~100)。经过计算后得出纳米药物IP中的载药量(loading capacity, LA) 和包封率(entrapment efficiency, EE)。载药率和包封率的计算公式分别如公式(1、2)。
$ \mathrm{L}\mathrm{A}=\frac{{W}_{\mathrm{I}\mathrm{P}\mathrm{中}\mathrm{药}\mathrm{物}\mathrm{的}\mathrm{质}\mathrm{量}}}{{W}_{\mathrm{I}\mathrm{P}\mathrm{的}\mathrm{质}\mathrm{量}}}\times 100\mathrm{ }\mathrm{\%} $
$ \mathrm{E}\mathrm{E}=\frac{{W}_{\mathrm{I}\mathrm{P}\mathrm{中}\mathrm{的}\mathrm{载}\mathrm{药}\mathrm{量}}}{{W}_{\mathrm{投}\mathrm{药}\mathrm{量}}}\times 100\mathrm{ }\mathrm{\%} $
纳米药物IP自组装机制的探索  将25 μL纳米药物IP分别加入到975 μL HCl水溶液和NaOH水溶液中(HCl水溶液和NaOH水溶液的pH分别为3和12), 测量其紫外-可见吸收光谱。配制不同摩尔浓度(0、0.25、0.5、1、1.5、2 mol·L-1) 的NaCl水溶液, 将25 μL纳米药物IP分别加入到975 μL不同浓度的NaCl水溶液中, 测量其紫外-可见吸收光谱。观察随着NaCl浓度的升高, Ppa在660 nm的最大吸收峰的变化。将20 mg十二烷基硫酸钠(sodium dodecyl sulfate, SDS) 加入到10 mL超纯水中, 混匀并超声, 得到0.2% SDS溶液。以超纯水做基线, 测量0.2% SDS溶液的紫外-可见吸收光谱。将25 μL纳米药物IP分别加入到975 μL的超纯水和0.2%的SDS溶液中, 观察在660 nm处的最大吸收峰的变化。将Ppa配成32.5 μg·mL-1的水溶液, 测量其紫外可见分光光谱, 与纳米药物IP的水溶液比较在660 nm处的最大吸收峰的变化。
细胞培养  小鼠乳腺癌细胞(4T1细胞, 购自美国菌种保藏中心), 加入到含10% FBS和1% PS的DMEM的细胞培养基中, 并放于37 ℃、5% CO2培养箱中。
纳米药物IP在4T1中的摄取  使用共聚焦小皿(广州晶欣生物科技有限公司) 培养4T1细胞, 分别加入5 μg·mL-1 Ppa、等浓度的纳米药物IP到细胞中孵育, 全程保持避光条件。孵育时间逐渐递增, 在6、12、18 h后弃去原有培养基, 用PBS清洗3次, 再使用Hoechst 33342染料染细胞核, 在37 ℃孵育20 min后用PBS清洗3次后。使用共聚焦显微镜观察4T1细胞中随摄取时间逐渐增加后Ppa产生的红色荧光强度的变化。保持孵育时间为12 h, Ppa和纳米药物IP的浓度逐渐增加, 分别为2、5、8 μg·mL-1。经Hoechst 33342处理后, 使用共聚焦显微镜观察随着药物浓度逐渐增加后的Ppa产生的红色荧光强度的变化。
使用Amnis成像流式细胞仪对摄取进入4T1细胞的纳米药物IP进行定量。使用6孔板培养4T1细胞, 在不同孔中分别加入5 μg·mL-1 Ppa和等浓度的纳米药物IP并在避光条件下孵育。分别于6、12、18 h后, 弃去原有培养基, 用PBS清洗3次, 再用胰酶消化细胞3 min后用DMEM停止消化并把细胞收集在EP管中。离心(3 000 r·min-1, 4 ℃) 后使用1 mL PBS清洗, 再次离心后使用200 μL PBS重悬, 使用流式细胞仪检测增加摄取时间后在4T1细胞中Ppa产生的红色荧光强度的变化。加入到4T1的Ppa和纳米药物IP的浓度逐渐增加(2、5、8 μg·mL-1)。处理后使用流式细胞仪检测随着药物浓度的增加, 摄取进入4T1细胞的药物中Ppa产生的红色荧光强度的变化。
