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Article(id=1209787633430032968, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1209787628224910065, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2021-0967, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1624982400000, receivedDateStr=2021-06-30, revisedDate=1626883200000, revisedDateStr=2021-07-22, acceptedDate=null, acceptedDateStr=null, onlineDate=1766365448577, onlineDateStr=2025-12-22, pubDate=1641916800000, pubDateStr=2022-01-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766365448577, onlineIssueDateStr=2025-12-22, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766365448577, creator=13701087609, updateTime=1766365448577, updator=13701087609, issue=Issue{id=1209787628224910065, tenantId=1146029695717560320, journalId=1189982191388893191, year='2022', volume='57', issue='1', pageStart='1', pageEnd='250', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1766365447336, creator=13701087609, updateTime=1766370687413, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1209809606755357571, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1209787628224910065, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1209809606755357572, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1209787628224910065, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=178, endPage=187, ext={EN=ArticleExt(id=1209787633975292536, articleId=1209787633430032968, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Tumor microenvironment responsive liposomes blocking CXCL12/CXCR4 pathway and synergistically enhancing immune efficacy of anti-PD-L1, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Blocking immune checkpoint programmed cell death receptor 1 (PD-1) or programmed death receptor-ligand 1 (PD-L1) can enhance anti-tumor activity of effector T cells. However, the lack of response in many patients to PD-1/PD-L1 therapy remains a question. Improving the immunosuppressive tumor microenvironment (TME) to enhance the efficacy of immune checkpoint inhibitors has become a promising cancer treatment strategy. We constructed a liposome system (PD-L1/siCXCL12-Lp) of CXCL12 siRNA and anti-PD-L1 peptide with matrix metalloproteinases (MMPs) responsiveness, which combined the TME regulation of siCXCL12 and the immune regulation of anti-PD-L1 peptide. All animal experiments were approved by the Biomedical Ethics Committee of Peking University. The authors found that PD-L1/siCXCL12-Lp directly down-regulated the expression of CXCL12 in vitro (33.8%) and in vivo (15.5%). It also effectively increased the ratio of CD8+/Treg by 20.0%, which helped the anti-PD-L1 peptide to better exert its immune effect. The combination therapy significantly inhibited tumor growth (52.08%) with great safety, which explored a new idea for cancer immunotherapy.

, correspAuthors=Xian-rong QI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2022 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=Ru-dong WANG, Yi-wei PENG, Zhen-zhen YANG, Yi-tian DU, Meng LIN, Qi SUN, Xian-rong QI), CN=ArticleExt(id=1209787637557228371, articleId=1209787633430032968, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=肿瘤微环境响应脂质体阻断CXCL12/CXCR4通路协同增加抗PD-L1的免疫疗效, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

阻断免疫检查点程序性细胞死亡受体-1（PD-1）或程序性死亡受体配体-1（PD-L1）可以增强效应T细胞的抗肿瘤活性。然而，许多患者对PD-1/PD-L1疗法缺乏反应。通过改善免疫抑制性肿瘤微环境（TME）以增强免疫检查点抑制剂的疗效已成为一种有前景的癌症治疗策略。本研究构建了具有基质金属蛋白酶（MMPs）响应能力的C-X-C趋化因子配体12（CXCL12）siRNA与抗PD-L1肽的共给药脂质体（PD-L1/siCXCL12-Lp），联合siCXCL12的TME调控与抗PD-L1肽的免疫调节作用，以协同增强抗肿瘤免疫反应。动物实验方案经由北京大学生物医学伦理委员会审查通过。作者发现PD-L1/siCXCL12-Lp在体外（33.8%）和体内（15.5%）直接下调了CXCL12的表达，并有效提高了CD8+/Treg的比例（20.0%），这有利于抗PD-L1肽更好地发挥其免疫作用。联合治疗显著抑制了肿瘤生长（52.08%），并且具有良好的安全性，为癌症免疫治疗探索了新的思路。

, correspAuthors=齐宪荣, authorNote=null, correspAuthorsNote=
*齐宪荣, Tel: 86-10-82801584, E-mail:
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Immunol Cell Biol, 2008, 86: 506-514., articleTitle=Synergistic antitumor effects of CpG oligodeoxynucleotide and STAT3 inhibitory agent JSI-124 in a mouse melanoma tumor model, refAbstract=null)], funds=[Fund(id=1209809062867374485, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, awardId=81973258, language=CN, fundingSource=国家自然科学基金资助项目(81973258), fundOrder=null, country=null), Fund(id=1209809062989009308, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, awardId=81673365, language=CN, fundingSource=国家自然科学基金资助项目(81673365), fundOrder=null, country=null), Fund(id=1209809063148392870, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, awardId=7202092, language=CN, fundingSource=北京市自然科学基金资助项目(7202092), fundOrder=null, country=null), Fund(id=1209809063286804914, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, awardId=L202044, language=CN, fundingSource=北京市自然科学基金资助项目(L202044), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1209809053094646387, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, xref=null, ext=[AuthorCompanyExt(id=1209809053128200822, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, companyId=1209809053094646387, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Beijing 100191, China), AuthorCompanyExt(id=1209809053325333135, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, companyId=1209809053300167307, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.