药学学报

仿生型纳米药物递送系统在神经系统疾病中的研究进展

PDF下载

刘陈霏 , 肖聪聪 , 刘艳红 , 陈丽青 , 刘超 , 赵鹤鸣 , 金明姬 , 高钟镐 , 黄伟 ^*

药学学报 | 综述 2023,58(8): 2300-2310

收起

药学学报 |综述 2023 , 58 (8) : 2300 -2310

仿生型纳米药物递送系统在神经系统疾病中的研究进展

全屏

[Author(id=1198960099663377080, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960099868898004, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960099663377080, language=EN, stringName=Chen-fei LIU, firstName=Chen-fei, middleName=null, lastName=LIU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960100015698663, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960099663377080, language=CN, stringName=刘陈霏, firstName=陈霏, middleName=null, lastName=刘, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960100166693628, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960100326077197, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960100166693628, language=EN, stringName=Cong-cong XIAO, firstName=Cong-cong, middleName=null, lastName=XIAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960100468683550, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960100166693628, language=CN, stringName=肖聪聪, firstName=聪聪, middleName=null, lastName=肖, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960100661621553, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960100858753858, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960100661621553, language=EN, stringName=Yan-hong LIU, firstName=Yan-hong, middleName=null, lastName=LIU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960101039108952, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960100661621553, language=CN, stringName=刘艳红, firstName=艳红, middleName=null, lastName=刘, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960101173326700, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=3, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960101320127355, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960101173326700, language=EN, stringName=Li-qing CHEN, firstName=Li-qing, middleName=null, lastName=CHEN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960101420790663, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960101173326700, language=CN, stringName=陈丽青, firstName=丽青, middleName=null, lastName=陈, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960101630505884, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=4, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960101815055278, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960101630505884, language=EN, stringName=Chao LIU, firstName=Chao, middleName=null, lastName=LIU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960102033159105, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960101630505884, language=CN, stringName=刘超, firstName=超, middleName=null, lastName=刘, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960102175765454, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=5, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960102519698409, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960102175765454, language=EN, stringName=He-ming ZHAO, firstName=He-ming, middleName=null, lastName=ZHAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960102708442106, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960102175765454, language=CN, stringName=赵鹤鸣, firstName=鹤鸣, middleName=null, lastName=赵, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960102834270208, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=6, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960102972682254, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960102834270208, language=EN, stringName=Ming-ji JIN, firstName=Ming-ji, middleName=null, lastName=JIN, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960103132065818, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960102834270208, language=CN, stringName=金明姬, firstName=明姬, middleName=null, lastName=金, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960103295643683, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=7, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1198960103496970290, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960103295643683, language=EN, stringName=Zhong-gao GAO, firstName=Zhong-gao, middleName=null, lastName=GAO, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960103664742457, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960103295643683, language=CN, stringName=高钟镐, firstName=钟镐, middleName=null, lastName=高, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])]), Author(id=1198960103836708936, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, orderNo=8, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=huangwei@imm.ac.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1198960104071589976, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960103836708936, language=EN, stringName=Wei HUANG, firstName=Wei, middleName=null, lastName=HUANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960104193224803, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, authorId=1198960103836708936, language=CN, stringName=黄伟, firstName=伟, middleName=null, lastName=黄, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=^*, address=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1198960099487216292, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, xref=null, ext=[AuthorCompanyExt(id=1198960099503993509, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1198960099512382118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652621377597656, companyId=1198960099487216292, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050)])])]

刘陈霏, 肖聪聪, 刘艳红, 陈丽青, 刘超, 赵鹤鸣, 金明姬, 高钟镐, 黄伟^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050

通讯作者:

*黄伟, Tel: 86-10-63026505, E-mail: huangwei@imm.ac.cn

Research progress of biomimetic nano drug delivery system in nervous system disease

Chen-fei LIU, Cong-cong XIAO, Yan-hong LIU, Li-qing CHEN, Chao LIU, He-ming ZHAO, Ming-ji JIN, Zhong-gao GAO, Wei HUANG^*

Affiliations

Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0549

文章导航

摘要

收起

由于血脑屏障(blood brain barrier, BBB) 的存在, 药物递送到大脑仍然具有挑战性。随着仿生型纳米药物递送技术的进步, 出现了药物脑部靶向递送的新可能。仿生型纳米药物递送系统具有高效脑靶向性和穿透BBB能力的同时, 具有良好的生物相容性和安全性, 可以实现药物的“隐形”递送。在这篇综述中, 介绍了5种不同类型的仿生策略并回顾了其在中枢神经系统疾病中的研究进展。最后, 总结了仿生型纳米递送技术在脑内给药方面面临的挑战和未来的前景。

关键词

仿生 / 纳米药物递送系统 / 中枢神经系统疾病 / 血脑屏障

Abstract

收起

Brain delivery of drugs remains challenging due to the presence of the blood-brain barrier (BBB). With advances in nanotechnology and biotechnology, new possibilities for brain-targeted drug delivery have emerged. Biomimetic nano drug delivery systems with high brain-targeting and BBB-penetrating capabilities, along with good biocompatibility and safety, can enable 'invisible' drug delivery. In this review, five different types of biomimetic strategies are presented and their research progress in central nervous system disorders is reviewed. Finally, the challenges and future prospects for biomimetic nano drug delivery systems in intracerebral drug delivery are summarized.

Key words

biomimetic / nano drug delivery system / central nervous system disease / blood brain barrier

引用本文

刘陈霏, 肖聪聪, 刘艳红, 陈丽青, 刘超, 赵鹤鸣, 金明姬, 高钟镐, 黄伟. 仿生型纳米药物递送系统在神经系统疾病中的研究进展. 药学学报, 2023 , 58 (8) : 2300 -2310 . DOI: 10.16438/j.0513-4870.2023-0549

Chen-fei LIU, Cong-cong XIAO, Yan-hong LIU, Li-qing CHEN, Chao LIU, He-ming ZHAO, Ming-ji JIN, Zhong-gao GAO, Wei HUANG. Research progress of biomimetic nano drug delivery system in nervous system disease[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2300 -2310 . DOI: 10.16438/j.0513-4870.2023-0549

正文

收起

当前, 随着人口数量的增长和老龄化的加剧, 中枢神经系统(central nervous system, CNS) 疾病患者的数量进一步增加, 对世界各国的社会经济和卫生保健系统都造成了沉重的负担^[1]。根据2016年全球疾病负担研究, 神经系统疾病是伤残调整生命年损失(DALYs) 的主要原因和第二大死因^[2]。