纳米药物IP产生的单线态氧  使用SOSG为单线态氧的检测试剂, 在荧光分光光度计检测纳米药物在水溶液中单线态氧的生成。根据定量, 以5 μg·mL-1 Ppa为标准, 把各组药物[IP (+)、IP、Ppa (+)、Ppa、Ica] 配成等量的1 mL的水溶液。其中, IP (+)、IP、Ppa (+)、Ppa、Ica分别为纳米药物IP加光照、纳米药物IP无光照、单纯的Ppa加光照、单纯的Ppa无光照、单纯的Ica无光照。将SOSG探针配成0.5 μmol·L-1的甲醇溶液, 取10 μL SOSG甲醇溶液与990 μL的各组药物混合, 成为检测溶液。光照组[IP (+)、Ppa (+)] 使用He-Ne激光(激光强度: 50 mW·cm-2) 照射检测溶液20 s, 并马上放入到荧光分光光度计中进行测量。其余组在黑暗中孵育相同时间后测量荧光。使用488 nm激发波长对溶液荧光进行检测, 以光照射PBS中SOSG (5 mol·L-1) 为空白对照(10 μL SOSG溶液加入到990 μL PBS)。
纳米药物IP在4T1产生的ROS  使用共聚焦小皿培养4T1细胞24 h, 并根据定量加入以5 μg·mL-1 Ppa为标准的各组别药物[IP (+)、IP、Ppa (+)、Ppa、Ica、Ppa + Ica、Ppa + Ica (+)], 孵育12 h。使用PBS洗涤细胞, 并与DCFH-DA一起孵育30 min后使用PBS洗涤细胞。对于无光照处理组(IP、Ppa、Ica、Ppa + Ica), 洗涤后直接拍摄; 而对于光照组[IP (+)、Ppa (+)、Ppa + Ica (+)], 细胞暴露于光下1 min后进行拍摄。加药组与空白组比较荧光强度。使用CellROXTM Green探针处理的步骤与此相同。
纳米药物IP在4T1诱导自噬  使用共聚焦小皿培养4T1细胞24 h, 分别加入10、20、40 μg·mL-1的Ica处理细胞, 孵育12 h后用PBS洗3次, 并使用Rhodamine 123孵育30 min并用PBS洗涤后, 使用共聚焦观察4T1细胞中加入Ica后发生自噬的变化。使用蛋白质印迹法(Western blot, WB) 检测自噬相关蛋白的表达。在6孔板培养4T1细胞24 h后, 根据定量加入以5 μg·mL-1 Ppa为标准的各组药物[IP (+)、IP、Ppa (+)、Ppa、Ica、Ppa + Ica、Ppa + Ica (+)] 处理细胞后, 光照30 s, 继续孵育4 h。经过PBS清洗细胞后, 在冰上利用RIPA裂解、提取缓冲液和蛋白酶抑制剂裂解细胞, 提取细胞总蛋白, 用BCA试剂盒测定总蛋白浓度, 并加入RIPA和SDS-PAGE蛋白上样缓冲液将各样品稀释成相同浓度, 在沸水中煮10 min后进行SDS-PAGE电泳, 使用半干法转PVDF膜, 恒流300 mV保持2 h。使用5%脱脂奶粉封闭90 min, 4 ℃过夜孵育一抗[LC3B抗体、ATG5 (D5F5U) rabbit mAb]; 使用TBST将洗膜5次, 室温孵育相应的荧光二抗2 h, 最后使用曝光显色。使用Image J软件扫描蛋白条带并定量分析。
纳米药物IP对4T1的体外毒性实验  首先通过MTT法评估纳米药物IP对4T1的PDT效果。使用96孔板培养4T1细胞, Ppa、Ica和纳米药物IP以10 μg·mL-1 Ppa为最高浓度标准向下梯度稀释, 配好的稀释药物分别加100 μL至96孔板中。每列留1个孔为空白对照组, 只加培养基。避光孵育12 h后, 光照组[IP (+)、Ppa (+)、Ppa + Ica (+)] 在LED照明灯下光照10 s后继续孵育12 h。无光照处理组(IP、Ppa、Ica、Ppa + Ica) 避光孵育24 h。然后, 每孔加入20 μL MTT (5 μg·mL-1), 继续避光孵育4 h, 吸走上清液后, 每孔加入150 μL DMSO, 并使用酶标仪检测570 nm处吸光度, 并计算细胞存活率。
使用流式细胞仪评估纳米药物IP对4T1的PDT效果。6孔板经4T1细胞种板后培养24 h, 经过Ppa、Ica、Ppa + Ica和IP分别处理后避光孵育12 h, 光照组[IP (+)、Ppa (+)、Ppa + Ica (+)] 细胞暴露于LED灯下30 s。所有组别用PBS洗3次后, 用不含EDTA的胰酶消化细胞, 孵育2 min, 收集细胞到EP管中。离心(3 000 r·min-1、3 min) 后弃上清, 沉淀用1 mL PBS重悬清洗, 转移至1.5 mL EP管中。再次离心后吸去上清, 加入195 μL Annexin V-FITC结合液重悬, 再加入5 μL Annexin V-FITC和10 μL碘化丙啶染色液混匀。于37 ℃孵育20 min后使用流式细胞仪进行检测。Ppa、Ica和IP加药浓度以定量后纳米药物IP中含0.5 μg·mL-1 Ppa时的浓度为准。