分子药剂学与新释药系统北京市重点实验室, 北京 100191)])], figs=[ArticleFig(id=1209809059398684839, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=POzyLcyU6ZYNVSC1/+7Vbw==, figureFileBig=mptxsVsHYTg84EH/f9NKyQ==, tableContent=null), ArticleFig(id=1209809059490959540, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 1, caption= Schematic illustration of the mechanism of the tumor microenvironment (TME) responsive liposomes for synergistic treatment of cancer immunotherapy and TME regulation. Ⅰ: Liberation of the anti-programmed death receptor-ligand 1 (PD-L1) peptide due to specific cleavage by matrix metalloproteinase-2 (MMP-2) secreted in tumor region, leading to the blockade of PD-1/PD-L1 interaction; Ⅱ: Transfection of C-X-C chemokine ligand 12 (CXCL12) siRNA in cancer-associated fibroblasts (CAFs). CAF-secreted CXCL12 contributes to tumor metastasis by promoting migration and invasion of tumor cells. The liposome nanosystem is internalized into CAFs, and then the released siRNA leads to <i>CXCL12</i> gene silencing. As a consequence, the immunosuppressive TME is improved, which contributes to the efficacy of anti-PD-1/PD-L1 therapy. RISC: RNA-induced silencing complex; mRNA: Messenger RNA; CTLs: Cytotoxic T lymphocytes; Tregs: Regulatory T cells , figureFileSmall=POzyLcyU6ZYNVSC1/+7Vbw==, figureFileBig=mptxsVsHYTg84EH/f9NKyQ==, tableContent=null), ArticleFig(id=1209809059641954495, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=Kg/apKEW6H4Z1KG/w09TlQ==, figureFileBig=Mth1Tggke+BhWon4JWLB/Q==, tableContent=null), ArticleFig(id=1209809059759395015, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 2, caption= Preparation and characterization of liposomes. A: Principle of the synthesis of DSPE-PEG<sub>2000</sub>-pep; B: Photos of PD-L1/siCXCL12-Lp treated RBCs in different concentrations after centrifugation; C: Gel retardation assay of PD-L1/siCXCL12-Lp at different N/P ratio; D: Particle size and zeta potential of PD-L1/siCXCL12-Lp during the storage for 74 h at 4 ℃; E: Photos of siCXCL12-Lp and PD-L1/siCXCL12-Lp by TEM , figureFileSmall=Kg/apKEW6H4Z1KG/w09TlQ==, figureFileBig=Mth1Tggke+BhWon4JWLB/Q==, tableContent=null), ArticleFig(id=1209809059893612755, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=uBt2TP9HglBZJz/GoVFirg==, figureFileBig=zq5ezHMHDR47+ioZ7Qg83g==, tableContent=null), ArticleFig(id=1209809060027830490, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 3, caption= Cell uptake and intracellular distribution of liposomes with siRNA at a final concentration of 100 nmol·L<sup>-1</sup> for 4 h. A: Mean fluorescence intensity of FAM-siRNA for different formulations. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± <i>s</i>. <sup>***</sup><i>P</i> < 0.001; B: CLSM images of FAM-siRNA for different formulations; C: CLSM images for the lysosomal escape of PD-L1/siRNA-Lp. FAM: 5-Carboxyfluorescein , figureFileSmall=uBt2TP9HglBZJz/GoVFirg==, figureFileBig=zq5ezHMHDR47+ioZ7Qg83g==, tableContent=null), ArticleFig(id=1209809060162048227, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=+sfzQlANI7+SSIforbtevA==, figureFileBig=U8qazUnzdu+uCDOlajLBWg==, tableContent=null), ArticleFig(id=1209809060338209016, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 4, caption= Blockade of PD-1/PD-L1 interaction <i>in vitro</i>. A: MMP-2 protein expression of B16F10 cells determined by ELISA; B: MMP-2 responsive cleavage of peptide <i>in vitro</i> determined by HPLC with MMP-2 buffer (15 ng·mL<sup>-1</sup>) or B16F10 cell culture medium (91.5 ng·mL<sup>-1</sup>); C: Flow cytometry analysis of the upregulation of PD-L1 on B16F10 cells treated with 30 ng·mL<sup>-1</sup> interferon-<i>γ</i> (IFN-<i>γ</i>) for 24 h; D: The concentration of PD-1 in B16F10 cells; E: The PD1/PD-L1 interaction blockade in B16F10 cells. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=+sfzQlANI7+SSIforbtevA==, figureFileBig=U8qazUnzdu+uCDOlajLBWg==, tableContent=null), ArticleFig(id=1209809060493398280, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=soMKM6KI3R0eiNL/hDPLsw==, figureFileBig=iQDVymsk/1GGCZorJEnTSA==, tableContent=null), ArticleFig(id=1209809060619227412, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 5, caption= <i>In vitro</i> gene-silencing effect and cytotoxicity of different formulations. A: The level of CXCL12 mRNA determined by quantitative real-time PCR. CAFs were transfected with various samples carrying siCXCL12 or siN.C. at 37 ℃ for 4 h; B: CXCL12 protein expression determined by ELISA after culturing with various formulations carrying CXCL12 siRNA or siN.C. in CAFs; C: Cell viability of CAFs and B16F10 after treated with different formulations for 48 h with 0.1 mg·mL<sup>-1</sup> peptide or 100 nmol·L<sup>-1</sup> siCXCL12. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=soMKM6KI3R0eiNL/hDPLsw==, figureFileBig=iQDVymsk/1GGCZorJEnTSA==, tableContent=null), ArticleFig(id=1209809061491642662, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=dmd07JIf9cYmqHaG85bM/Q==, figureFileBig=b1e6sEv96z/VuQLHkaP4MA==, tableContent=null), ArticleFig(id=1209809061600694572, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 6, caption= Tumor inhibition efficiency and systemic toxicity of different formulations using B16F10 tumor-bearing C57BL/6 mice. A: Relative tumor volume-time curve. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05; B: Tumor weight; C: Organ coefficient; D: Net body weight; E: Body weight changes; F: Observation of lung metastasis; G: Staining of H&E in tumor sections; H: Staining of H&E in main organs , figureFileSmall=dmd07JIf9cYmqHaG85bM/Q==, figureFileBig=b1e6sEv96z/VuQLHkaP4MA==, tableContent=null), ArticleFig(id=1209809061755883837, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=2hfZqgVsBrtyECAL04GrHw==, figureFileBig=zYlMGIxDnAmWRzuvfqFJuw==, tableContent=null), ArticleFig(id=1209809061973987655, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 7, caption= Flow cytometry analysis results of the changes of immune cells in tumor, spleen or lymph nodes. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=2hfZqgVsBrtyECAL04GrHw==, figureFileBig=zYlMGIxDnAmWRzuvfqFJuw==, tableContent=null), ArticleFig(id=1209809062137565525, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=gY1UhMxFtINx63gj5YBSVQ==, figureFileBig=qS7i8kVxmohzvfBJSO3vlA==, tableContent=null), ArticleFig(id=1209809062275977570, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Figure 8, caption= ELISA analysis results of the changes of cytokines. <i>n</i> = 3, <span class="mag-xml-inline-formula">$ \overline{x} $</span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01. IL-10: Interleukin-10; TNF-<i>α</i>: Tumor necrosis factor-<i>α</i> , figureFileSmall=gY1UhMxFtINx63gj5YBSVQ==, figureFileBig=qS7i8kVxmohzvfBJSO3vlA==, tableContent=null), ArticleFig(id=1209809062368252270, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Reagent/mLNo.
123456
1.5% RBCs222222
Normal saline1.71.81.91.952—
PD-L1/siCXCL12-Lp0.30.20.10.05——
Distilled water—————2
), ArticleFig(id=1209809062481498488, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1209787633430032968, language=CN, label=Table 1, caption=

Red blood cell hemolysis test. RBCs: Red blood cells

, figureFileSmall=null, figureFileBig=null, tableContent=
Reagent/mLNo.
123456
1.5% RBCs222222
Normal saline1.71.81.91.952—
PD-L1/siCXCL12-Lp0.30.20.10.05——
Distilled water—————2
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肿瘤微环境响应脂质体阻断CXCL12/CXCR4通路协同增加抗PD-L1的免疫疗效
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王如东 1, 2 , 彭祎玮 1, 2 , 仰浈臻 1, 2 , 杜祎甜 1, 2 , 林萌 1, 2 , 孙琪 1, 2 , 齐宪荣 1, 2, *
药学学报 | 研究论文 2022,57(1): 178-187
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药学学报 | 研究论文 2022, 57(1): 178-187
肿瘤微环境响应脂质体阻断CXCL12/CXCR4通路协同增加抗PD-L1的免疫疗效
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王如东1, 2, 彭祎玮1, 2, 仰浈臻1, 2, 杜祎甜1, 2, 林萌1, 2, 孙琪1, 2, 齐宪荣1, 2, *
作者信息
  • 1.北京大学药学院, 北京 100191
  • 2.分子药剂学与新释药系统北京市重点实验室, 北京 100191

通讯作者:

*齐宪荣, Tel: 86-10-82801584, E-mail:
Tumor microenvironment responsive liposomes blocking CXCL12/CXCR4 pathway and synergistically enhancing immune efficacy of anti-PD-L1
Ru-dong WANG1, 2, Yi-wei PENG1, 2, Zhen-zhen YANG1, 2, Yi-tian DU1, 2, Meng LIN1, 2, Qi SUN1, 2, Xian-rong QI1, 2, *
Affiliations
  • 1. School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
  • 2. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Beijing 100191, China
出版时间: 2022-01-12 doi: 10.16438/j.0513-4870.2021-0967
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摘要
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阻断免疫检查点程序性细胞死亡受体-1（PD-1）或程序性死亡受体配体-1（PD-L1）可以增强效应T细胞的抗肿瘤活性。然而，许多患者对PD-1/PD-L1疗法缺乏反应。通过改善免疫抑制性肿瘤微环境（TME）以增强免疫检查点抑制剂的疗效已成为一种有前景的癌症治疗策略。本研究构建了具有基质金属蛋白酶（MMPs）响应能力的C-X-C趋化因子配体12（CXCL12）siRNA与抗PD-L1肽的共给药脂质体（PD-L1/siCXCL12-Lp），联合siCXCL12的TME调控与抗PD-L1肽的免疫调节作用，以协同增强抗肿瘤免疫反应。动物实验方案经由北京大学生物医学伦理委员会审查通过。作者发现PD-L1/siCXCL12-Lp在体外（33.8%）和体内（15.5%）直接下调了CXCL12的表达，并有效提高了CD8+/Treg的比例（20.0%），这有利于抗PD-L1肽更好地发挥其免疫作用。联合治疗显著抑制了肿瘤生长（52.08%），并且具有良好的安全性，为癌症免疫治疗探索了新的思路。

脂质体  /  小干扰核糖核酸  /  C-X-C趋化因子配体12/C-X-C趋化因子受体4  /  程序性细胞死亡受体-1/程序性死亡受体配体-1  /  基质金属蛋白酶-2

Blocking immune checkpoint programmed cell death receptor 1 (PD-1) or programmed death receptor-ligand 1 (PD-L1) can enhance anti-tumor activity of effector T cells. However, the lack of response in many patients to PD-1/PD-L1 therapy remains a question. Improving the immunosuppressive tumor microenvironment (TME) to enhance the efficacy of immune checkpoint inhibitors has become a promising cancer treatment strategy. We constructed a liposome system (PD-L1/siCXCL12-Lp) of CXCL12 siRNA and anti-PD-L1 peptide with matrix metalloproteinases (MMPs) responsiveness, which combined the TME regulation of siCXCL12 and the immune regulation of anti-PD-L1 peptide. All animal experiments were approved by the Biomedical Ethics Committee of Peking University. The authors found that PD-L1/siCXCL12-Lp directly down-regulated the expression of CXCL12 in vitro (33.8%) and in vivo (15.5%). It also effectively increased the ratio of CD8+/Treg by 20.0%, which helped the anti-PD-L1 peptide to better exert its immune effect. The combination therapy significantly inhibited tumor growth (52.08%) with great safety, which explored a new idea for cancer immunotherapy.