CNS疾病包括脑血管病变(如脑梗死、脑出血)、神经退行性病变[如帕金森病、阿尔茨海默病(AD)、亨廷顿病、肌萎缩侧索硬化症等]、脑部肿瘤(如神经胶质瘤、髓母细胞瘤) 等多种疾病, 是造成人群死亡和残疾的主要原因。大量研究表明多种CNS疾病都与血脑屏障(blood brain barrier, BBB) 密切相关。BBB是由脑毛细血管和星形胶质细胞等脑细胞组成的血浆与脑组织间的保护性屏障。为了维持和保护大脑的功能, BBB严格控制物质进入, 仅允许2%~3%的小分子透过, 包括蛋白质、多肽、siRNA、多克隆抗体等几乎所有大分子被排除在外^{[3, 4]}; 另外, BBB上还存在非常活跃的外排泵, 在将有毒、代谢和其他废物从脑中清除的同时还会清除进入脑内的药物^[5]。因此, BBB在使中枢神经系统免受毒性成分、病原体等有害因素伤害的同时, 也阻止了治疗药物的进入^[6]。

随着纳米技术的发展, 基于纳米颗粒(nanoparticles, NPs) 的药物递送系统(drug delivery system, DDS) 在脑部疾病中也进行了广泛研究。NPs通过内吞作用内化进入脑部毛细血管内皮细胞中, 还可通过实体瘤的高通透性和滞留(enhanced permeability and retention effect, EPR) 效应被动靶向脑部肿瘤组织^{[7, 8]}。当前, 各种基于NPs的DDS被开发出来作为治疗CNS疾病的有效工具, 并表现出了优异的靶向性, 但仍然存在安全问题、生物相容性差等局限性。近年来, 基于天然微粒的仿生型纳米药物递送系统成为克服传统纳米药物递送系统问题的一种新手段。这种新颖的仿生DDS通常利用和模仿人体内成分的特征, 并模仿许多自然机制来达到目标效果, 将药物准确递送至脑内靶部位的同时, 具有良好的生物相容性和安全性, 能使药物实现更佳的治疗效果^[9]。本文主要综述了基于细胞膜、内源性物质、外泌体、蛋白冠和病毒的5类仿生型纳米药物递送系统近年来的研究进展。

1 基于细胞膜的仿生型纳米药物递送系统

收起

基于细胞膜的仿生型纳米药物递送系统是指由修饰过的细胞膜包覆的药物纳米粒子(cell membrane coated nano drug delivery systems, CM-NDDS), 通常为核-壳结构, 其内部是预先制备的NPs, 外层为修饰后的不同细胞膜(图 1)^[10]。目前, 已经有不同类型的细胞膜被应用, 包括红细胞膜、白细胞膜、血小板膜、巨噬细胞膜和癌细胞膜等。CM-NDDS不仅保留了NPs的优点, 而且增加了其安全性和生物相容性, 可以保护NPs不被人体免疫系统清除, 延长药物在血液中的循环时间从而使更多的药物在脑内靶部位中聚集。2011年Hu等^[11]首次制备了红细胞膜包被的NPs, 该CM-NDDS在体内循环时间长达40 h, 这大大延长了药物的半衰期, 并且经细胞膜包裹的NPs不会对机体产生免疫刺激, 具有良好的生物相容性和安全性。自此之后基于CM-NDDS的研究如雨后春笋般蓬勃发展。2013年, Parodi等^[12]利用白细胞膜制备的CM-NDDS具有良好稳定性和在体循环时间, 同时可以避免被机体的免疫系统清除; 2014年, Fang等^[13]将肿瘤细胞膜设计应用于促进抗肿瘤免疫反应和实现新的肿瘤靶向策略。随着CM-NDDS的发展, 研究发现由细胞膜简单包覆制成的CM-NDDS也具有一定的局限性, 例如: 由红细胞膜制成的CM-NDDS虽然实现了药物的在体长循环, 但具有较差的脑部靶向性, 难以实现更好的治疗效果^[14]。因此, 为了改善CM-NDDS的局限性, 许多研究在保留源细胞膜固有结构和功能的基础上通过修饰赋予CM-NDDS新的功能, 从而在脑部肿瘤、AD等疾病的诊断和治疗中取得更好的效果^{[15, 16]}。常用的生物膜修饰方法包括膜杂交法、插入后法、化学法、代谢工程和基因工程^[17]。

1.1 基于红细胞膜的仿生型纳米药物递送系统(red blood cells membrane coated nano drug delivery systems, RM-NDDS)

红细胞是人体血液中数量最多、寿命最长的一类血细胞, 成熟红细胞无细胞核和细胞器、易于提取和纯化, 并且具有独特的膨胀特性, 可以包载包括蛋白质类大分子药物在内的多种药物, 因此红细胞被广泛应用于CM-NDDS的研究中^[18]。RM-NDDS在中枢神经疾病的诊断与治疗中具有独特的优势: ①易于突破BBB, 脑是人体中血液供应相对丰富的器官, RM-NDDS具有畅通无阻穿过BBB的能力^[19]; ②生物相容性和可降解性, 在制备RM-NDDS时保留了红细胞表面特异性功能蛋白, 在降低免疫原性和毒性的同时避免了其被网状内皮系统作为外来物质清除, 并且异常的RM-NDDS可以被脾脏中的巨噬细胞吞噬清除; ③延长药物半衰期, 人体内正常红细胞寿命约120天, RM-NDDS在增加药物稳定性的同时可以实现药物在体内的长循环; ④高载药量, 成熟红细胞内缺乏细胞核和各种细胞器。因此, 与传统NPs相比RM-NDDS拥有更高的载药量, 甚至可以轻松包载酶、多肽、蛋白质等分子量较大的药物。

虽然RM-NDDS具有透过BBB的潜力, 但是对脑部的主动靶向性很差, 因此需要经过如靶向肽、配体等的修饰后才能发挥更好的效果^{[20, 21]}。Cui等^[22]以大戟因子L1 (EFL1) 为模型药物制备聚乳酸-羟基乙酸共聚物(PLGA)NPs, 而后在其外包覆经脂质插入法制备的^DWSW和NGR肽修饰的RBCM, 制成一种双重修饰的靶向制剂^DWSW/NGR-RBCNPs。^DWSW/NGR-RBCNPs在体内外实验中都具有更好的靶向和透过BBB的表现; 此外, ^DWSW/NGR-RBCNPs经静脉注射进小鼠体内后, 能够更好地靶向脑部肿瘤组织并显著延长寿命, 并且表现出更优异的安全性(图 2)。Zou等^[23]以angiopep-2修饰的红细胞膜为外壳, 以pH敏感的多柔比星(Dox) 和lexiscan (Lex) 共载NPs为内核, 制备得到Ang-RBCm@NM-(Dox/Lex)。经angiopep-2功能化的RM-NDDS具有高效的脑靶向能力, 并且内部包载的Lex能提高NPs对BBB的渗透效率, 从而提高DOX的治疗效果。实验结果表明, 经Ang-RBCm@NM-(Dox/Lex) 治疗的原位U87MG人胶质母细胞瘤荷瘤裸鼠具有更长的生存时间。