对于活/死细胞染色实验, 聚焦小皿经4T1细胞种板后培养24 h, 经过Ppa、Ica、Ppa + Ica和纳米药物IP分别处理后孵育6 h, 用PBS洗3次后, 光照组[IP (+)、Ppa (+)、Ppa + Ica (+)] 细胞暴露于LED灯下3 min, 使用活/死细胞染料(1 mL培养基加0.5 μL钙黄绿素、1.5 μL碘化丙啶) 染色孵育20 min。通过共聚焦观察各组别细胞中活细胞(488 nm处的绿色荧光) 和死细胞(535 nm处的红色荧光) 间的比例。Ppa、Ica和IP组加药浓度以定量后纳米药物IP中含5 μg·mL-1 Ppa时的浓度为准。
统计学分析  用SPSS 20.0统计软件进行分析, 数据用x±s表示, 组间比较采用Student's t test, P < 0.05表示差异具有统计学意义。
结果
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1 纳米药物IP的合成与表征
纳米药物IP通过Ppa和Ica间的π-π堆积自组装制备而成, 为证实这一点, 通过在透射电子显微镜中观察纳米药物的形态。如图 1A, 游离Ppa和Ica由于具有疏水性, 在水中表现出严重的聚集行为。为得到理想的纳米药物, 调节Ppa与Ica的投料比, 并观察其形态(图 1A)。随着Ica比例逐渐增高, 纳米药物的聚集现象得到明显改善, 粒径形态逐渐均匀, 表现出均匀的短棒状。其中Ppa与Ica投料比为1∶1的纳米药物, 颗粒间形态差别较大, 有较多絮状物; 投料比为1∶2时, 形成的纳米药物逐渐形成较为均匀的棒状物, 但粒径过大; 当投料比为1∶3时, 呈现出形态均一的短棒状纳米药物, 且分散性良好, 粒径较小。类似的结果通过马尔文纳米颗粒分析仪也能再次证实。如图 1B~D所示, 3种不同投料比的纳米药物经过马尔文纳米颗粒分析仪测量得出纳米药物的粒径大小及多分散系数。连续7天测量纳米药物的粒径大小及多分散系数, 以探究其在水中的稳定性(图 1E~G)。在7天内, 相对于投料比为1∶1和1∶2形成的纳米药物, 投料比为1∶3 (Ppa∶Ica) 的纳米药物的粒径大小和多分散系数较为稳定, 且无明显大颗粒。如图 1D、G所示, 投料比为1∶3 (Ppa∶Ica) 的纳米药物粒径稳定在176 nm左右, PDI约为0.171, 且测得电势为-18.2 ± 0.45 mV (图 2A), 具有较好的稳定性。综合以上考虑, 选择投料比为1∶3形成的纳米药物进行后续实验, 并命名为纳米药物IP。
2 纳米药物IP的表征与载药量
为进一步验证纳米药物IP是否组装成功, 使用紫外可见光分光光度计分别检测Ppa和IP在水中的紫外光谱。从图 2B可知, Ppa在660 nm处有最大特征吸收峰, 但IP的最大特征吸收峰发生蓝移, 因此可得出Ppa与Ica可组装成纳米药物IP。Ppa在酸性水溶液中会聚集成团, 而在碱性水溶液中会呈分散状态。通过紫外光谱图可发现, 在酸碱环境中, Ppa在660 nm处的最大吸收峰与IP在水中的有所区别, IP的最大吸收峰出现明显红移(图 2C、D), 表明分子间相互作用力影响了IP中Ppa的电子跃迁。而在不同浓度的氯化钠溶液中, 含相同浓度的IP溶液的紫外光谱几乎无变化(图 2E、F), 证明在IP中, Ppa与Ica这两个药物间不存在静电作用力。如图 2G可知, 加入0.2% SDS后, IP溶液在660 nm处出现蓝移, 证明纳米药物IP的组装是通过分子间疏水作用力形成的。通过高效液相色谱仪对IP的载药量与包封率进行探究。图 2H、I分别为Ppa和Ica标准曲线, 通过纳米药物IP样品的峰面积测得所含有药物的具体浓度, 最后经过计算得出载药量和包封率。Ppa和Ica的包封率分别为24.52%和61.11%, 载药量分别为16.45%和83.53%。综上所述, 纳米药物IP具有良好的稳定性、分散性和较高的载药量。
3 纳米药物IP的摄取能力