liposome  /  small interfering ribonucleic acid  /  C-X-C chemokine ligand 12/C-X-C chemokine receptor type 4  /  programmed cell death protein 1/programmed death receptor-ligand 1  /  matrix metalloproteinase-2
王如东, 彭祎玮, 仰浈臻, 杜祎甜, 林萌, 孙琪, 齐宪荣. 肿瘤微环境响应脂质体阻断CXCL12/CXCR4通路协同增加抗PD-L1的免疫疗效. 药学学报, 2022 , 57 (1) : 178 -187 . DOI: 10.16438/j.0513-4870.2021-0967
Ru-dong WANG, Yi-wei PENG, Zhen-zhen YANG, Yi-tian DU, Meng LIN, Qi SUN, Xian-rong QI. Tumor microenvironment responsive liposomes blocking CXCL12/CXCR4 pathway and synergistically enhancing immune efficacy of anti-PD-L1[J]. Acta Pharmaceutica Sinica, 2022 , 57 (1) : 178 -187 . DOI: 10.16438/j.0513-4870.2021-0967
正文
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近年来, 基于检查点抑制剂的癌症免疫治疗备受关注[1]。程序性细胞死亡受体-1 (programmed cell death protein 1, PD-1)/程序性死亡受体配体-1 (programmed death receptor-ligand 1, PD-L1) 免疫疗法通过阻断T细胞免疫检查点, 使免疫正常化, 提高了患者的生存率[2-4]。然而该疗法目前仅对部分癌症类型和20%~30%的患者有效[5], 全身性递送PD-1/PD-L1抗体还可能会出现免疫相关不良事件, 这限制了其进一步应用[6]。T细胞是抗肿瘤免疫的关键介质[7], 由免疫抑制性肿瘤微环境(tumor microenvironment, TME) 引起的有限的T细胞浸润是检查点抑制剂治疗失败的关键原因之一[8]。因此, 改善免疫抑制性TME或可增强检查点抑制剂的功效。
癌症相关成纤维细胞(cancer-associated fibroblasts, CAFs) 是TME中含量最丰富的基质细胞之一, 通过分泌多种细胞因子、蛋白酶和细胞外基质, 在塑造免疫抑制性TME中起着重要作用[9]。CAFs分泌的促炎介质C-X-C趋化因子配体12 (C-X-C chemokine ligand 12, CXCL12) 可以通过CXCL12/CXCR4信号通路加速肿瘤的生长和转移[10]。研究发现, CXCL12会抑制肿瘤内T细胞的浸润[8, 11, 12], 阻断CXCL12/CXCR4通路可以提高检查点抑制剂的疗效, 这种联合疗法已成为一种有前途的癌症治疗策略[13, 14]。
由此, 本研究构建了一种基于阳离子脂质体的共给药体系(图 1), 将针对CXCL12的基因疗法和针对PD-L1的免疫疗法联合起来, 以协同增强抗肿瘤免疫反应。选取阳离子脂质体作为共递送载体, 能够有效地将基因药物和多肽药物同时携载。作者将CXCL12 siRNA (siCXCL12) 包载进脂质体内部, 将抗PD-L1肽(NYSKPTDRQYHF) 通过基质金属蛋白酶-2 (matrix metalloproteinase-2, MMP-2) 底物肽CPLGVRGK共价连接至脂质体表面。进入TME后, PD-L1/siCXCL12-Lp响应过表达的MMP-2释放出抗PD-L1肽, 阻断PD-1/PD-L1相互作用; siRNA脂质体进入CAFs以沉默CXCL12基因, 将免疫调节与TME调控相结合, 增强T细胞浸润, 减少调节性T细胞(regulatory T cell, Treg) 的产生, 为癌症免疫治疗探索新的思路。
材料与方法
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材料与试剂   CXCL12 siRNA (sense 5'-UCGCCA GAGCCAACGUCAATT-3', antisense 5'-UUGACGUU GGCUCUGGCGATT-3')、羧基荧光素标记的siRNA (FAM-siRNA) (上海吉玛制药公司); 功能肽(pep, 上海强耀公司); (2, 3-二油酰基-丙基)-三甲基氯化铵(DOTAP, 美国MCE公司); 大豆卵磷脂(SPC)、DSPE-mPEG2000 (日本油脂株式会社); 胆固醇(Chol, 日本和光纯药株式会社); GelStain核酸染料(北京全式金公司); Hoechst 33342 (上海翊圣公司); Lysotracker red DND-99 (美国Invitrogen公司); 小鼠MMP-2重组蛋白(北京博知源公司); 小鼠PD-1重组蛋白(上海爱必信公司); 干扰素-γ (interferon-γ, IFN-γ, 北京义翘神州公司); qPCR引物(北京奥科鼎盛公司); Reverse Transcription System、GoTaq® qPCR Master Mix (美国Promega公司); 小鼠MMP-2、PD-1、CXCL12、白细胞介素-10 (interleukin-10, IL-10)、IFN-γ、肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α) ELISA试剂盒(北京冬歌博业公司)。