1.2 基于白细胞膜的仿生型纳米药物递送系统(white cell membrane coated nano drug delivery systems, WM-NDDS)

白细胞是一类具有免疫功能的血细胞, 根据其形态、功能和来源可以分为三大类: 粒细胞、单核细胞和淋巴细胞^[24]。白细胞因其独特的募集效应和归巢效应, 不经修饰就具有靶向炎症部位和肿瘤组织的功能^[25]。

中性粒细胞是数量最丰富的粒细胞, 占白细胞的40%~70%^[26]。脑卒中会引起强烈的炎症反应^[27], 当发生缺血性脑卒中时, 中性粒细胞会在1 h内出现在缺血区, 因此利用中性粒细胞膜制备的CM-NDDS在治疗脑卒中疾病中具有巨大潜力^[28]。Dong等^[29]用中性粒细胞膜制备了包载Resolvin D2 (RvD2) 的DDS, 该DDS可以特异性靶向缺血性脑卒中小鼠模型中发炎的脑内部位并输送RvD2, 从而有利于缺血性脑卒中治疗期间炎症的消退。Feng等^[30]制备了中性粒细胞膜包载的介孔普鲁士蓝纳米酶(MPBzyme@NCM), 该制剂有效提高了普鲁士蓝纳米酶的脑部递送效率, 能有效减轻缺血性脑卒中的损伤及帮助神经功能恢复, 并且能够提高缺血性脑卒中后的存活率。

巨噬细胞源自单核细胞, 具有抗感染、抗炎、抗肿瘤和呈递抗原等重要功能^[31]。巨噬细胞能够通过其表面的特异性受体和黏附因子, 如C-C趋化因子受体2 (CCR2) 对肿瘤相关信号做出反应, 而后募集到肿瘤组织中^[32]。Yin等^[33]利用巨噬细胞这一特点制备了巨噬细胞膜包被的PD-1纳米颗粒(PD-1-MM@PLGA/RAPAs), 经体内外实验验证, 该制剂可以穿透BBB且响应肿瘤微环境的募集, 携带PD-1直接作用于肿瘤部位, 具有更强治疗效果的同时减少了药物的全身不良反应。Xiao等^[34]也基于此特点制备了一种巨噬细胞膜包覆的二氧化锰和顺铂共载纳米凝胶制剂, 可同时发挥对原位脑胶质瘤的诊断和治疗作用。

自然杀伤细胞(natural killer cell, NK) 是独特的淋巴细胞, 其表面有许多可以识别肿瘤的抗体, 包括NKG2D、NKp44、NKp46、NKp30和DNAM等^{[35, 36]}。Deng等^[37]开发出NK细胞膜包覆的具有聚集诱导发射特性的NK细胞模拟纳米机器人(NK@AIEdots), 依靠NK细胞膜上的受体可以主动聚集在脑胶质瘤中, 一方面能够进行高对比度和穿透颅骨肿瘤成像, 另一方面通过近红外光照射产生NK@AIEdots诱导的局部热疗效应, 从而有效抑制胶质瘤的生长。

1.3 基于血小板膜的仿生型纳米药物递送系统(platelet cell membrane coated nano drug delivery systems, PM-NDDS)

与红细胞类似, 血小板也是一种无细胞核的血细胞, 因此血小板膜的提取亦较为容易, 但血小板膜表面除CD47外, 还有包括CD55和CD59在内的其他表达簇来防止被免疫细胞吞噬和清除, 因此具有更强的免疫逃避能力^[38]。

血小板在血管损伤、炎症反应、血栓形成和止血中至关重要^[39]。Wang等^[40]开发了一种由RGD修饰血小板膜包载人脂肪提取物的隐形NPs (RGD-PLT@PLGA-FE), 经实验证明该DDS具有靶向治疗缺血性脑卒中的潜力。Xu等^[41]设计制备的tP-NP-rtPA/ZL006e, 可在外层血小板膜介导下靶向到血栓部位释放, 有效提高了对缺血性脑卒中的疗效。Mehdi-Alamdarlou等^[42]利用血小板在炎症反应中的作用原理, 设计一种包载了富马酸二甲酯的PCMCNPs, 这一DDS在实验中表现出更高的脑部摄取率, 可以作为多发性硬化症的潜在治疗DDS。

1.4 基于癌细胞膜的仿生型纳米药物递送系统(tumor cell membrane coated nano drug delivery systems, TM-NDDS)

TM-NDDS是用于癌症治疗的理想DDS, 具有其他CMCNPs不具有的优点: ①癌细胞具有无限增殖的能力, 易于在体外大量培养来收集源细胞膜; ②癌细胞膜具有同源靶向性, 癌细胞在进入血液后倾向于在主要附着部位形成多细胞同源聚集体^[43]; ③肿瘤转移时能透过BBB并黏附在脑部组织上, 因此提示其不经修饰就具有穿透BBB的能力^[44]。癌细胞膜因其独特的同源靶向特性和免疫逃避能力, 已被广泛用于脑部肿瘤的诊断和治疗的研究中。

目前, 已经有很多研究基于癌细胞的同源靶向性利用多形性胶质母细胞瘤制备TM-NDDS, 将不同的化疗药物如多柔比星和基因治疗药物等靶向递送至脑内肿瘤部位, 实现更好的治疗效果^[45]。Wang等^[46]以负载吲哚菁绿的聚合物NPs为核心, 制备了基于多形性胶质母细胞瘤的TM-NDDS, 该DDS可实现脑肿瘤早期的成像和光热治疗。Fan等^[47]利用C6细胞膜包载10-羟基喜树碱纳米混悬剂(HCPT-NS) 制得胶质母细胞瘤细胞膜伪装的HCPT-NS/CCM, HCPT-NS/CCM制备简单、载药量高, 且能在没有任何修饰的情况下主动靶向并穿透BBB聚集在胶质瘤部位, 经该TM-NDDS治疗的荷瘤小鼠肿瘤体积最小且生存期明显延长(图 3)。

2 基于内源性物质的仿生型纳米药物递送系统

收起

内源性生物活性物质是指人体内天然存在的具有生理功能和生物活性的物质。蛋白质约占人体全部质量的18%, 是生命的物质基础, 其中的载体蛋白如白蛋白、脂蛋白对维持人体正常的生命活动至关重要, 并且二者因其独特的结构和天然靶向性被广泛应用于仿生型药物递送系统的研究中。基于白蛋白和脂蛋白的仿生型纳米药物递送系统具有无毒、无免疫原性、高载药量和靶向性等优异特点, 目前在靶向治疗CNS疾病中得到重点研究^[48]。

