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Article(id=1200860515066048603, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-1087, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1695139200000, receivedDateStr=2023-09-20, revisedDate=1709740800000, revisedDateStr=2024-03-07, acceptedDate=null, acceptedDateStr=null, onlineDate=1764237057701, onlineDateStr=2025-11-27, pubDate=1715443200000, pubDateStr=2024-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764237057701, onlineIssueDateStr=2025-11-27, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764237057701, creator=13701087609, updateTime=1764237057701, updator=13701087609, issue=Issue{id=1200860506031518620, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='5', pageStart='1101', pageEnd='1508', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764237055547, creator=13701087609, updateTime=1764241222263, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200877982563824311, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200877982563824312, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1430, endPage=1440, ext={EN=ArticleExt(id=1200860515829411979, articleId=1200860515066048603, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Photothermal-sensitive biomimetic liposomes coated with DOX and IR820 for chemo-photothermal-photodynamic therapy of cancer in lung cancer cells, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

In this study, doxorubicin (DOX) was used as the model drug, new indocyanine green (IR820) as the photosensitizer, and temperature sensitive liposomes (TSL) as the carrier. H460-NCI photoheat-sensitive liposomes coated with cell membrane of human cell lung cancer (DOX-IR820-TSL@CCM) for highly effective multi-pathway tumor targeting in chemical-photothermal therapy and photodynamic therapy. DOX-IR820-TSL was prepared by reverse evaporation, cancer cell membrane (CCM) was prepared by lysis, crushing and centrifugation, and DOX-IR820-TSL@CCM was prepared by nanomembrane extrusion. The drug-loading conditions of DOX-IR820-TSL were finally determined: the ratio of organic phase to aqueous phase was 4.02, the dosage of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was 10.04 mg, and the lipid ratio was 0.12, and the significant phase transition temperature (Tm) of DOX-IR820-TSL was 43.05 ℃. The average particle size of DOX-IR820-TSL@CCM was 153.4 nm, the PDI was 0.279, and the zeta potential was -26.2 mV. The transmission electron microscope (TEM) image shows a homogeneous spherical structure and a translucent film layer. Under near-infrared irradiation, the drug release rate reaches 63.98%, which has adjustable photothermal conversion capacity and the ability to generate reactive oxygen species. Through SDS-PAGE electrophoresis, Western blot, cytotoxicity experiments and cell uptake experiments, it was proved that the design of cell membrane coating can well retain CD47, N-cadherin, CD44, CD326 and other related functional proteins, so that DOX-IR820-TSL@CCM has good immune evasion, homologous adhesion and homologous targeting. In this paper, DOX-IR820-TSL@CCM with camouflage properties and tumor targeting properties were successfully prepared, which can be used as a promising synergistic therapeutic diagnostic platform for future lung cancer treatment. All animal research programs have been approved by the Animal Ethics Committee of Heilongjiang University of Chinese Medicine (number: 2022121011).

, correspAuthors=Xue-ying YAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Shi-zhuang LI, Yu-ping KAN, Ming CHEN, Hui SU, Xue-ying YAN), CN=ArticleExt(id=1200860521349116399, articleId=1200860515066048603, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=肺癌细胞膜涂层的DOX和IR820的光热敏感型仿生脂质体用于癌症的化学-光热-光动力治疗, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

本研究构建以多柔比星(doxorubicin, DOX) 为模型药物、新吲哚菁绿(IR820) 为光敏剂、温度敏感脂质体(temperature sensitive liposomes, TSL) 为载体, H460-NCI人大细胞肺癌细胞膜涂层的光热敏感脂质体(DOX-IR820-TSL@CCM), 用于化学-光热治疗-光动力治疗的多途径高效肿瘤靶向作用。采用逆向蒸发法制备DOX-IR820-TSL, 通过裂解、破碎、离心等方法制备癌细胞膜(cancer cell membrane, CCM), 采用纳米膜挤压法制备DOX-IR820-TSL@CCM; 并对上述脂质体进行表征。最终确定DOX-IR820-TSL的载药条件如下: 有机相与水相比例为4.02, 二棕榈酰磷脂酰胆碱(dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) 用量为10.04 mg, 药脂比为0.12, DOX-IR820-TSL显著相变温度(Tm)为43.05 ℃, DOX-IR820-TSL@CCM平均粒径为153.4 nm, PDI为0.279, zeta电位为-26.2 mV。透射电子显微镜图像在图中显示出均匀的球形结构和半透明膜层。在近红外光照射下, 药物释放率达到了63.98%, 具有可调节的光热转化能力和产生活性氧的能力。通过SDS-PAGE电泳、Western blot、细胞毒性实验和细胞摄取实验, 证明了细胞膜涂层的设计能够很好地保留CD47、N-cadherin、CD44、CD326等相关功能蛋白, 使DOX-IR820-TSL@CCM具备良好的免疫逃逸、同源黏附和同源靶向作用。本文制备了具有伪装特性和肿瘤靶向性的DOX-IR820-TSL@CCM, 可作为一种协同治疗诊断平台用于未来的肺癌治疗。所有动物研究方案均已通过黑龙江中医药大学动物伦理委员会批准(编号为: 2022121011)。