主要仪器   MOLDI-TOF MS、LC-20A HPLC系统(日本岛津公司); MZ Nano-ZS型激光粒度仪(英国马尔文公司); JEM-200CX型透射电子显微镜(日本JEOL公司); BD Gallios流式细胞仪(美国BD公司); STED 3x型激光共聚焦显微镜(德国Leica公司); Mx3000pTM荧光定量PCR仪(美国安捷伦公司)。
实验细胞   小鼠黑色素瘤细胞(B16F10) 购自美国模式培养物集存库, 小鼠CAFs取自荷4T1乳腺癌的BALB/c雌性裸鼠[9], 在含10% FBS、1%青霉素和1%链霉素的DMEM培养液中于37 ℃、5% CO2条件下培养。
实验动物   雌性C57BL/6小黑鼠(18~20 g, 4~6周龄), 购自北京维通利华公司, 所有动物实验均在北京大学动物实验的指导原则下进行, 实验方案经由北京大学生物医学伦理委员会审查通过。
pep的合成   pep (CPLGVRGK-GGG-NYSKPTD RQYHF) 使用标准Fmoc固相肽合成方法获得[15]。SH-CPLGVRGK是MMP-2的底物肽, NYSKPTDRQYHF (D型氨基酸) 是PD-L1的抑制剂[16]。
DSPE-PEG2000-pep的合成   称取一定量pep和DSPE-PEG2000-Mal (多肽∶脂材= 1∶1.25, mol/mol), 溶于N, N-二甲基甲酰胺(DMF) 中, 加入三乙胺(TEA) (TEA∶pep = 5∶1, mol/mol), 氮气保护下避光反应24 h, 蒸馏水透析(3 500 Da) 48 h即得。取少量样品进行MALDI-TOF MS鉴定。
脂质体的制备及表征   将DOTAP∶SPC∶Chol∶DSPE-mPEG2000 (25∶40∶30∶5, mol/mol) 溶于氯仿/甲醇(4∶1, v/v), 旋蒸成膜, 加入siRNA的葡萄糖溶液水化, 探头超声3 min, 无菌滤膜过滤, 制得包载siRNA的脂质体(siCXCL12-Lp)。共递送siRNA和抗PD-L1肽的脂质体(PD-L1/siCXCL12-Lp) 采用同样方法制备, 不同的是DSPE-mPEG2000被DSPE-PEG2000-pep取代。使用激光粒度仪测定粒径分布、多分散指数(polymer dispersity index, PDI) 和zeta电位, 使用透射电镜(transmission electron microscopy, TEM) 观察形态。
凝胶电泳实验   制备不同N/P的PD-L1/siCXCL12-Lp和含有GelStain核酸染料的琼脂糖凝胶块, 将样品混合液(10 μL待测物+ 2 μL 5 × loading buffer) 加入各样品孔进行电泳, 使用凝胶成像仪拍摄胶片。
红细胞溶血实验   取新鲜大鼠血液8 mL, 放入有玻璃珠的三角瓶中振摇10 min以除去纤维蛋白, 加入生理盐水100 mL混匀。1 500 r·min-1离心15 min, 去上清。取沉淀的红细胞1.5 mL, 加入生理盐水100 mL摇匀, 制得1.5%的红细胞悬液。取4 mL EP管, 编号1~6, 其中1~4号为供试管, 5号为阴性对照, 6号为阳性对照。按表 1依次加入各组分, 混匀后置于37 ℃恒温水浴, 3 h后离心, 观察溶血情况。取上清, 用紫外分光光度计在540 nm下检测吸光度值, 计算溶血率。
细胞摄取实验   选取FAM-siRNA作为模型药物标记脂质体。将CAFs以2×105个/孔接种于6孔板中培养24 h。使用100 nmol·L-1的free siRNA、siRNA-Lp和PD-L1/siRNA-Lp与细胞共孵育4 h。磷酸盐缓冲液(phosphate buffered saline, PBS) 洗涤, 消化收集细胞, 使用流式细胞仪测定胞内荧光强度。
共聚焦观察   将CAFs以2×105个/皿接种于共聚焦小皿中培养24 h。使用100 nmol·L-1的free siRNA、siRNA-Lp和PD-L1/siRNA-Lp与细胞共孵育4 h。使用4%多聚甲醛固定, Hoechst 33342染细胞核。采用激光共聚焦显微镜(confocal laser scanning microscopy, CLSM) 观察。
溶酶体逃逸实验   将CAFs以2×105个/皿接种于共聚焦小皿中培养24 h。使用100 nmol·L-1的PD-L1/siRNA-Lp与细胞共孵育0.5和4 h。使用Hoechst 33342染细胞核, Lysotracker red染溶酶体。采用CLSM观察溶酶体逃逸情况。
pep响应MMP-2释放抗PD-L1肽   将pep溶液加入MMP-2缓冲液(15 ng·mL-1) 或预孵育12 h的B16F10细胞培养液中, 于37 ℃水浴, 在不同时间点取样进行HPLC分析检测抗PD-L1肽。色谱柱: Diamonsil C18柱(250 mm × 4.6 mm, 5 μm); 流动相: 乙腈/水在20 min内从17%∶83%到42%∶58%的线性梯度; 流速: 1 mL·min-1; 检测波长: 220 nm; 柱温: 25 ℃; 进样体积: 10 μL。