2.1 基于白蛋白的仿生型纳米药物递送系统

白蛋白是血液中含量最高的内源性蛋白质, 具有维持血浆胶体渗透压、运输难溶性小分子物质和营养物质的功能^[49]。人血清白蛋白上具有许多药物结合位点, 且含有疏水结构域, 因此可以结合疏水性药物; 此外, 白蛋白表面具有很多功能基团, 经过修饰后可以实现药物的靶向递送, 因此白蛋白是优异的仿生型药物递送载体(结构如图 4^[50]所示)^[51]。白蛋白在人体内的半衰期平均约为19天, 因此以其为基础的仿生型纳米药物递送系统能有效延缓药物的代谢时间从而提高药物的治疗效果^[52]。此外, 白蛋白还是一种出色的冻干保护剂, 有利于白蛋白纳米粒的大规模生产和临床应用^[53]。首个基于白蛋白载体的纳米药物Abraxane已被FDA批准并上市, 用于治疗转移性乳腺癌、胰腺癌和非小细胞肺癌, 为白蛋白仿生型纳米药物的发展树立了里程碑^[53]。

为给快速成长的癌细胞提供充足的营养和能量, 白蛋白结合蛋白如SPARC和gp60在脑部肿瘤细胞中过表达, 因此白蛋白结合蛋白是实现药物靶向递送的潜在靶标, 可以基于此特点构建基于白蛋白的仿生型纳米药物递送系统用于脑部肿瘤的诊断和治疗^[54-56]。Gregory等^[57]设计制备了基于人血清白蛋白经细胞穿膜肽iRGD修饰的靶向脑胶质瘤的NPs (STAT3i SPNP), 该NPs包载了针对STAT3的siRNA。在实验中, 经细胞穿膜肽iRGD修饰的STAT3i SPNP表现出了更优异的脑靶向能力, 其中87.5%经STAT3i SPNP和放疗联合治疗的小鼠达到长期生存时间点; 在这些小鼠中, STAT3水平均显著降低, 且具有正常的大脑结构, 没有明显的残留肿瘤组织。Gao等^[58]针对脑肿瘤中过表达的gp60受体, 利用白蛋白构建聚集诱导发射(AIE) 纳米探针, 增强了AIE发光体(AIEgens) 的主动靶向能力、提高了荧光量子产率, 为脑部肿瘤的诊断开发了一种高灵敏和高分辨率成像平台。

白蛋白表面的多官能团结构易于修饰, 经过功能化修饰可以实现主动靶向BBB的药物递送, 以治疗其他中枢系统疾病^[49]。Feczkó等^[59]设计制备了共载神经生长因子和超小颗粒氧化铁的白蛋白纳米颗粒, 并以载脂蛋白E进行表面修饰。该NPs能够穿过人造BBB, 并能诱导神经元轴突生长; 在脑卒中动物模型中, 梗死体积的轻微减少也表明该NPs能成功靶向递送至BBB。Xue等^[60]采用静电喷涂技术制备了负载Rh-促红细胞生成素(rh-EPO) 的Tween 80改性白蛋白纳米颗粒(rh-EPO-Tw-ABNPs), 用于治疗创伤性脑损伤。体内实验证明, 该白蛋白NPs可以增强rh-EPO在脑中的分布, 能更有效地缓解脑水肿, 表现出更优异的靶向治疗效果。Monge-Fuentes等^[61]设计制备了载有多巴胺的白蛋白纳米颗粒(ALNP-DA) 以恢复帕金森小鼠的运动功能, 发现ALNP-DA能有效地穿过BBB在黑质-纹状体通路补充多巴胺, 小鼠的帕金森症状得到显著改善。

2.2 基于脂蛋白的仿生型纳米药物递送系统

脂蛋白是由甘油三酯、磷脂、胆固醇和蛋白质分子聚集形成的颗粒, 根据密度大小可分为: 乳糜微粒(chylomicrons, CM)、极低密度脂蛋白(very low density lipoproteins, VLDL)、中间密度脂蛋白(intermediate density lipoproteins, IDL)、低密度脂蛋白(low density lipoproteins, LDL) 和高密度脂蛋白(high density lipoproteins, HDL)。作为人体内源性物质, 脂蛋白无免疫原性且具有较长体内循环时间, 且一些脂蛋白如HDL、LDL还可以通过BBB运输, 是将治疗药物、成像剂等靶向递送至目标部位的绝佳载体, 其中LDL和HDL是研究最广泛的脂蛋白载体^{[62, 63]}。目前, 有3种方法利用脂蛋白制备仿生型药物递送系统的载体: 通过磷脂壳上的非共价结合进行表面药物负载、通过磷脂或蛋白质进行共价修饰以及通过重构技术重组脂蛋白包载药物^[64]。

LDL可通过血液循环将胆固醇运载转运至外周组织细胞^[65], 且是密度脂蛋白受体(LDLR) 的主要配体。LDLR是各种脑部肿瘤中过表达的多种受体之一, 可通过受体介导的内吞作用摄取LDL, 因此提示LDL可以作为靶向脑部肿瘤的仿生型载体^[66]。Liang等^[67]将硫酸长春新碱封装载到T7肽配体修饰的天然LDL中(T7-LDL) 用于靶向治疗神经胶质瘤, T7-LDL具有LDL和T7肽的双靶向功能, 在体内和体外实验中都表现出有效的抗胶质瘤作用。

HDL是体积最小的脂蛋白, 直径约为8~12 nm, 具有去除血液中多余胆固醇并将其运输回肝脏的功能, 而且HDL还具有抗炎和抗氧化作用^[68]。但天然的HDL难以进行修饰和包载药物, 目前由各种脂质和载脂蛋白自组装形成的重组高密度脂蛋白(rHDL) 被广泛应用于化学药物、基因治疗药物和荧光探针等靶向递送载体的研究^[69]。rHDL具有与天然HDL相似的大小和结构, 在具有相同优异的生物相容性和安全性的同时更易于修饰和包载药物(图 5)^[70]。Wang等^[71]先用穿透肽tLyP-1修饰rHDL (ptHDL), 而后将光敏剂吲哚菁绿(ICG) 包载在疏水核心中, 同时将胆固醇偶联的小干扰RNA siHIF嵌入磷脂层内, 最终制备得到了靶向脑胶质瘤新生血管内皮细胞的仿生型纳米药物递送系统ptHDL/siHIF-ICG。该DDS可以有效穿透BBB并递送至脑胶质瘤部位, 实现原位脑胶质瘤成像和基因/光热协同治疗抑制肿瘤生长, 为脑胶质瘤的诊断和治疗开发了一种新的仿生型递送策略。rHDL与天然HDL相似, 可与肿瘤细胞表面过表达的HDL清道夫受体B1 (SCARB1) 结合, 促进胆固醇外排干扰细胞胆固醇水平, 从而导致肿瘤细胞的死亡。目前已有研究证明, SCARB1可在髓母细胞瘤细胞尤其是SHH亚型中高表达, 根据这一特点Bell等^[72]制备了载有荧光标记的rHDL NPs, 并证明髓母细胞瘤细胞可通过SCARB1摄取该NPs, 并表现出抗肿瘤作用, 为髓母细胞瘤的诊断和治疗提供了新的仿生型策略。HDL还在AD中起关键作用, 虽然目前机制尚不明确, 但是富含载脂蛋白A-I (apoA-I) 的HDL亚型可以降低AD风险^[73]。Zhang等^[74]利用apoA-I制备了负载多奈哌齐的rHDL (rHDL/Do), 其可同时发挥靶向清除β-淀粉样蛋白和中枢乙酰胆碱酯酶(AChE) 抑制作用, rHDL/Do经注射给药后可以透过BBB实现药物靶向递送, 通过抑制AChE活性改善神经损伤, 同时减少淀粉样蛋白沉积, 能有效改善AD小鼠认知功能障碍, 为载脂蛋白在AD中的应用提供了有力依据, 同时为AD的治疗开辟了新的仿生型纳米药物递送平台。