, correspAuthors=阎雪莹, authorNote=null, correspAuthorsNote=
*阎雪莹, Tel: 18855754007, E-mail:
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A: Particle size of DOX-IR820-TSL; B: Zeta potential of DOX-IR820-TSL; C: Particle size of DOX-IR820-TSL@CCM; D: Zeta potential of DOX-IR820-TSL@CCM; E: Particle size of different nanoparticles; F: Zeta potential of different nanoparticles. <i>n</i> = 3, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i> , figureFileSmall=bP3b0raNJalm6kMO5/PrCw==, figureFileBig=zKKs6Z0TeTeWCKAstrSrrg==, tableContent=null), ArticleFig(id=1201106663370613125, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=EN, label=null, caption=null, figureFileSmall=F3uZo76BZcZfitKJpDOAaA==, figureFileBig=47iaYpn3793DwTLMOjbvyw==, tableContent=null), ArticleFig(id=1201106663563551121, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=CN, label=Figure 3, caption= Analysis of related proteins in DOX-IR820-TSL@CCM. A: TEM images of DOX-IR820-TSL; B: TEM images of DOX-IR820-TSL@CCM; C: DSC curve of DOX-IR820-TSL; D: SDS-PAGE analysis diagram (Ⅰ: CCL, Ⅱ: CCM, Ⅲ: DOX-IR820-TSL@CCM); E: WB analysis diagram (Ⅰ: CCL, Ⅱ: CCM, Ⅲ: DOX-IR820-TSL@CCM). TEM: Transmission electron microscope; DSC: Differential scanning calorimetry; WB: Western blot , figureFileSmall=F3uZo76BZcZfitKJpDOAaA==, figureFileBig=47iaYpn3793DwTLMOjbvyw==, tableContent=null), ArticleFig(id=1201106663794237854, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=EN, label=null, caption=null, figureFileSmall=thx3g+sEdwxXPf/Pl0FiPA==, figureFileBig=dv2g7mZwnqYF3sK0Izd2SA==, tableContent=null), ArticleFig(id=1201106664016535981, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=CN, label=Figure 4, caption= Study on drug release properties of DOX-IR820-TSL@CCM. A: Fluorescence content in DOX-IR820-TSL and DOX-IR820-TSL@CCM cells was detected by flow cytometry; B: Mean fluorescence intensity of NCI-H460 cells uptake of cancer cell membrane-mediated liposomes prepared with different methods (<sup>**</sup><i>P</i> < 0.01, <i>n</i> = 3, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i>); C: DOX-IR820-TSL and DOX-IR820-TSL@CCM DOX release curve at different temperatures (<i>n</i> = 3, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i>); D: DOX-IR820-TSL@CCM DOX release curve under laser irradiation (808 nm, 2 W·cm<sup>-2</sup>, 5 min) (arrow indicates the time point of receiving laser irradiation); E: Temperature rise curve of IR820 aqueous solution and different components under near-infrared laser irradiation; F: Temperature rise curve of different component aqueous solutions under near-infrared laser irradiation; G: Decrease in UV absorption value at 417 nm of DPBF reactive oxygen probe with NIR light irradiation (808 nm, 2 W·cm<sup>-2</sup>, 5 min) of DOX-IR820-TSL@CCM, DOX-IR820-TSL, DOX-TSL and IR820 aqueous solution (0-10 min). DPBF: 1, 3-Diphenylisobenzofuran , figureFileSmall=thx3g+sEdwxXPf/Pl0FiPA==, figureFileBig=dv2g7mZwnqYF3sK0Izd2SA==, tableContent=null), ArticleFig(id=1201106664213668285, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=EN, label=null, caption=null, figureFileSmall=VlCMZ4zzw4ShL+a2p6Xcrg==, figureFileBig=gOD1FQigZ+134KENP8VCTg==, tableContent=null), ArticleFig(id=1201106664326914502, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=CN, label=Figure 5, caption= Cytotoxicity of DOX-IR820-TSL@CCM. A: DOX-IR820-TSL@CCM results of hemolytic test; B: IC<sub>50</sub> values histogram of NCI-H460 human lung cancer cells; C: Histograms of survival rate of NCI-H460 human lung cancer cells. <i>n</i> = 3, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i>. <sup>**</sup><i>P</i> < 0.01 <i>vs</i> Free IR820; <sup>##</sup><i>P</i> < 0.01 <i>vs</i> DOX-IR820-TSL; <sup>☆☆</sup><i>P</i> < 0.01 <i>vs</i> DOX-IR820-TSL+Laser , figureFileSmall=VlCMZ4zzw4ShL+a2p6Xcrg==, figureFileBig=gOD1FQigZ+134KENP8VCTg==, tableContent=null), ArticleFig(id=1201106664456937938, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Factor/responseNameUnitMinimumMaximumGoal
A (v/v)Organic/aqueous ratio-35-
BDPPC dosagemg515-
C (m/v)Drug/liposomes ratio-0.050.02-
Y1EE-DOX%--Maximize
Y2Sizenm--Minimize
Y3EE-IR820%--Maximize
), ArticleFig(id=1201106664553406941, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=CN, label=Table 1, caption=

Factors and responses used in Box Behnken design. DPPC: Dipalmitoyl-sn-glycero-3-phosphocholine; EE: Drug entrapment efficiency; DOX: Doxorubicin; IR820: New indocyanine green

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Factor/responseNameUnitMinimumMaximumGoal
A (v/v)Organic/aqueous ratio-35-
BDPPC dosagemg515-
C (m/v)Drug/liposomes ratio-0.050.02-
Y1EE-DOX%--Maximize
Y2Sizenm--Minimize
Y3EE-IR820%--Maximize
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RunABCY1Y2Y3
101153.96352.9037.13
2-10-136.32215.3018.91
3-10132.83263.7026.82
401-163.28317.4057.64
500070.96132.9052.13
6-1-1030.85128.5013.27
7-11041.46371.6035.12
811052.74374.3039.27
90-1-148.37127.6030.16
100-1147.61184.2022.93
1100071.39134.3052.74
1210-143.26271.2017.89
1300072.12133.9552.31
1400071.52133.2051.97
1510142.61233.8015.77
161-1040.27264.7030.83
1700071.23133.5052.18
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Box-Behnken design arrangement and results

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RunABCY1Y2Y3
101153.96352.9037.13
2-10-136.32215.3018.91
3-10132.83263.7026.82
401-163.28317.4057.64
500070.96132.9052.13
6-1-1030.85128.5013.27
7-11041.46371.6035.12
811052.74374.3039.27
90-1-148.37127.6030.16
100-1147.61184.2022.93
1100071.39134.3052.74
1210-143.26271.2017.89
1300072.12133.9552.31
1400071.52133.2051.97
1510142.61233.8015.77
161-1040.27264.7030.83
1700071.23133.5052.18
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IndexPredicted valueActual valueRE
EE-DOX / %71.6470.75 ± 0.42-1.24
EE-IR820 / %52.5152.53 ± 0.760.04
Size / nm127.6126.4 ± 0.66-0.94
), ArticleFig(id=1201106665140609545, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=CN, label=Table 3, caption=

Verification results of optimal preparation technology (n = 3, x ± s). RE: Relative deviation

, figureFileSmall=null, figureFileBig=null, tableContent=
IndexPredicted valueActual valueRE
EE-DOX / %71.6470.75 ± 0.42-1.24
EE-IR820 / %52.5152.53 ± 0.760.04
Size / nm127.6126.4 ± 0.66-0.94
), ArticleFig(id=1201106665279021588, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
IndexDOX-IR820-TSL@CCM
EE-DOX / %70.32 ± 0.29
EE-IR820 / %52.45 ± 0.17
), ArticleFig(id=1201106665551651370, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=CN, label=Table 4, caption=

The encapsulation rate of DOX-IR820-TSL@CCM (n = 3, x ± s). TSL: Temperature sensitive liposomes; CCM: Cancer cell membrane

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IndexDOX-IR820-TSL@CCM
EE-DOX / %70.32 ± 0.29
EE-IR820 / %52.45 ± 0.17
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GroupRed cell suspension/mLSaline/mLH2O/mLDOX-IR820-TSL@CCM/mLResultHemolysis ratio/%
12.52.4-0.1Unhemolysis1.36
22.52.3-0.2Unhemolysis1.49
32.52.2-0.3Unhemolysis2.04
42.52.1-0.4Unhemolysis2.15
52.52.0-0.5Unhemolysis2.32
62.52.5--Unhemolysis0
72.5-2.5-Hemolysis100
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The result of hemolysis