PD-1/PD-L1相互作用的阻断   使用小鼠MMP-2 ELISA试剂盒测量B16F10细胞培养液中MMP-2的浓度。在用IFN-γ (30 ng·mL-1) 体外上调PD-L1的表达后, 将B16F10细胞接种于6孔板中培养24 h。将培养基更换为含有游离肽、siN.C.-Lp或PD-L1/siN.C.-Lp的无血清培养基, 并加入重组小鼠PD-1蛋白(200 ng·mL-1) 孵育4 h。PBS洗3次, 加入RIPA细胞裂解液和蛋白酶抑制剂提取蛋白样品, 离心取上清, 使用小鼠CXCL12 ELISA试剂盒检测样品中CXCL12的浓度。
CXCL12蛋白表达的测定   将CAFs以2×105个/孔接种于6孔板中培养24 h。使用100 nmol·L-1的free siCXCL12、siCXCL12-Lp、PD-L1/siCXCL12-Lp和PD-L1/si N.C.-Lp与细胞共孵育4 h。PBS洗涤, 继续培养6 h后更换新的培养液培养24 h。使用小鼠CXCL12 ELISA试剂盒测量培养液中的CXCL12蛋白表达。
反转录-实时定量PCR   使用TRNzol Universal从细胞中分离总RNA。使用反转录试剂盒进行反转录过程以获得第一链cDNA。使用引物和GoTaq® qPCR Master Mix进行聚合酶链式反应, 通过实时定量PCR (real-time quantitative polymerase chain reaction, RT-qRCR) 对基因表达进行量化。3-磷酸甘油醛脱氢酶(glyceraldehyde 3-phosphate dehydrogenase, GAPDH) 引物: 正向5'-GGGTGTGAACCATGAGAAGT-3', 反向: 5'-GAC TGTGGTCATGAGTCCT-3'; CXCL12引物: 正向5'-CCTGACGGTAAACTCTTCCCT-3', 反向5'-GCTAGG CAGCTCCTCTTTGG-3'。选取GAPDH作为内参, 使用ΔΔC相对定量法分析。
细胞毒性实验   将CAFs和B16F10细胞分别以8 000个/孔接种于96孔板中培养24 h, 将细胞与free siCXCL12、free peptide、siCXCL12-Lp、PD-L1siCXCL12-Lp和PD-L1siN.C.-Lp共孵育48 h。使用CCK-8法检测细胞活性。
体内药效学考察   将1×106个B16F10细胞皮下注射到小鼠腋窝造模, 将荷瘤小鼠随机分成4组: PBS组、游离肽组、siCXCL12-Lp组和PD-L1/siCXCL12-Lp组, 每组5只。除游离肽组腹腔给药外, 其余组均尾静脉给药, siRNA浓度为1.33 mg·kg-1, 肽浓度为2 mg·kg-1。将初次给药定为第1天, 每隔两天给药1次。每日测量小鼠体重及肿瘤的长径(a) 和短径(b), 按V = 0.5 × a × b2 (mm3) 计算瘤体积。于第10天处死小鼠, 分离肿瘤及各脏器, 称重并进行苏木精&伊红(H&E) 染色观察。
体内免疫细胞分析   解剖小鼠, 分离腹股沟淋巴结、脾和肿瘤并提取淋巴细胞。对于T细胞的标记, 向脾和肿瘤淋巴细胞中加入FITC-CD3、APC-CD25、PerCP/Cyanine5.5-CD4和PE/Cyanine7-CD8a抗体, 孵育30 min, PBS洗涤2次。加入细胞固定液和破膜液孵育30 min, 离心去上清, 破膜液洗涤, 加入PE-FoxP3抗体孵育30 min。对于DC的标记: 向淋巴结和脾淋巴细胞中分别加入APC-CD11c和PE/Cyanine7-I-A/I-E抗体孵育30 min。通过流式细胞术分析T细胞和树突细胞(dendritic cell, DC) 的浸润情况。
趋化因子/细胞因子检测   解剖小鼠, 分离肿瘤, 加入一定量PBS研磨获得细胞悬液, 离心取上清, 使用小鼠CXCL12 ELISA试剂盒检测肿瘤内CXCL12的水平。收集全血, 室温静置后离心取上清, 使用小鼠IL-10、IFN-γ、TNF-α ELISA试剂盒检测血清中相关细胞因子的水平。
统计学方法   使用GraphPad Prism 7软件进行分析, 数据用$ \overline{x} $ ± s表示。数据经ANOVA分析和Bartlett检验, P < 0.05认为有显著性差异。
结果与讨论
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1 脂质体的制备与表征
采用薄膜分散法制备了siRNA脂质体(siCXCL12-Lp)。为了制备抗PD-L1肽修饰的siRNA脂质体(PD-L1/siCXCL12-Lp), 根据已有方法[17], 将pep (CPLGVRGK-GGG-NYSKPTDRQYHF) 与DSPE-PEG2000-MAL的马来酰亚胺基团偶联, 合成了DSPE-PEG2000-pep以代替原处方中的DSPE-mPEG2000 (图 2A)。从图 2B可以观察到, 不同浓度PD-L1/siCXCL12-Lp (1~4号) 处理后的红细胞与阴性对照(5号) 相同, 上清无色澄明, 说明没有造成溶血, 与阳性对照(6号) 的全溶血形成鲜明对比。1~5号管的溶血率均几乎为0, 进一步说明PD-L1/siCXCL12-Lp没有造成溶血现象。凝胶电泳阻滞实验表明, siRNA可以以8/1或者更高的N/P有效包封在脂质体中(图 2C), 从而防止其在血液中过早释放, 因此本研究中载有siRNA的脂质体的N/P均设定为8/1。PD-L1/siCXCL12-Lp在4 ℃储存的74 h过程中, 外观无明显变化, 直径和电位保持稳定(图 2D), 表明其没有发生解散或聚集, 能够稳定储存至少3天。