3 基于外泌体的仿生型纳米药物递送系统

收起

外泌体(exosome) 是细胞释放的粒径在40~100 nm、具有脂质双层结构的天然纳米膜泡, 起源于细胞膜内陷形成的胞内小体, 与细胞膜融合后排出细胞, 因此其结构和成分较为复杂。不同细胞来源的外泌体可以包含细胞的许多成分, 如RNA、脂质、细胞质和细胞表面蛋白(图 6)。外泌体具有调节细胞间交流的作用, 具体功能取决于其所来源的细胞类型, 已有研究表明外泌体可以参与机体免疫应答、抗原呈递和细胞因子转运等多种生命活动中^[75]。基于外泌体的仿生型纳米药物递送系统具有以下优点: ①外泌体是内源性物质, 具有良好的生物相容性, 无免疫原性和细胞毒性; ② BBB对从间充质干细胞、神经元等特定细胞中分离得到的外泌体具有高度渗透性, 可以实现药物在脑部的靶向聚集; ③外泌体具有优异的载药能力, 无论亲水性还是疏水性药物均可被包载, 还可包载蛋白质和RNA类等易在制备NPs过程中被破坏的药物; ④用外泌体作为载体可以避免药物被网状内皮细胞吞噬清除, 实现药物的“隐形”递送; ⑤外泌体具有较长的血液循环时间, 可以延长药物的半衰期、延缓药物代谢, 增强药物的治疗效果^[76]。外泌体是具有巨大临床应用潜力的仿生型纳米药物递送系统载体, 目前已经被广泛研究用于CNS疾病的诊断和治疗中。

Li等^[77]利用电穿孔法将具有抗肿瘤作用的miRNA-21反义寡核苷酸(AMO-21) 加载到经T7肽修饰的外泌体(T7-exo) 中, 以未修饰的外泌体(Unmod-exo) 和RVG修饰的外泌体(RVG-exo) 为对照组。在体外实验中, T7-exo对C6细胞的递送效率明显高于其他两组; 在体内实验中, T7-exo有效地降低了胶质母细胞瘤miRNA-21的表达水平, 缩小了肿瘤体积。Qi等^[78]制备了负载AD的潜力治疗药物槲皮素(Que) 的外泌体(Exo-Que) 以改善Que的生物利用度, 利用外泌体表面的热休克蛋白HSP70和内皮TLR4与脑中高表达的受体特异性结合实现主动靶向穿透BBB, 与游离Que组相比, Exo-Que能减少冈田酸(OA) 诱导的AD小鼠的神经细胞凋亡、提高记忆力和空间学习能力, 显著减轻了OA诱导的小鼠神经退行性病变。此外, Exo-Que可显著抑制CDK5的活性, 降低tau蛋白过度磷酸化, 从而减少NFT的形成。因此证明, Exo-Que作为tau蛋白聚集的有效抑制剂能有效改善AD小鼠的认知功能, 并为AD提供了新的治疗策略。

4 基于原位蛋白冠的仿生型纳米药物递送系统

收起

NPs具有较大的比表面积和较高的表面能, 当与生理介质接触时, 易吸附蛋白质和其他生物分子在表面形成一层或多层以蛋白质为主的蛋白冠(protein corona, PC), 从而形成纳米粒-蛋白冠(NP-PC) 复合物^[79]。PC可以改变NPs的大小、表面特征和功能等多种物理化学性质, 并赋予NP-PC不同的生物学特性, PC很大程度上决定了NPs与细胞受体结合效率、内化机制、细胞内运输途径、体内分布特性及随后的生物学效应, 最重要是的PC可显著影响NPs的靶向性^[80]。尽管已经发现并验证了蛋白冠对NPs治疗效果的不利影响, 但在某些情况下, 蛋白冠是达成“隐身”递送不可或缺的^[81]。NPs表面形成的PC种类、数量及性质也受NPs大小、表面电荷及表面修饰等影响, 而且在形成PC时, 除了大量惰性或功能未知的蛋白外, 许多功能性的蛋白亦被吸附^{[82, 83]}。因此, 已有研究人员通过调整NPs的理化性质来控制PC的形成, 从而实现“隐形”地主动靶向递送。

有些载脂蛋白可以通过受体介导的转吞作用穿过BBB, 并且载脂蛋白通常被认为是PC的主要成分之一, 吸附在NPs上形成PC并影响其细胞摄取^[62]。例如, ApoE作为LDLR的配体, 可以主动靶向脑胶质瘤上过表达的LDLR并通过其介导的内吞作用透过BBB^[84]。因此, NPs表面被专门设计为选择性吸附ApoE形成PC以增强其对脑部的靶向能力。占昌友及其团队^[85]设计制备了硫醇化Aβ1-42修饰的脂质体(SP-sLip) 用于包载多柔比星, 经静脉注射后在体内吸附ApoAⅠ、ApoE和ApoJ形成PC, 从而通过LRP1、LRP2和SR-B1介导的转吞作用进行脑靶向递送。SP-sLip通过调控蛋白冠的组分来实现脑部靶向递送, 因此与负载多柔比星的普通脂质体相比表现出显著增强的脑分布和抗脑癌作用。Zhang等^[86]构建了基于体内原位PC介导的脑靶向纳米递药系统, 将紫杉醇“隐形”、靶向递送至脑部, 发挥抗胶质瘤作用。该研究使用酰胺形式的Aβ25-35 (Aβ-CN) 对纳米胶束(PMs) 进行表面修饰, 使PMs经静脉注射后在体内以可控方式结合ApoE的脂质结合域, 形成富含ApoE的蛋白冠, 利用ApoE对BBB上高表达的LDLR和LRP1的特异性靶向作用, 将药物递送至脑内发挥治疗作用(图 7)。

基于原位蛋白冠的仿生型纳米药物递送系统具有良好的生物相容性, 可以避免体外蛋白质修饰合成的NPs对机体潜在的免疫原性风险, 同时PC内的主要成分载脂蛋白可以克服药物在BBB渗透率方面的限制, 提高药物的脑靶向递送效率。