, figureFileSmall=null, figureFileBig=null, tableContent=
GroupRed cell suspension/mLSaline/mLH2O/mLDOX-IR820-TSL@CCM/mLResultHemolysis ratio/%
12.52.4-0.1Unhemolysis1.36
22.52.3-0.2Unhemolysis1.49
32.52.2-0.3Unhemolysis2.04
42.52.1-0.4Unhemolysis2.15
52.52.0-0.5Unhemolysis2.32
62.52.5--Unhemolysis0
72.5-2.5-Hemolysis100
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CroupIC50
DOX-IR820-TSL298.75
IR820+Laser113.64
Free DOX88.93
DOX+Laser79.37
DOX-IR820-TSL+Laser38.16
DOX-IR820-TSL@CCM66.85
DOX-IR820-TSL@CCM+Laser17.83
), ArticleFig(id=1201106667267121770, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860515066048603, language=CN, label=Table 6, caption=

IC50 of NCI-H460 human lung cancer cells

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CroupIC50
DOX-IR820-TSL298.75
IR820+Laser113.64
Free DOX88.93
DOX+Laser79.37
DOX-IR820-TSL+Laser38.16
DOX-IR820-TSL@CCM66.85
DOX-IR820-TSL@CCM+Laser17.83
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肺癌细胞膜涂层的DOX和IR820的光热敏感型仿生脂质体用于癌症的化学-光热-光动力治疗
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李士壮 1 , 阚玉萍 1 , 陈铭 2 , 苏慧 1 , 阎雪莹 1, *
药学学报 | 研究论文 2024,59(5): 1430-1440
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药学学报 | 研究论文 2024, 59(5): 1430-1440
肺癌细胞膜涂层的DOX和IR820的光热敏感型仿生脂质体用于癌症的化学-光热-光动力治疗
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李士壮1, 阚玉萍1, 陈铭2, 苏慧1, 阎雪莹1, *
作者信息
  • 1.黑龙江中医药大学, 黑龙江 哈尔滨 150040
  • 2.哈尔滨市二四二医院, 黑龙江 哈尔滨 150040

通讯作者:

*阎雪莹, Tel: 18855754007, E-mail:
Photothermal-sensitive biomimetic liposomes coated with DOX and IR820 for chemo-photothermal-photodynamic therapy of cancer in lung cancer cells
Shi-zhuang LI1, Yu-ping KAN1, Ming CHEN2, Hui SU1, Xue-ying YAN1, *
Affiliations
  • 1. Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, China
  • 2. Harbin 242 Hospital, Harbin 150040, China
出版时间: 2024-05-12 doi: 10.16438/j.0513-4870.2023-1087
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摘要
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本研究构建以多柔比星(doxorubicin, DOX) 为模型药物、新吲哚菁绿(IR820) 为光敏剂、温度敏感脂质体(temperature sensitive liposomes, TSL) 为载体, H460-NCI人大细胞肺癌细胞膜涂层的光热敏感脂质体(DOX-IR820-TSL@CCM), 用于化学-光热治疗-光动力治疗的多途径高效肿瘤靶向作用。采用逆向蒸发法制备DOX-IR820-TSL, 通过裂解、破碎、离心等方法制备癌细胞膜(cancer cell membrane, CCM), 采用纳米膜挤压法制备DOX-IR820-TSL@CCM; 并对上述脂质体进行表征。最终确定DOX-IR820-TSL的载药条件如下: 有机相与水相比例为4.02, 二棕榈酰磷脂酰胆碱(dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) 用量为10.04 mg, 药脂比为0.12, DOX-IR820-TSL显著相变温度(Tm)为43.05 ℃, DOX-IR820-TSL@CCM平均粒径为153.4 nm, PDI为0.279, zeta电位为-26.2 mV。透射电子显微镜图像在图中显示出均匀的球形结构和半透明膜层。在近红外光照射下, 药物释放率达到了63.98%, 具有可调节的光热转化能力和产生活性氧的能力。通过SDS-PAGE电泳、Western blot、细胞毒性实验和细胞摄取实验, 证明了细胞膜涂层的设计能够很好地保留CD47、N-cadherin、CD44、CD326等相关功能蛋白, 使DOX-IR820-TSL@CCM具备良好的免疫逃逸、同源黏附和同源靶向作用。本文制备了具有伪装特性和肿瘤靶向性的DOX-IR820-TSL@CCM, 可作为一种协同治疗诊断平台用于未来的肺癌治疗。所有动物研究方案均已通过黑龙江中医药大学动物伦理委员会批准(编号为: 2022121011)。

光热敏感脂质体  /  癌细胞膜仿生  /  新吲哚菁绿  /  化学治疗-光热治疗-光动力治疗

In this study, doxorubicin (DOX) was used as the model drug, new indocyanine green (IR820) as the photosensitizer, and temperature sensitive liposomes (TSL) as the carrier. H460-NCI photoheat-sensitive liposomes coated with cell membrane of human cell lung cancer (DOX-IR820-TSL@CCM) for highly effective multi-pathway tumor targeting in chemical-photothermal therapy and photodynamic therapy. DOX-IR820-TSL was prepared by reverse evaporation, cancer cell membrane (CCM) was prepared by lysis, crushing and centrifugation, and DOX-IR820-TSL@CCM was prepared by nanomembrane extrusion. The drug-loading conditions of DOX-IR820-TSL were finally determined: the ratio of organic phase to aqueous phase was 4.02, the dosage of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was 10.04 mg, and the lipid ratio was 0.12, and the significant phase transition temperature (Tm) of DOX-IR820-TSL was 43.05 ℃. The average particle size of DOX-IR820-TSL@CCM was 153.4 nm, the PDI was 0.279, and the zeta potential was -26.2 mV. The transmission electron microscope (TEM) image shows a homogeneous spherical structure and a translucent film layer. Under near-infrared irradiation, the drug release rate reaches 63.98%, which has adjustable photothermal conversion capacity and the ability to generate reactive oxygen species. Through SDS-PAGE electrophoresis, Western blot, cytotoxicity experiments and cell uptake experiments, it was proved that the design of cell membrane coating can well retain CD47, N-cadherin, CD44, CD326 and other related functional proteins, so that DOX-IR820-TSL@CCM has good immune evasion, homologous adhesion and homologous targeting. In this paper, DOX-IR820-TSL@CCM with camouflage properties and tumor targeting properties were successfully prepared, which can be used as a promising synergistic therapeutic diagnostic platform for future lung cancer treatment. All animal research programs have been approved by the Animal Ethics Committee of Heilongjiang University of Chinese Medicine (number: 2022121011).