siCXCL12-Lp和PD-L1/siCXCL12-Lp显示出均匀的尺寸分布和正zeta电位, 流体动力学直径在125~155 nm内, PDI小于0.25。TEM图像显示(图 2E), 脂质体呈球形, 直径为50~70 nm, 小于动态光散射测量的水合粒径。脂质体的正电荷由阳性脂材DOTAP提供, PD-L1/siCXCL12-Lp的zeta电位(20.1 mV) 小于siCXCL12-Lp (24.2 mV), 表明电负性多肽的表面修饰会对整体电荷起到一定屏蔽作用。制备的脂质体制剂直径小于200 nm且表面有亲水性PEG包覆, 可以有效减少调理素的识别及网状内皮系统的清除, 从而延长体内循环时间[18]。
2 细胞摄取与溶酶体逃逸
为了研究针对CAFs的siRNA递送, 以FAM-siRNA为指标评估了siRNA的细胞内化情况。游离siRNA几乎无法进入细胞。siRNA-Lp和PD-L1/siRNA-Lp表现出显著增强的siRNA内化(图 3A), 表明阳离子脂质体能够促进siRNA内化到CAFs中。相应的结果通过CLSM观察到(图 3B), 与对照组相比, 在siRNA-Lp和PD-L1/siRNA-Lp处理的CAFs中观察到更多的FAM-siRNA (绿色), 发现siRNA-Lp组比PD-L1/siRNA-Lp组具有更强的siRNA摄取, 推测这可能是由于抗PD-L1肽的连接对细胞摄取产生了一定的不利影响, 而这种影响预计可通过肿瘤微环境中抗PD-L1肽的MMP-2响应性断裂得到改善。
siRNA被摄取入胞后必须从溶酶体中逃逸才能发挥其基因沉默作用[19]。将CAFs与PD-L1/siRNA-Lp共孵育, 并在CLSM成像前用Lysotracker red对溶酶体进行染色, 可以观察到FAM-siRNA (绿色) 在0.5 h时与溶酶体(红色) 有较强的共定位, 而在4 h时不再共定位(图 3C), 表明siRNA已成功从溶酶体中逃逸, 以发挥其后续的基因沉默作用。
3 体外阻断PD-1/PD-L1相互作用
MMPs在TME中高表达, 已被广泛用作癌症的生物标志物和治疗靶标[20]。使用ELISA试剂盒测量B16F10细胞MMP-2的体外分泌情况, 12 h培养液中MMP-2达到91.5 ng·mL-1 (图 4A)。HPLC分析证实了pep的MMP-2敏感性裂解能力。pep在11.3 min出峰, 加入15 ng·mL-1的MMP-2缓冲液后, 随着时间延长, 原始峰不断减小, 在12.3 min处出现新的产物峰且不断增大, 说明pep在MMP-2的作用下出现时间依赖性断裂(图 4B)。在与MMP-2浓度为91 ng·mL-1的B16F10细胞培养液孵育10 min后, 在12.3 min处同样出现新的产物峰, 证明了pep能够有效响应MMP-2并释放出抗PD-L1肽。
由于PD-L1在体外肿瘤细胞培养过程中低表达[21], 使用IFN-γ体外上调了B16F10细胞上的PD-L1, 并通过流式细胞术进行了证实(图 4C)。据文献[16]报道, 抗PD-L1肽以高亲和力与PD-L1结合, 从而竞争性阻断PD-1与PD-L1的结合。将PBS、游离肽、siN.C.-Lp或PD-L1/siN.C.-Lp与重组小鼠PD-1蛋白共同给药, 通过测量与肿瘤细胞PD-L1结合的PD-1的量(图 4D) 推算PD-1/PD-L1的阻断效率(图 4E)。游离肽和PD-L1/siN.C.-Lp显著阻断了PD1/PD-L1的相互作用, 相比对照组, 分别达到了42.9%和28.8%的抑制率。结果表明, B16F10细胞分泌的MMP-2可以裂解pep并释放抗PD-L1肽, 在体外有效破坏PD-1/PD-L1的相互作用。
4 体外基因沉默效果和细胞毒性
脂质体可以成功地将siRNA递送至CAFs并实现溶酶体逃逸, 因此作者进一步评估了其基因沉默效率。以GAPDH为内参基因, 使用RT-qPCR法研究了CXCL12 mRNA的相对表达量。PD-L1/siCXCL12-Lp和siCXCL12-Lp分别实现了38.0%和49.7%的基因沉默效率(图 5A)。mRNA的下调直接降低了CXCL12蛋白的表达(图 5B)。ELISA结果显示, siCXCL12-Lp和PD-L1/siCXCL12-Lp组中CXCL12的表达分别降低了36.4%和33.8%, 这与mRNA检测结果一致。结果表明, 设计的脂质体制剂能够有效沉默CAFs中CXCL12 mRNA的表达, 从而实现CXCL12蛋白表达的下调。为了评估细胞毒性, 将各给药制剂与CAFs和B16F10细胞共孵育, 使用CCK-8法研究了细胞活力, 在两种细胞中都未检测到明显的细胞毒性(图 5C)。
5 体内药效与安全性考察
使用荷B16F10黑色素瘤的C57BL/6小鼠研究了PD-L1/siCXCL12-Lp的抗肿瘤效果和全身毒性。当肿瘤生长到100~200 mm3时, 将小鼠随机分成4组并分别给予PBS、游离肽、siCXCL12-Lp和PD-L1/siCXCL12-Lp治疗。PD-L1/siCXCL12-Lp的肿瘤体积(图 6A) 和重量(图 6B) 显著低于PBS组, 肿瘤生长抑制率达到52.08%。结果表明, PD-L1/siCXCL12-Lp联合了针对CXCL12的基因疗法和针对PD-L1的免疫疗法, 在体内实验中达到了最好的肿瘤治疗效果。
实验期间所有小鼠的脏器指数(图 6C) 无明显差异, 体重正常增加(图 6D), 净体重(图 6E) 无明显差异。观察肿瘤肺转移发现, 仅有PBS组出现1例(图 6F) 大面积的肿瘤转移, 其他组均未观察到明显的肺转移结节。各组肿瘤的H&E染色显示(图 6G), PBS组表现出明显的肿瘤快速增殖现象, siCXCL12-Lp和PD-L1/siCXCL12-Lp组则出现了一定程度上的核固缩和坏死现象。主要脏器H&E染色(图 6H) 显示, 与PBS组相比, 各给药组小鼠的心、肝、脾、肺和肾的图像均未显示出明显差异。结果表明, 各制剂对小鼠没有造成明显的系统毒性, 体内安全性良好。