5 基于病毒的纳米药物递送系统

收起

病毒具有独特的嗜性, 能有效穿透细胞膜将遗传物质带入细胞, 因此大多作为基因治疗药物的递送载体^[87]。然而, 病毒载体存在潜在的安全隐患, 如免疫原性较强、毒性高等, 目前已经被模拟病毒结构和功能的仿生型递送载体所代替。基于病毒的仿生型纳米药物递送系统可以改善以上局限性的同时, 能保留病毒特殊的靶向侵袭能力, 从而实现更好的治疗效果^[88]。

腺相关病毒载体(adeno-associated virus, AAV) 是由天然存在的腺相关病毒经基因工程改造后得到的仿生型载体, 已有研究证明工程化衣壳改造的AAV可以靶向并穿过BBB, 如AAV-PHP·B和AAV-PHP.eB具有极强的CNS转导效率, 是治疗CNS疾病最有潜力的载体之一^[89]。

狂犬病病毒糖蛋白(rabies virus glycoprotein, RVG) 是狂犬病病毒表面的一种糖蛋白, 可通过与n型乙酰胆碱受体(nAchR) 的G蛋白结合来感染哺乳动物神经细胞^{[90, 91]}。RVG其中含有的29个氨基酸(序列: YTIWMPENPRPGTPCDIFTNSRGKRASNG) 可以特异性靶向结合BBB处的nAchR并透过BBB。将RVG29与NPs结合可以制备得到模拟狂犬病病毒功能的仿生型纳米药物递送系统^[92]。Xin等^[93]筛选了与RVG29活性相当、长度相对较短的15肽片段RVG15连接到DSPE-mPEG2000上, 制备了包载紫杉醇的脂质体脑靶向制剂RVG15-PEG-DSPE, RVG15-PEG-DSPE通过模拟狂犬病病毒的功能, 为脑胶质瘤等CNS疾病的治疗提供了新的可能(图 8)。Wu等^[94]设计制备了RVG15肽修饰的沸石咪唑酸盐框架NPs (RVG15-PEG@DTX@ZIF-8) 用于多西紫杉醇的脑靶向递送, 该仿生纳米药物递送系统在体内外实验中都表现出优异的靶向性和高BBB穿透效率, 是穿透BBB和治疗胶质母细胞瘤的强有力的工具。

6 总结与展望

收起

仿生型纳米药物递送系统通过模拟天然存在的生物学机制并将特定的功能加载到合成NPs上, 以实现更好的治疗效果或改善合成NPs的局限性。仿生型纳米药物递送系统具有良好的生物相容性、安全性和优异的靶向性, 可以实现药物的“隐形”递送, 目前已被广泛应用于多种疾病的诊断和治疗中。FDA于2005年批准首个紫杉醇白蛋白纳米粒药物Abraxane用于治疗联合化疗失败后的转移性乳腺癌, FDA于2021年批准西罗莫司白蛋白结合型纳米粒Fyarro上市, 用于治疗局部晚期不可切除性或转移性恶性血管周围上皮样细胞肿瘤。自张良方及其团队2011年首次发表报道基于红细胞膜的仿生型纳米药物制剂, 时至今日, 其名下公司研制的CTI-005已完成全部临床前动物实验和毒理学研究, 并通过IND申报进入了临床试验。基于外泌体的癌症诊断产品ExoDxLung (ALK)、ExoDx LungT (790M) 和ExoDx®Prostate于2016年陆续问世, 针对疾病治疗的基于外泌体的药物制剂也陆续进入到临床试验中, 如exoSTING于2020年进行了针对晚期实体瘤的I/II期临床试验(NCT04592484)。尽管目前暂无针对CNS疾病的仿生型纳米药物制剂获批上市或进入临床试验, 但仿生型纳米药物递送系统具有良好的生物相容性、安全性和优异的靶向性。仿生型纳米药物递送系统可以减轻药物的全身不良作用, 使纳米药物逃脱机体免疫系统的清除, 在实现药物的脑靶向递送同时改善药物半衰期使药物易于在脑部蓄积达有效治疗浓度, 具有优秀的临床转化前景。但仿生型纳米药物递送系统的局限性也不容忽视。仿生型纳米药物递送系统的载体并不是简单的使用生物分子, 因此这些载体通常不稳定且难以控制, 在进入体内后也可能产生脱靶效应, 在产生脱靶效应后是否会产生毒副作用等仍需进一步的研究探讨。除此之外, 仿生型纳米药物递送系统的载体多数是来源于生物材料, 都可能存在致病风险, 需要经过严格的来源筛选和消毒。不同的仿生型DDS还存在其他风险: CMCNPs在使用前需要进行严格的血型匹配, 以避免引起溶血等风险; 在基于LDL的仿生型纳米药物递送系统中, LDL的过量使用和结构改变可能会引起其他疾病, 例如氧化的LDL会导致动脉硬化; 在基于HDL的仿生型纳米药物递送系统中, 富含Apo E的HDL可能会诱导AD。在临床转化和放大生产方面, 依据目前已有研究, 仿生型纳米药物递送系统较难放大生产, 只局限于实验研究阶段。与合成纳米药物递送系统相比, 仿生型纳米药物递送系统的载体来源单一且较难获取和进行分离纯化, 不同批次间难以进行质量控制。并且, 目前仍缺少将实验室成果与临床转化和放大生产相联接起来的关键研究。

尽管在仿生型纳米药物的研究应用中仍存在许多需要解决的问题, 但相信随着纳米技术和生物技术的发展, 以及实验研究与临床转化研究的进一步结合, 其中存在的局限性必将被解决, 在不久的将来成为一种新的治疗中枢神经系统疾病的有力手段。

作者贡献: 刘陈霏负责阅读、文章构思、撰写和修改; 刘超、赵鹤鸣负责文献和图片的收集整理; 刘艳红负责文章图文摘要的撰写; 肖聪聪、陈丽青、金明姬参负责内容讨论、审阅和校对; 高钟镐、黄伟负责文章的选题、指导、审阅和修改。

利益冲突: 所有作者均声明不存在利益冲突。

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019[J]. Lancet Neurol, 2021, 20: 795-820.

https://doi.org/10.1016/S1474-4422(21)00252-0

[2]

GBD 2016 Brain and Other CNS Cancer Collaborators. Global, regional, and national burden of brain and other CNS cancer, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016[J]. Lancet Neurol, 2019, 18: 376-393.

https://doi.org/10.1016/S1474-4422(18)30468-X

[3]

Kim J, Ahn SI, Kim Y. Nanotherapeutics engineered to cross the blood-brain barrier for advanced drug delivery to the central nervous system[J]. J Ind Eng Chem, 2019, 73: 8-18.