photothermal sensitive liposome  /  cancer cell membrane biomimetic  /  new indocyanine green  /  chemotherapy-photothermal therapy-photodynamic therapy
李士壮, 阚玉萍, 陈铭, 苏慧, 阎雪莹. 肺癌细胞膜涂层的DOX和IR820的光热敏感型仿生脂质体用于癌症的化学-光热-光动力治疗. 药学学报, 2024 , 59 (5) : 1430 -1440 . DOI: 10.16438/j.0513-4870.2023-1087
Shi-zhuang LI, Yu-ping KAN, Ming CHEN, Hui SU, Xue-ying YAN. Photothermal-sensitive biomimetic liposomes coated with DOX and IR820 for chemo-photothermal-photodynamic therapy of cancer in lung cancer cells[J]. Acta Pharmaceutica Sinica, 2024 , 59 (5) : 1430 -1440 . DOI: 10.16438/j.0513-4870.2023-1087
正文
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癌症是严重威胁人类健康的危险疾病之一[1]。长期以来, 原发性和转移性癌症临床的标准疗法为化疗, 采用细胞毒性化学药物诱导肿瘤细胞凋亡或坏死[2]。目前, 已经有很多用于抗肿瘤的新型化学药物被开发。然而, 化疗引起的各种毒副作用[3]和多重耐药性(multi-drug resistance, MDR) [4, 5]使癌症的治疗极为不易[6]。因此, 亟需寻找和开发更有效、更安全的癌症治疗方案。
脂质体是临床前和临床研究中使用较多的纳米颗粒药物载体之一[7], 其具有制备简单、生物相容性好、不良反应少以及可延长药物的循环时间来增加药物在肿瘤中的蓄积等优势[8, 9]。目前多种脂质体抗癌药物已用于临床治疗[10], 与传统化学药物相比, 脂质体介导的细胞毒性化疗已被证明能显著提高患者的药物耐受性, 但根本问题是其不能提高抗癌疗效[11]。为了解决这一难题, Needham等[12]提出热敏脂质体, 可在加热到轻度热疗范围内的温度时快速释放药物来提高抗肿瘤效果。
热敏脂质体(temperature sensitive liposomes, TSL) 纳米药物在化疗方面已显示出理想的抗肿瘤疗效, 但单一化疗策略往往无法消除癌细胞, 随着对肿瘤生物学、分子机制、肿瘤微环境和人体免疫机制的深入了解, 目前基于纳米医学的研究趋势逐步由单一疗法转向多模式协同癌症治疗[13-15]。通过特异性响应肿瘤内的生物因素(pH、氧化还原电位和酶) 以及其他外源性刺激(光、磁、超声和X射线), 智能纳米平台不仅可以作为有效药物负载的运输载体并促进其原位转化, 还可以联合其他治疗方式, 如光热疗法(photothermal therapy, PTT)、光动力疗法(photodynamic therapy, PDT)、化学动力学治疗(chemodynamic therapy, CDT) 等, 以增强化疗抗癌作用[16-18]。
光学疗法是一种新型癌症治疗方法, 因时间和空间上的响应性、高选择性和非侵入性等特点使其在癌症的临床治疗中具有极大的发展潜力, 近年来受到了广泛关注[19]。PTT和PDT是高效精准的肿瘤治疗[20]。PTT中光热敏脂质体在特定波长激光照射下可以升高温度将药物按需释放, 有研究表明, 光热敏感脂质具有良好的光热响应释药能力及抗肿瘤作用[21-24]。PDT是美国食品和药品监督管理局(FDA) 批准进行临床癌症治疗的手段[25]。其治疗机制是通过特定波长的光、光敏剂及氧气的相互作用, 从而产生活性氧来消灭癌细胞[26]。目前, 光热-光动力-化疗协同治疗手段在提高抗癌疗效方面具有极大潜能。
然而, 脂质体纳米平台通过高通透性和滞留效应[27] (enhanced permeability and retention effect, EPR) 靶向肿瘤组织的作用是有限的。为了克服靶向不足的问题, Zhang等[28]制备了红细胞膜包裹的PLGA NPs, 体外实验中发现红细胞膜包覆可以有效减缓药物释放, 并提高纳米粒的靶向性。细胞膜修饰具有良好的同源靶向作用及抗肿瘤效果[29-31], 癌细胞膜包覆的载药纳米系统在肿瘤靶向诊断和治疗中有很好的应用前景[32, 33]。因此, 本课题以多柔比星(doxorubicin, DOX) 为模型药物、新吲哚菁绿(IR820) 为光敏剂, 构建H460-NCI人大细胞肺癌细胞膜靶向的光热敏感免疫脂质体, 将其伪装成自体细胞, 躲避免疫系统的识别和消除, 延长血液循环时间, 增强药物对肿瘤的靶向性。协同化学治疗、光热治疗、光动力学治疗, 以达到免疫逃逸、肿瘤高效靶向、多途径协同治疗的目的。
材料与方法
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仪器  Waters2695高效液相色谱仪(美国Waters公司); 热电偶双通道测温器(东莞市希玛仪表有限公司); LR-MFJ-808 nm近红外激光器(长春镭锐光电科技有限公司); DNM-9602酶标仪(北京普朗新技术有限公司); 动态光散射激光粒度仪(Malvern panalytical, UK); FEI Tecnai F30透射电子显微镜(美国FEI公司); TGL-16C高速台式离心机(上海安亭科学仪器厂); BD Accuri C5流式细胞仪(美国BD公司)
细胞与试剂  盐酸多柔比星对照品(纯度≥ 98%, 批号: wkq19031505, 北京华奉联博科技有限公司); 新吲哚菁绿(批号: c12872066, 美国默克公司); 硬脂酰溶血卵磷脂[批号: 76343-22-1, 阿拉丁科技(中国) 有限公司]; 二棕榈酰磷脂酰胆碱(dipalmitoyl-sn-glycero-3-phosphocholine, DPPC, 批号: 63-89-8)、二硬脂酸磷脂酰乙醇胺-聚乙二醇2000 (DSPE-PEG2000, 批号: 147867-65-0) (上海麦克林生化科技有限公司); 甲醇(色谱纯, 美国Sigma公司); RIPA裂解液、预染标准蛋白、CCK-8细胞计数试剂盒(上海碧云天生物技术有限公司); 澳洲胎牛血清、1%青霉素-链霉素(美国Hyclone公司); RPMI1640基础培养基、0.25%胰蛋白酶、0.5 μmol·L-1乙二胺四乙酸(大连美仑生物科技有限公司); 微型蛋白酶抑制剂片(美国Roche公司); 全聚偏二氟乙烯(polyvinylidene difluoride, PVDF)膜(杭州联科生物技术股份有限公司); 兔抗人CD47抗体、兔抗人N-cadherin抗体、兔抗人CD44抗体、兔抗人CD326抗体、兔抗人Histone H3抗体兔抗人二抗(北京博奥森生物技术有限公司)。