为验证纳米药物IP是否能比游离Ppa更易被4T1细胞摄取, 通过观察4T1分别经过Ppa和IP孵育一段时间后, 细胞内荧光强度的变化。结果显示, 保持孵育时间不变, 随着加药浓度升高, 红色荧光逐渐增强(图 3A)。且自组装形成纳米药物IP后, IP组的红色荧光相比同样浓度的Ppa更强。当保持加药浓度不变而孵育时间延长后, 红色荧光逐渐增强(图 3B)。孵育18 h后, 细胞内的Ppa逐渐趋于饱和。图 3C、D为对应的荧光强度统计结果。使用同样的孵育方法, 在流式细胞检测仪中可看到相似结果(图 3E、F)。相比共聚焦显微镜拍摄的统计, 流式细胞仪方法检测的Ppa与IP在不同孵育时间的荧光强度的差别更大, 可能是由于细胞在摄入Ppa后在PBS中更易被细胞排出。但这些摄取实验可证明, 相对于游离的Ppa, 纳米药物IP被4T1摄取的能力明显更强。
4 纳米药物IP增强的细胞中ROS的产生
上述实验验证了相对于Ppa, 纳米药物IP被4T1摄取的能力更强。因此继续研究了纳米药物IP能否促进ROS的产生。首先使用SOSG作为指示剂, 通过荧光光谱的变化值来评估各组药物单线态氧的产生(图 4A)。在没有光照或无光敏剂的组别中, 荧光强度变化不大, 荧光倍数几乎没有增加, 表示这些组别产生的单线态氧可忽略不计。而IP组和Ppa组在光照后, 荧光强度明显增强, 倍数达到7~8倍。这表明IP和Ppa在溶液中能产生大量单线态氧。在细胞实验中, 使用DCFH-DA探针对不同组别产生的ROS进行检测(图 4B)。无光照处理组由于没有产生ROS, 几乎没有荧光。相反在各个光照组中, 都显示出明亮荧光, 其中IP (+) 组的荧光强度要比其他组更强, 表明纳米药物IP在光照后能产生出更多ROS。同样地, 使用CellROXTM Green处理各组别细胞后能得到相似的结果(图 4C), IP (+) 组荧光强度最强, 表明光照后纳米药物IP比其他组别产生更多ROS, 与前面结果相似。
5 纳米药物IP诱导细胞自噬
根据文献[21]报道, PDT过程中产生的ROS可引发细胞自噬, 在使用自噬激活剂后, 自噬能进一步被激活。Ica可激活线粒体自噬, 有研究表明[15], Ica激活自噬后线粒体的形态会由条状变成团状。从图 5A可知, 加入Ica处理细胞后, 线粒体的形态由原来正常的线状, 变成聚集在一起的团状和球状, 表明Ica能激活自噬。此外, 本研究还通过WB分析了经过各组别处理4T1细胞后ATG5和LC3B的表达, 来判定纳米药物对自噬的激活程度。从WB条带可看出, 加入Ica后ATG5表达明显增加, 表明了自噬的激活(图 5B)。经过统计后得出, 纳米药物IP组中ATG5的增加最高, 且具有统计学意义, 表明纳米药物IP能有效激活自噬。LC3B-I在经过纳米药物IP处理和光照后明显下降(图 5C)。Ica可上调LC3B-II表达, 形成纳米药物IP后, LC3B-II的表达量更高, 这些结果都具有统计学意义(图 5D~F), 表明纳米药物IP通过提高细胞的摄取进而促进自噬的激活。Ppa (+) 组别的LC3B-II表达量会轻微上调, 且纳米药物IP (+) 光照后LC3B-II的表达量最高, 证实了纳米药物IP介导的PDT能有效激活自噬。
线粒体形态的改变及自噬相关蛋白表达的变化不仅证明自噬激活剂Ica会引发细胞自噬, 也表明PDT过程中产生的ROS可进一步引发细胞的自噬。而且由于纳米药物IP有更强的细胞摄取能力, 促进自噬的效果比游离组更强, 证明了纳米药物IP能协同PDT与自噬激活剂共同激活自噬。
6 纳米药物IP诱导的自噬与ROS协同促进细胞凋亡
为了验证纳米药物IP产生的ROS与诱导的自噬是否可协同促进PDT引起的细胞凋亡, 比较各组药物处理后对细胞的毒性。在MTT实验中, 低剂量Ica几乎没有毒性(图 6A), 高剂量时显示轻微毒性, 表明过度自噬可诱发凋亡。而上述结果(图 5) 表明, Ica联合PDT可进一步引发细胞自噬。本结果也表明这一点, 经过光照后, Ica + Ppa (+) 组和IP (+) 组都表现出非常明显的细胞毒性(图 6B), 且明显比游离Ppa (+) 组或游离Ica组的细胞毒性更强, 表明Ica与PDT协同治疗后, 能通过增强自噬加强PDT治疗效果。IP (+) 组表现明显剂量依赖性且相对于游离的Ica + Ppa (+) 毒性更强, 这也体现出纳米药物IP良好的摄取作用, 证实了IP (+) 组具有最强的抗肿瘤能力。此外, 使用流式细胞仪对各组别处理后的细胞进行凋亡分析, 结果与MTT结果类似, 如图 6C、D所示, 细胞分群结果显示, 纳米药物IP经光照后, 细胞发生凋亡的数量占比最多, 可达65.4%, 与其他组别相比也具有统计意义。