https://doi.org/10.1016/j.jiec.2019.01.021

[4]

Pardridge WM. Blood-brain barrier delivery[J]. Drug Discov Today, 2007, 12: 54-61.

https://doi.org/10.1016/j.drudis.2006.10.013

[5]

Abbott NJ, Patabendige AAK, Dolman DEM, et al. Structure and function of the blood-brain barrier[J]. Neurobiol Dis, 2010, 37: 13-25.

https://doi.org/10.1016/j.nbd.2009.07.030

[6]

Pawar B, Vasdev N, Gupta T, et al. Current update on transcellular brain drug delivery[J]. Pharmaceutics, 2022, 14: 2719.

https://doi.org/10.3390/pharmaceutics14122719

[7]

Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood-brain barrier by nanoparticles[J]. J Control Release, 2012, 161: 264-273.

https://doi.org/10.1016/j.jconrel.2011.08.017

[8]

Shi Y, van der Meel R, Chen X, et al. The EPR effect and beyond: strategies to improve tumor targeting and cancer nanomedicine treatment efficacy[J]. Theranostics, 2020, 10: 7921-7924.

https://doi.org/10.7150/thno.49577

[9]

Chen Z, Chen X, Huang J, et al. Harnessing protein corona for biomimetic nanomedicine design[J]. Biomimetics, 2022, 7: 126.

https://doi.org/10.3390/biomimetics7030126

[10]

Luk BT, Zhang L. Cell membrane-camouflaged nanoparticles for drug delivery[J]. J Control Release, 2015, 220: 600-607.

https://doi.org/10.1016/j.jconrel.2015.07.019

[11]

Hu CM, Zhang L, Aryal S, et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform[J]. Proc Natl Acad Sci U S A, 2011, 108: 10980-10985.

https://doi.org/10.1073/pnas.1106634108

[12]

Parodi A, Quattrocchi N, van de Ven AL, et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions[J]. Nat Nanotechnol, 2013, 8: 61-68.

https://doi.org/10.1038/nnano.2012.212

[13]

Fang RH, Hu CM, Luk BT, et al. Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery[J]. Nano Lett, 2014, 14: 2181-2188.

https://doi.org/10.1021/nl500618u

[14]

He L, Shao M, Xu J, et al. Engineered red blood cell membrane for sensitive and precise electrochemical detection of salivary exosomes[J]. Anal Methods, 2021, 13: 5859-5865.

https://doi.org/10.1039/D1AY01507A

[15]

Lopes D, Lopes J, Pereira-Silva M, et al. Bioengineered exosomal-membrane-camouflaged abiotic nanocarriers: neurodegenerative diseases, tissue engineering and regenerative medicine[J]. Mil Med Res, 2023, 10: 19.

[16]

Li J, Wei Y, Zhang C, et al. Cell-membrane-coated nanoparticles for targeted drug delivery to the brain for the treatment of neurological diseases[J]. Pharmaceutics, 2023, 15: 621.

https://doi.org/10.3390/pharmaceutics15020621

[17]

Wu Z, Zhang H, Yan J, et al. Engineered biomembrane-derived nanoparticles for nanoscale theranostics[J]. Theranostics, 2023, 13: 20-39.

https://doi.org/10.7150/thno.76894

[18]

Föller M, Huber SM, Lang F. Erythrocyte programmed cell death[J]. IUBMB Life, 2008, 60: 661-668.

https://doi.org/10.1002/iub.106

[19]

Han L, Jiang C. Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies[J]. Acta Pharm Sin B, 2021, 11: 2306-2325.

https://doi.org/10.1016/j.apsb.2020.11.023

[20]

Fang RH, Hu CM, Chen KN, et al. Lipid-insertion enables targeting functionalization of erythrocyte membrane-cloaked nanoparticles[J]. Nanoscale, 2013, 5: 8884-8888.

https://doi.org/10.1039/c3nr03064d

[21]

Liu X, Chen Y, Geng D, et al. Aptamer-modified erythrocyte membrane-coated pH-sensitive nanoparticles for c-met-targeted therapy of glioblastoma multiforme[J]. Membranes (Basel), 2022, 12: 744.

https://doi.org/10.3390/membranes12080744

[22]

Cui Y, Sun J, Hao W, et al. Dual-target peptide-modified erythrocyte membrane-enveloped PLGA nanoparticles for the treatment of glioma[J]. Front Oncol, 2020, 10: 563938.

https://doi.org/10.3389/fonc.2020.563938

[23]

Zou Y, Liu Y, Yang Z, et al. Effective and targeted human orthotopic glioblastoma xenograft therapy via a multifunctional biomimetic nanomedicine[J]. Adv Mater, 2018, 30: e1803717.

https://doi.org/10.1002/adma.201803717

[24]

Garrood T, Lee L, Pitzalis C. Molecular mechanisms of cell recruitment to inflammatory sites: general and tissue-specific pathways[J]. Rheumatology (Oxford), 2006, 45: 250-260.

https://doi.org/10.1093/rheumatology/kei207

[25]

Chu D, Dong X, Shi X, et al. Neutrophil-based drug delivery systems[J]. Adv Mater, 2018, 30: e1706245.

https://doi.org/10.1002/adma.201706245

[26]

Lahoz-Beneytez J, Elemans M, Zhang Y, et al. Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives[J]. Blood, 2016, 127: 3431-3438.

https://doi.org/10.1182/blood-2016-03-700336

[27]

Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy?[J]. Acta Neuropathol, 2019, 137: 693-714.

https://doi.org/10.1007/s00401-018-1930-z

[28]

Perez-de-Puig I, Miró-Mur F, Ferrer-Ferrer M, et al. Neutrophil recruitment to the brain in mouse and human ischemic stroke[J]. Acta Neuropathol, 2015, 129: 239-257.

https://doi.org/10.1007/s00401-014-1381-0

[29]

Dong X, Gao J, Zhang CY, et al. Neutrophil membrane-derived nanovesicles alleviate inflammation to protect mouse brain injury from ischemic stroke[J]. ACS Nano, 2019, 13: 1272-1283.