细胞  NCI-H460人大细胞肺癌细胞(上海富衡生物科技有限公司)。
实验动物  SD大鼠(200 ± 15 g) 购买于黑龙江中医药大学实验动物中心, 合格证号: SCXK (黑) 2008004。所有动物研究方案均通过黑龙江中医药大学动物伦理委员会批准(编号为: 2022121011)。
DOX和IR820检测条件
DOX的色谱条件  色谱柱: Dikma diamonsil (C18, 5 μm, 250 mm × 4.6 mm); 流动相: 乙腈: 1%磷酸水溶液= 27∶73; 流速: 0.8 mL·min-1; 柱温: 25 ℃; 进样量: 10 μL; 进样时间: 30 min; 检测波长: 232 nm。DOX线性回归方程为: y = 78 298 x + 101 033 (R2 = 0.999 5), DOX质量浓度为5.0~80.0 μg·mL-1内与其峰面积的线性关系良好。
IR820的检测  IR820作为红外光光敏剂在可见-红外波段698 nm处有明显吸收峰而DOX与DOX-IR820-TSL在此处无吸收, 故采用紫外-可见分光光度计在680 nm处测定IR820含量。
DOX-IR820-TSL的制备  在溶有硬脂酰溶血卵磷脂、DPPC和DSPE-PEG2000 (摩尔比为76∶19∶5) 的三氯甲烷溶液中缓慢加入DOX和IR820的混合溶液, 超声乳化至形成稳定乳化剂后, 采用旋转蒸发仪在35 ℃下减压除去有机溶剂, 同时蒸发洗掉磷脂膜, 将脂质体混悬液进行超声破碎, 即得脂质体混悬液。
DOX-IR820-TSL包封率和载药量的测定  采用超滤离心法获得脂质体[34], 通过HPLC和紫外-可见光分光光度计分别测定DOX和IR820的包封率(drug entrapment efficiency, EE)。精密量取40 μL脂质体溶液, 加入20倍量的甲醇, 超声20 min破乳, 检测药物的总量。另精密吸取200 μL DOX-IR820-TSL溶液于超滤离心管中, 4 ℃, 转速为10 000 r·min-1, 离心30 min收集超滤离心管下层液体, 并检测游离DOX和IR820含量。规定DOX-IR820-TSL中游离的药物的含量为W游, 投入药物的总量为W总, 载体药物的总量为W载; 重复操作3次, 记录结果。EE及载药量(drug loading capacity, DL) 计算公式(1) (2) 如下。
$ \mathrm{EE} \%=\left(W_{\text {总 }}-W_{\text {游 }}\right) / W_{\text {总 }} \times 100 \% $
$\mathrm{DL} \%=\left(W_{\text {总 }}-W_{\text {游 }}\right) / W_{\text {载 }} \times 100 \%$
Box-Behnken设计-响应面法优化DOX-IR820-TSL的制备工艺  本实验选取Box-Behnken设计-响应面法(Box Behnken design-response surface method, BBD-RSM) [35]来进行处方工艺优化设计。通过单因素考察, 发现有机相与水相比例、DPPC用量及药脂比对包封率和粒径的影响较大。故本研究进一步以有机相与水相比例(organic/ aqueous ratio) (A)、DPPC用量(DPPC dosage) (B)、和药脂比(drug/liposomes ratio) (C)作为考察因素, 以载药脂质体中DOX的平均包封率(EE-DOX) (Y1)、光热敏感脂质体的平均粒径(size) (Y2)和IR820的平均包封率(EE-IR820) (Y3)为评价指标(表 1), 通过BBD-RSM构建了包含17个实验运行的设计矩阵, 进行DOX-IR820-TSL的制备工艺的优化。
DOX-IR820-TSL@CCM的制备
癌细胞膜(cancer cell membrane, CCM) 的提取与制备  取对数生长期的NCI-H460肺癌细胞, PBS冲洗2次, 消化后, 300×g离心5 min收集细胞, 用PBS重悬细胞并离心洗涤2次, 加入pH为7.4的低渗裂解液, 重悬细胞, 并在4 ℃下裂解2 h; 超声破碎5 min, 3 500×g离心5 min收集上清液(2次), 合并两次上清液以20 000×g离心20 min, 弃去沉淀保存上清液, 再次以100 000×g离心1.5 h, 弃去上清液, 即得到CCM沉淀, 10 mmol·L-1 Tris-HCl重悬CCM沉淀后, 100 000×g离心1.5 h洗涤, 最终沉淀用PBS分散即得纯化的CCM。
包膜脂质体的制备  将CCM用BCA蛋白定量法进行蛋白定量, 并将CCM多次通过400 nm聚碳酸酯膜, 形成微小囊泡后, 取一定量的小囊泡与DOX-IR820-TSL涡旋混合, 多次挤压通过200 nm聚碳酸酯膜, 即得DOX-IR820-TSL@CCM混悬液。
DOX-IR820-TSL和DOX-IR820-TSL@CCM的表征  将稀释好的混悬液滴于铜网上, 用1%的磷钨酸负染, 干燥后在透射电子显微镜下观察。将两种样品用纯水稀释至一定浓度, 使用激光粒度仪测定粒径、PDI、zeta电位, 并相互对比, 验证DOX-IR820-TSL@CCM上的细胞膜修饰情况。并将制备的载药脂质体稀释至磷脂质量浓度约为5 mg·mL-1, 吸取10 μL于铝盘中, 0~80 ℃范围扫描, 扫描速度为10 ℃·min-1, 测定脂质体相变温度。
DOX-IR820-TSL@CCM相关蛋白分析
十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE) 细胞总蛋白(CCL) 的制备  取对数生长期的NCI-H460细胞, 使用PBS清洗3次, 加入RIPA细胞裂解液0.5 mL, 在4 ℃条件下裂解30 min, 超声破碎2 min, 在4 ℃条件下以12 000×g离心15 min, 取上清即得CCL。将CCL、CCM、DOX-IR820-TSL@CCM样品溶液用BCA法测定蛋白浓度, 并稀释至相同浓度, 离心管中分别加入50 μL样品溶液, 10 μL的蛋白上样缓冲液(2×), 煮沸5 min, 进行上样, 上样量为10 μL, 80 V, 30 min, 待样品进入分离胶再将电压调至120 V恒压跑开, 结束后取出胶进行染色、脱色、拍照进行分析。
Western blot (WB)  按上述方法将样品进行SDS-PAGE, 取出凝胶, 使用半干转将蛋白转移至PVDF膜上。将PVDF膜进行封闭, 用一抗稀释液(1∶1 000稀释) 将PVDF膜完全浸入, 4 ℃下孵育12 h。一抗孵育结束后, 使用TBST溶液洗涤3次, 用二抗稀释液室温孵育1 h。二抗孵育结束后, 用TBST溶液洗涤3次, 每次3 min, 将ECLA和ECLB两种试剂按体积比1∶1的比例在离心管中混匀后, 均匀滴在PVDF膜上, 使其充分反应3 min后, 放在暗匣中进行曝光拍照。利用ImageJ软件对各组蛋白条带进行分析。