最后, 使用钙黄绿素和碘化丙啶荧光染料对各组别的活细胞和死细胞进行区分, 通过共聚焦比较各组别的抗增殖能力, 绿色荧光表示活细胞, 红色荧光表示死细胞(图 6E)。没有光照时, 各组别几乎没有毒性或毒性很小。经过光照后, 游离的Ppa (+) 只有少量红色荧光, 加入游离的Ica与Ppa共同处理细胞后, 红色荧光加强, 而IP (+) 组荧光强度最强, 表明自噬与PDT协同造成癌细胞死亡。上述这些结果都表明了, 在光照条件下, 纳米药物IP可通过激活自噬来协同PDT, 并显示出有效的抗细胞增殖和抗肿瘤治疗效果, 体现出自组装策略对于光动力肿瘤治疗具有巨大潜力。
讨论
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作为一种细胞的新陈代谢反应, 自噬既有可能保护细胞, 也有可能使细胞发生凋亡, 这取决于自噬发生的程度[21]。本研究表明, 低剂量Ica引发的自噬不足以令细胞发生死亡, 还有可能促进细胞增殖(图 6A)。而当Ica达到13 μg·mL-1时, 细胞存活率有所下降, 表明过度的自噬超过细胞所能承受的压力后, 引发细胞凋亡。而PDT中光敏剂产生的ROS也是自噬的重要诱导物, 游离的Ppa (+) 诱导的自噬程度与游离的Ica组几乎相同(图 5E、F)。Ica与光敏剂联用后, 明显增强了自噬效果, 实验也验证了Ica + Ppa (+) 与IP (+) 组的自噬程度与细胞毒性程度都表现出1 + 1 > 2的效果(图 5E、F和图 6B)。
本研究设计了一种通过Ica与Ppa自组装形成的纳米药物IP, 可有效增强光敏剂被细胞摄取的能力, 且具有较强的稳定性和良好的分散性, 同时表现出良好的载药量和包封率。纳米药物IP摄取进入细胞后, 在光照条件下产生的ROS会诱导细胞发生保护性自噬, 而Ica作为自噬诱导剂能进一步激活自噬, 并将保护细胞的自噬从促进细胞存活转化成促进细胞发生凋亡。实验证实了IP中的Ica能协同PDT带来的过度自噬与光敏剂产生的ROS共同促进小鼠乳腺癌细胞凋亡, 产生良好的抗肿瘤效果。本研究提出了一种合成方法简单而有效地促进自噬协同PDT的策略, 将有助于自组装纳米药物与PDT协同抗肿瘤机制的进一步研究。
作者贡献: 关润钿主要负责文章中数据的收集、分析与解释及稿件撰写; 郑蓉蓉主要负责研究文章的构思、设计及文章修改; 杨妮、饶小娜在数据收集及文章修改中给予帮助; 李仕颖主要负责资金支持及指导文章修改。
利益冲突: 所有作者均声明不存在任何利益冲突。
基金
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  • 国家重点研发计划项目(2021YFD1800600)
  • 广东省基础与应用基础项目(2021B1515020043)
文献
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参考文献 引证文献
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2023年第58卷第8期
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文章信息
doi: 10.16438/j.0513-4870.2022-0997
  • 接收时间：2022-08-18
  • 首发时间：2025-11-21
  • 出版时间：2023-08-12
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  • 收稿日期：2022-08-18
  • 修回日期：2022-09-06
基金
国家重点研发计划项目(2021YFD1800600)
广东省基础与应用基础项目(2021B1515020043)
作者信息
    1.广州医科大学药学院, 广东 广州 511436
    2.广东药科大学药学院, 广东 广州 510006

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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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