6 体内免疫学分析
为了进一步探究抗肿瘤免疫效果, 检测了小鼠免疫细胞和相关细胞因子的变化。CD4+ T、CD8+ T和Treg细胞是T细胞的主要亚群。分析给药后肿瘤和脾内T细胞的结果(图 7) 发现, 尽管各组制剂对CD4+和CD8+ T细胞未起到显著的促进作用, 但PD-L1/siCXCL12-Lp在一定程度上抑制了Treg的增殖, 从而导致CD8+/Treg有所提高。一般认为CD8+/Treg越高, 抗肿瘤效果越好[22], 联合给药抑制了Treg增殖, 改善了免疫抑制性TME, 有利于抗PD-L1免疫疗法更好地发挥作用。PD-L1/siCXCL12-Lp组的脾和淋巴结内DC表达的MHC-II相比其他组均有提高, 表明联合治疗增强了小鼠DC的成熟和抗原呈递能力, 进一步增强了免疫疗效。
检测肿瘤部位的CXCL12发现(图 8), siCXCL12-Lp和PD-L1/siCXCL12-Lp组的CXCL12水平均低于PBS组, 表明siCXCL12在体内发挥了基因沉默作用, 有效抑制了CXCL12分泌。IL-10是Th-2型细胞因子, 对癌症的免疫抑制和转移至关重要[23]。siCXCL12-Lp和PD-L1/siCXCL12-Lp都显著抑制了IL-10的分泌, 说明siRNA通过沉默CXCL12, 改善了免疫抑制性TME。IFN-γ和TNF-α是细胞毒性T细胞分泌的Th-1型细胞因子, 会促进T细胞对肿瘤的杀伤作用[24]。PD-L1/siCXCL12-Lp组IFN-γ和TNF-α的水平都显著高于PBS组, 说明其有效促进了T细胞的抗肿瘤活性。
结论
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本研究成功构建了共递送CXCL12 siRNA和抗PD-L1肽的阳离子脂质体(PD-L1/siCXCL12-Lp), 脂质体具有良好的制剂学性质、细胞摄取能力和溶酶体逃逸效果, 能够响应TME中高表达的MMP-2而释放出抗PD-L1肽, 以破坏PD-1/PD-L1的相互作用, 并且具有良好的基因沉默效果和安全性。在动物实验中, PD-L1/siCXCL12-Lp联合了针对CXCL12的siRNA疗法和针对PD-L1的免疫疗法, 改善了免疫抑制性TME, 提高了免疫细胞的浸润及抗肿瘤活性, 最终有效抑制了肿瘤生长, 并且具有良好的体内安全性。
作者贡献: 齐宪荣、仰浈臻和王如东提出研究的整体思路; 王如东负责主要实验操作及文章的撰写; 彭祎玮、杜祎甜、林萌和孙琪负责协助实验操作及数据分析; 齐宪荣负责最终版本修订。
利益冲突: 所有作者声明无利益冲突。
基金
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  • 国家自然科学基金资助项目(81973258)
  • 国家自然科学基金资助项目(81673365)
  • 北京市自然科学基金资助项目(7202092)
  • 北京市自然科学基金资助项目(L202044)
文献
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参考文献 引证文献
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2022年第57卷第1期
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doi: 10.16438/j.0513-4870.2021-0967
  • 接收时间：2021-06-30
  • 首发时间：2025-12-22
  • 出版时间：2022-01-12
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  • 收稿日期：2021-06-30
  • 修回日期：2021-07-22
基金
国家自然科学基金资助项目(81973258)
国家自然科学基金资助项目(81673365)
北京市自然科学基金资助项目(7202092)
北京市自然科学基金资助项目(L202044)
作者信息
    1.北京大学药学院, 北京 100191
    2.分子药剂学与新释药系统北京市重点实验室, 北京 100191

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*齐宪荣, Tel: 86-10-82801584, E-mail:
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genus		 种数
Number of
species		 占总种数比例
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total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
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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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