细胞摄取与肿瘤细胞膜蛋白浓度比较  将对数生长期的NCI-H460细胞以3×105个/孔的密度分别接种到6孔板中, 分别加入培养基稀释的制剂(DOX质量浓度为0.5 μg·mL-1), 孵育1.5 h, 胰酶消化, 去清液, 加0.5 mL PBS混匀, 离心, 去除上清液, 加入PBS重悬, 置于流式管中, 流式细胞仪读取荧光强度, 以空白培养液孵育的细胞作为对照, 每组平行3份。
分别将肿瘤细胞膜的蛋白质量浓度稀释到100、200、300 μg·mL-1, 然后将不同蛋白含量的肿瘤细胞膜与DOX-IR820-TSL进行挤出。按照上述细胞摄取进行后续实验操作, 进行BCA蛋白质量浓度的测定。
DOX-IR820-TSL@CCM的释药性能考察
DOX-IR820-TSL@CCM的温度和时间依赖释药  取1 mL质量浓度为1 mg·mL-1的DOX-IR820-TSL及DOX-IR820-TSL@CCM的溶液, 加入到8~14 kDa的纤维素透析袋中, 将其浸入PBS (0.2 mol·L-1, pH = 7.4) 中, 分别将DOX-IR820-TSL于37 ℃水浴、DOX-IR820-TSL及DOX-IR820-TSL@CCM于43 ℃水浴, 100 r·min-1恒速振摇。分别在1、2、3、4、5、10、20、25、50、60 h后吸取1 mL透析外液, 同时补充1 mL透析外液, 通过HPLC测定释放介质中DOX的质量浓度。每组实验均设3组平行实验组, 计算累积释放百分率。
DOX-IR820-TSL@CCM的光热响应释药  将1 mL DOX-IR820-TSL@CCM (1 mg·mL-1), 放入透析袋中, 于37 ℃水浴, 100 r·min-1恒速振摇。分别在透析后的1、3、5 h从透析袋中取出样品3次, 放入试管中, 然后用808 nm, 2 W·cm-2的近红外激光照射5 min。分别在1、2、3、4、5、6 h后吸取1 mL透析外液, 同时补充1 mL透析外液。使用HPLC测定其DOX的含量。将无激光照射的DOX-IR820-TSL@CCM作为对照组。每组实验均设3组平行实验组, 计算累积释放率。
光热性能考察  首先, 配制1 mL质量浓度为50~250 μg·mL-1的IR820水溶液, 采用近红外激光(808 nm, 2 W·cm-2) 照射10 min, 每隔15 s记录一次溶液温度, 评价不同质量浓度IR820水溶液的光热性能, 从而确定最佳IR820质量浓度进行后续实验。为了进一步探究DOX-IR820-TSL@CCM及其组分的光热性能, 采用同一方法进行考察。设置4个实验组与1个对照组, 分别为: ①IR820水溶液; ② DOX-IR820-TSL@CCM水溶液; ③ DOX-IR820-TSL水溶液; ④ DOX水溶液; ⑤纯水作为对照组。
光动力性能考察  1, 3-二苯基异苯并呋喃(1, 3-diphenylisobenzofuran, DPBF) 被用于体外活性氧产生情况的检测, 首先配制溶于DMSO的DPBF溶液(1.5 mg·mL-1), 然后将20 μL DPBF溶液加入装有3 mL DOX-IR820-TSL@CCM纳米粒子的比色皿中, 混匀后在近红外激光(808 nm, 2 W·cm-2) 照射下, 每隔1 min测定一次紫外吸收光谱, 以412 nm处光吸收的下降值作为光动力效果的评判标准。DOX-IR820-TSL与游离IR820水溶液的光动力效果也使用相同方法进行测定。
溶血实验  使用大鼠的红细胞(RBC) 进行溶血实验, 将红细胞PBS混合液与DOX-IR820-TSL@CCM (0~800 μg·mL-1) 混合, 阳性和阴性对照为重蒸水和纯PBS溶液, 37 ℃下孵育6 h混匀溶液后, 将样本离心(10 000 r·min-1, 10 min) 取上清液, 在540 nm处测量测试样品(Atest), 阳性对照(Apos)和阴性对照(Aneg)的吸光度, 根据公式(3) 确定溶血率:
$\text { 溶血率 } \%=\left(A_{\text {test }}-A_{\text {neg }}\right) /\left(A_{\text {pos }}-A_{\text {neg }}\right) \times 100 \%$
细胞毒性实验  将DOX、DOX-IR820-TSL、DOX-IR820-TSL@CCM、IR820用1640培养基分别稀释为DOX、IR820相对质量浓度为0.000 1、0.000 5、0.02、0.1、0.5、2.5 μg·mL-1的溶液, 4 ℃保存。将对数生长期的NCI-H460肺癌细胞消化后, 以300×g离心5 min收集细胞, 每孔100 μL的细胞悬液(每毫升1×105个) 接种到96孔板中, 孵育12 h, PBS冲洗两次, 分别加入100 μL适量浓度的空白脂质体和上述配制的各质量浓度溶液, 每组做3个复孔。非激光组培养24 h, 用于考察暗毒性。激光组培养6 h, 以808 nm, 2 W·cm-2激光照射5 min, 继续培养24 h, 用于考察光毒性。结束后, 两组再加入10 μL新鲜CCK-8溶液进一步孵育2 h。使用酶标仪在450 nm处测定A值, 根据A值计算出相对细胞存活率, 并将各剂量及相应存活率用非线性回归拟合计算细胞半数抑制率IC50。
$细胞存活率 \mathrm{SR}=\left[\left(A_{\mathrm{t}}-A_{\mathrm{b}}\right) /\left(A_{\mathrm{r}}-A_{\mathrm{b}}\right)\right] \times 100 \% $
$细胞抑制率 \mathrm{IR}=\left[\left(A_{\mathrm{r}}-A_{\mathrm{t}}\right) /\left(A_{\mathrm{r}}-A_{\mathrm{b}}\right)\right] \times 100 \%$
其中: At为实验组的吸光度; Ar为对照组的吸光度; Ab为空白组的吸光度。
统计学方法  本文所有数据均表示为平均数±标准差(x ± s)。采用SPSS19.0软件的单因子方差分析进行统计学分析, P < 0.05认为具有统计学差异。
结果
收起
1 BBD-RSM实验
根据实验方案进行17组实验, 使用所建立的检测方法对所制备的复合纳米粒进行包封率与载药量的测定, 实验设计及结果见表 2。Design-Expert V8.0.6软件模型拟合功能显示, 采用二次多项式方程拟合效果较好, 拟合方程为:
$\begin{aligned}& \quad\quad Y_1=71.44+4.68 A+5.54 B-1.78 C+0.46 A B-0.71 A C- \\& 2.14 B C-22.33 A^2-7.78 B^2-10.36 C^2, P<0.000\;1 \\& \quad\quad Y_2=133.57+20.61 A+88.90 B+12.89 C-33.38 A B- \\& 21.45 A C-5.27 B C+75.84 A^2+75.37 B^2+36.59 C^2, P< \\& 0.000\;1 \\& \quad\quad Y_3=62.27+3.71 A+5.25 B-1.49 C-0.85 A B-003 A C- \\& 3.32 B C-22.38 A^2-7.76 B^2-7.54 C^2, P<0.000\;1\end{aligned}$
由方差分析表可知, 3个模型均具有显著性差异(P < 0.000 1), 提示该模型能较好地反映考察因素对响应值的影响, r2均大于0.9, 说明该模型设计的拟合效果及预测性均较好。
通过上述的回归方程与Design-Expert V8.0.6软件绘制自变量对因变量的三维效应面如图 1所示。选择Y1、Y3最大值, Y2最小值作为优化目标, 对每个模式进行叠加, 得到的最优条件区间, 得到最优处方为: 有机相与水相比例4.02, DPPC用量10.04 mg, 药脂比0.12。预测该条件下的DOX包封率为71.64%, IR820包封率为52.51%, 粒径为127.6 nm, 载药量为5.1%。
根据最佳制备工艺平行制备3批DOX-IR820-TSL并测量其中DOX的包封率与光热敏脂质体粒径, 结果如表 3所示, 实测值与预测值相对偏差(relative deviation, RE) 绝对值均小于± 5%, 表明DOX-IR820-TSL处方工艺优化具有较高的指导意义。此外, 对该制备方法进行了肺癌细胞膜修饰后的包封率进行了验证, 如表 4所示, NCI-H460肺癌细胞膜包载后对该纳米脂质体的包封率无影响, 综上所述, 该方法稳定可靠, 为DOX-IR820-TSL@CCM的制备提供了参考。
2 DOX-IR820-TSL和DOX-IR820-TSL@CCM的表征
2.1 粒径及zeta电位
粒径及其分布如图 2A、C所示, DOX-IR820-TSL的平均水合粒径为133.5 nm, PDI为0.181, DOX-IR820-TSL@CCM的水合粒径为153.4 nm, PDI为0.279, 表明光热敏感脂质体大小分布均匀, 且分散性良好, 符合制剂要求。zeta电位如图 2B、D所示, DOX-IR820-TSL的zeta电位值为-19.2 mV, DOX-IR820-TSL@CCM的zeta电位值为-26.2 mV。DOX-IR820-TSL和DOX-IR820-TSL@CCM的粒径分布对比如图 2E所示, DOX-IR820-TSL@CCM比DOX-IR820-TSL的平均粒径大19.9 nm, 二者粒径差值正好与两层CCM的厚度(10~20 nm) 相符, 初步验证了DOX-IR820-TSL@CCM上的CCM已经修饰成功。DOX-IR820-TSL、CCM、DOX-IR820-TSL@CCM的电位对比如图 2F所示, DOX-IR820-TSL@CCM的zeta电位低于DOX-IR820-TSL, 并且与CCM的zeta电位值相近, 表明低负电性的DOX-IR820-TSL被较高负电性的CCM所覆盖, 进一步证明DOX-IR820-TSL@CCM上的CCM已经修饰成功。
2.2 透射电子显微镜(transmission electron microscope, TEM) 分析
TEM观察结果如图 3A、B所示, DOX-IR820-TSL为规则球形结构, 大小较为均匀, 粒径大小与动态光散射激光粒度仪测得结果一致(图 2A), 但是由于TEM成像时, 样品需要经过高压电子的冲击, 会发生一定程度的膨胀和崩解, 出现点状及蠕虫状物; DOX-IR820-TSL@CCM为规则球形结构, 粒径大小与激光粒度仪测得结果一致(图 2C), 外部有一层半透明膜层, 厚度在10 nm左右, 与单层CCM的厚度相符, 证明DOX-IR820-TSL@CCM的CCM修饰成功, 而考虑到制备脂质体的TEM样品时, 脂质体会在一定程度上失水收缩, 所以视野内会有部分脂质粒径有偏差。
2.3 脂质体相变温度的测定
热敏脂质体的相变温度为43.05 ℃ (图 3C), 相变明显, 热量变化达到6.947 J·g-1, 表明相变明显且温度变化范围较窄。
3 DOX-IR820-TSL@CCM相关蛋白分析
3.1 十二烷基硫酸钠-聚丙烯酰胺凝胶电泳
SDS-PAGE结果如图 3D所示, CCL中含有CCM、DOX-IR820-TSL@CCM不存在的蛋白条带, 推测是由于裂解、破碎、离心后而缺失的细胞核蛋白; CCM和DOX-IR820-TSL@CCM的蛋白条带一致, 说明DOX-IR820-TSL@CCM上的膜蛋白保留情况良好。
3.2 蛋白质印迹
WB结果如图 3E所示, 只有CCL中存在细胞核Histone H3蛋白, 表明裂解、破碎、离心等方法可去除肿瘤细胞的核成分, 并仍能保留CD47、N-cadherin、CD44、CD326等相关功能蛋白。
4 细胞摄取
流式细胞仪分析结果如图 4A所示, DOX-IR820-TSL@CCM组的荧光强度远高于DOX-IR820-TSL组, 约为6.9倍, 表明NCI-H460肺癌细胞对DOX-IR820-TSL@CCM的摄取是DOX-IR820-TSL的6.9倍。表明通过癌细胞膜涂层的修饰, 利用功能蛋白的同源靶向性及黏附性, 提高了肿瘤细胞对光热敏感脂质体的摄取。
肿瘤细胞膜蛋白浓度对细胞摄取杂化脂质体的研究表明, 肿瘤细胞膜的同源结合能力与膜蛋白有关, 是肿瘤靶向作用的关键。不同膜蛋白浓度对于细胞摄取脂质体的影响如图 4B所示, 蛋白浓度越大, 细胞对于杂化脂质体的摄取量越大, 当蛋白质量浓度从200 μg·mL-1增大到300 μg·mL-1时, 摄取量无显著性差异, 说明膜表面的蛋白处于饱和状态。因此, 选择蛋白质量浓度为200 μg·mL-1进行后续实验。
5 DOX-IR820-TSL@CCM的释药性能考察
5.1 体外性能研究
如图 4C所示, DOX-IR820-TSL在37 ℃, 60 h的释放量为(33.92 ± 0.52) %, DOX-IR820-TSL及DOX-IR820-TSL@CCM在43 ℃, 60 h的累计释放量分别是(83.02 ± 0.49) %和(78.73 ± 0.31) %, 证实了温度的可控“打开”, 当温度达到至43 ℃时, 磷脂外壳发生相转变并释药。而且与DOX-IR820-TSL相比, DOX-IR820-TSL@CCM在每个时间点的药物释放量均呈递减趋势, 在10 h内释放量具有显著变化, 说明肺癌细胞膜可增强光热敏脂质体的缓释作用, 从而降低给药前期的突释现象。近红外激光(808 nm, 2 W·cm-2, 5 min) 对DOX释放影响如图 4D所示, 第1次照射DOX从DOX-IR820-TSL@CCM中释放的药量从(12.22 ± 0.33) %迅速增长至(23.52 ± 0.35) %, 第2次和第3次照射下, DOX的释放量分别从(32.77 ± 1.09) %和(51.59 ± 1.11) %增长至(43.02 ± 1.09) %和(61.66 ± 0.91) %, 最终在6 h内达到(63.98 ± 0.34) %的药物释放量, 是37 ℃条件下DOX-IR820-TSL@CCM药物释放量的3倍, 表明DOX-IR820-TSL@CCM包载的IR820可将近红外光能转换为热能, 使内部温度上升至43 ℃以上, 促使光热敏感脂质体发生相转变, 被包载的药物能够快速释放。
5.2 光热性能考察
近红外光(808 nm, 2 W·cm-2) 照射装有1 mL样品溶液的石英皿, 观察其温度变化, 探究不同质量浓度IR820水溶液组分的光热性能。如图 4E所示, 不同质量浓度的Free-IR820 (50~250 μg·mL-1) 在近红外光照射后上升了7.9~33.4 ℃, 表明IR820质量浓度越高光照后温度变化越明显, 因此, 选择质量浓度为250 μg·mL-1 IR820水溶液进行后续实验。如图 4F所示, 250 μg·mL-1游离IR820、DOX-IR820-TSL和DOX-IR820-TSL@CCM水溶液在激光照射下, 前5 min快速升温, 8 min时温度分别达到56.7、59.9和58.9 ℃, 而游离DOX溶液和PBS的温度仅升高了7.5和7.1 ℃, 表明经过脂质体包载提高了IR820的光热效率。近红外诱导光热敏脂质体产生的温度大于43 ℃, 此温度可使TSL发生相变。
5.3 光动力性能考察
DPBF高特异性结合某些活性氧, 结合后DPBF被不可逆氧化, 紫外-可见光的吸收强度迅速降低, 可用来指示活性氧的生成。如图 4G所示, DPBF活性氧探针在417 nm处紫外吸收值的下降显示了溶液中活性氧的增加。为了证实单线态氧是由IR820产生的, 以近红外光照射下的DOX-TSL作为对照组。紫外吸收值几乎没有变化, 说明缺少了IR820的光热敏感脂质体, 将不能转化红外光能进而生成单线态氧, 从而证实了单线态氧是由IR820产生的。在相同的IR820含量下, DOX-IR820-TSL@CCM产生活性氧的能力要远强于游离IR820。说明纳米载体很好地提升了IR820的稳定性。
6 溶血实验
溶血实验结果如图 5A所示, 1~6号离心管红细胞全部沉淀, 肉眼观察无明显溶血现象; 7号离心管完全溶血。表 5中显示了由上清液吸光度计算所得的溶血率结果, 1~5号离心管内样品溶血率均小于5%, 证明所制备的DOX-IR820-TSL@CCM血液相容性良好, 安全性较高。
7 细胞毒性实验
为了探究DOX-IR820-TSL@CCM的化学-光热-光动力治疗效果, 通过CCK-8法检测了纳米脂质体对NCI-H460细胞的暗毒性和光毒性。如图 5B和表 6所示, DOX-IR820-TSL@CCM+Laser的IC50值为17.83 ng·mL-1, 对NCI-H460细胞的抑制率及IC50值与DOX-IR820-TSL+Laser相比具有统计学意义(P < 0.01)。如图 5C所示, 未经激光照射时, Free-IR820表现出良好的细胞安全性, 而Free-IR820+Laser随着浓度的增加, 对NCI-H460肺癌细胞的抑制率不断增加, 表现出良好的PTT作用。当样品质量浓度为0.001~2.5 μg·mL-1时, 随着药物浓度的增加, 样品对NCI-H460肺癌细胞的抑制率也不断增加。与NCI-H460肺癌细胞孵育后, 对比DOX-IR820-TSL@CCM与DOX-IR820-TSL@CCM+Laser可知, 该纳米脂质体表现出优异的光毒性。结果表明通过保留肿瘤细胞膜的相关功能蛋白, 提高免疫逃逸、同源黏附作用, 增加了癌细胞对脂质体的摄取, 使细胞内药物浓度增加, 抗癌活性提高。
讨论
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本研究以DOX为模型药物, IR820为光敏剂, 构建了NCI-H460人大细胞肺癌细胞膜靶向的多功能纳米递送系统, 并对DOX-IR820-TSL@CCM的制备工艺、表征、释药性能、体外细胞学等进行了科学研究及相关评价。该多功能纳米递送系统DOX-IR820-TSL@CCM的粒径大小、zeta电位、TEM图和SDS-PAGE凝胶电图泳的结果均证明了CCM包载成功。DOX-IR820-TSL@CCM具有良好的释药性能, 在近红外光(808 nm) 照射下, IR820将光能转换为热能, 光热敏感脂质体响应性释药, 同时生成单线态氧, 能够精确有效地杀伤肿瘤细胞。在体外细胞实验中均表现出良好的肿瘤靶向性、生物安全性及抗肿瘤效果。
该多功能纳米递送系统的构建用于肺癌的光热疗法/光动力疗法/化疗的联合治疗, 既可以延长体内药物循环时间, 又可以减少药物过早释放及对机体的毒副作用, 从而达到靶向治疗肿瘤的效果, 为后续体内研究提供了实验基础。综上所述, 癌细胞膜包被的仿生多功能纳米递送系统的构建为癌症治疗药物的应用提供了新的策略。
作者贡献: 李士壮和阚玉萍负责实验操作、数据处理及文章撰写; 陈铭和苏慧协助动物实验及流式数据分析; 阎雪莹负责提供研究思路和文章的修改。
利益冲突: 本文所有作者声明不存在利益冲突关系。
基金
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  • 黑龙江省自然科学基金资助项目(LH2020H096)
  • 黑龙江省自然科学基金资助项目(LH2021H102)
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doi: 10.16438/j.0513-4870.2023-1087
  • 接收时间：2023-09-20
  • 首发时间：2025-11-27
  • 出版时间：2024-05-12
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  • 收稿日期：2023-09-20
  • 修回日期：2024-03-07
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黑龙江省自然科学基金资助项目(LH2020H096)
黑龙江省自然科学基金资助项目(LH2021H102)
作者信息
    1.黑龙江中医药大学, 黑龙江 哈尔滨 150040
    2.哈尔滨市二四二医院, 黑龙江 哈尔滨 150040

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species		 占总种数比例
Percentage of
total species (%)		 属
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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