[30]

Feng L, Dou C, Xia Y, et al. Neutrophil-like cell-membrane-coated nanozyme therapy for ischemic brain damage and long-term neurological functional recovery[J]. ACS Nano, 2021, 15: 2263-2280.

https://doi.org/10.1021/acsnano.0c07973

[31]

Huangfu H, Du S, Zhang H, et al. Facile engineering of resveratrol nanoparticles loaded with 20(S)-protopanaxadiol for the treatment of periodontitis by regulating the macrophage phenotype[J]. Nanoscale, 2023, 15: 7894-7908.

https://doi.org/10.1039/D2NR06452A

[32]

Dehne N, Mora J, Namgaladze D, et al. Cancer cell and macrophage cross-talk in the tumor microenvironment[J]. Curr Opin Pharmacol, 2017, 35: 12-19.

https://doi.org/10.1016/j.coph.2017.04.007

[33]

Yin T, Fan Q, Hu F, et al. Engineered macrophage-membrane-coated nanoparticles with enhanced PD-1 expression induce immunomodulation for a synergistic and targeted antiglioblastoma activity[J]. Nano Lett, 2022, 22: 6606-6614.

https://doi.org/10.1021/acs.nanolett.2c01863

[34]

Xiao T, He M, Xu F, et al. Macrophage membrane-camouflaged responsive polymer nanogels enable magnetic resonance imaging-guided chemotherapy/chemodynamic therapy of orthotopic glioma[J]. ACS Nano, 2021, 15: 20377-20390.

https://doi.org/10.1021/acsnano.1c08689

[35]

Parodi M, Favoreel H, Candiano G, et al. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans[J]. Front Immunol, 2019, 10: 719.

https://doi.org/10.3389/fimmu.2019.00719

[36]

Smyth MJ, Hayakawa Y, Takeda K, et al. New aspects of natural-killer-cell surveillance and therapy of cancer[J]. Nat Rev Cancer, 2002, 2: 850-861.

https://doi.org/10.1038/nrc928

[37]

Deng G, Peng X, Sun Z, et al. Natural-killer-cell-inspired nanorobots with aggregation-induced emission characteristics for near-infrared-II fluorescence-guided glioma theranostics[J]. ACS Nano, 2020, 14: 11452-11462.

https://doi.org/10.1021/acsnano.0c03824

[38]

Hu CM, Fang RH, Wang KC, et al. Nanoparticle biointerfacing by platelet membrane cloaking[J]. Nature, 2015, 526: 118-121.

https://doi.org/10.1038/nature15373

[39]

Sun Y, Langer HF. Platelets, thromboinflammation and neurovascular disease[J]. Front Immunol, 2022, 13: 843404.

https://doi.org/10.3389/fimmu.2022.843404

[40]

Wang C, Yang X, Jiang Y, et al. Targeted delivery of fat extract by platelet membrane-cloaked nanocarriers for the treatment of ischemic stroke[J]. J Nanobiotechnol, 2022, 20: 249.

https://doi.org/10.1186/s12951-022-01461-2

[41]

Xu J, Wang X, Yin H, et al. Sequentially site-specific delivery of thrombolytics and neuroprotectant for enhanced treatment of ischemic stroke[J]. ACS Nano, 2019, 13: 8577-8588.

https://doi.org/10.1021/acsnano.9b01798

[42]

Mehdi-Alamdarlou S, Ahmadi F, Azadi A, et al. A cell-mimicking platelet-based drug delivery system as a potential carrier of dimethyl fumarate for multiple sclerosis[J]. Int J Pharm, 2022, 625: 122084.

https://doi.org/10.1016/j.ijpharm.2022.122084

[43]

Lin Q, Peng Y, Wen Y, et al. Recent progress in cancer cell membrane-based nanoparticles for biomedical applications[J]. Beilstein J Nanotechnol, 2023, 14: 262-279.

https://doi.org/10.3762/bjnano.14.24

[44]

Brastianos PK, Carter SL, Santagata S, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets genomics of brain metastases[J]. Cancer Discov, 2015, 5: 1164-1177.

https://doi.org/10.1158/2159-8290.CD-15-0369

[45]

De Pasquale D, Marino A, Tapeinos C, et al. Homotypic targeting and drug delivery in glioblastoma cells through cell membrane-coated boron nitride nanotubes[J]. Mater Des, 2020, 192: 108742.

https://doi.org/10.1016/j.matdes.2020.108742

[46]

Wang C, Wu B, Wu Y, et al. Camouflaging nanoparticles with brain metastatic tumor cell membranes: a new strategy to traverse blood-brain barrier for imaging and therapy of brain tumors[J]. Adv Funct Mater, 2020, 30: 1909369.

https://doi.org/10.1002/adfm.201909369

[47]

Fan Y, Hao W, Cui Y, et al. Cancer cell membrane-coated nanosuspensions for enhanced chemotherapeutic treatment of glioma[J]. Molecules, 2021, 26: 5103.

https://doi.org/10.3390/molecules26165103

[48]

Elzoghby AO, Samy WM, Elgindy NA. Protein-based nanocarriers as promising drug and gene delivery systems[J]. J Control Release, 2012, 161: 38-49.

https://doi.org/10.1016/j.jconrel.2012.04.036

[49]

Zhang Y, Wang J, Xing H, et al. Redox-responsive paclitaxel-pentadecanoic acid conjugate encapsulated human serum albumin nanoparticles for cancer therapy[J]. Int J Pharm, 2023, 635: 122761.

https://doi.org/10.1016/j.ijpharm.2023.122761

[50]

Tan H, Hu J, Liu S. Efficacy and safety of nanoparticle albumin-bound paclitaxel in non-small cell lung cancer: a systematic review and meta-analysis[J]. Artif Cells Nanomed Biotechnol, 2019, 47: 268-277.

https://doi.org/10.1080/21691401.2018.1552595

[51]

Van de Sande L, Cosyns S, Willaert W, et al. Albumin-based cancer therapeutics for intraperitoneal drug delivery: a review[J]. Drug Deliv, 2020, 27: 40-53.

https://doi.org/10.1080/10717544.2019.1704945

[52]

Lee ES, Youn YS. Albumin-based potential drugs: focus on half-life extension and nanoparticle preparation[J]. J Pharm Invest, 2016, 46: 305-315.

https://doi.org/10.1007/s40005-016-0250-3

[53]

Tong R, Yala L, Fan TM, et al. The formulation of aptamer-coated paclitaxel-polylactide nanoconjugates and their targeting to cancer cells[J]. Biomaterials, 2010, 31: 3043-3053.

https://doi.org/10.1016/j.biomaterials.2010.01.009

[54]

Rempel SA, Golembieski WA, Fisher JL, et al. SPARC modulates cell growth, attachment and migration of U87 glioma cells on brain extracellular matrix proteins[J]. J Neurooncol, 2001, 53: 149-160.

https://doi.org/10.1023/A:1012201300188

[55]

Shi Q, Bao S, Song L, et al. Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases[J]. Oncogene, 2007, 26: 4084-4094.

https://doi.org/10.1038/sj.onc.1210181

[56]

Zhang DY, Dmello C, Chen L, et al. Ultrasound-mediated delivery of paclitaxel for glioma: a comparative study of distribution, toxicity, and efficacy of albumin-bound versus cremophor formulations[J]. Clin Cancer Res, 2020, 26: 477-486.

https://doi.org/10.1158/1078-0432.CCR-19-2182

[57]

Gregory JV, Kadiyala P, Doherty R, et al. Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy[J]. Nat Commun, 2020, 11: 5687.

https://doi.org/10.1038/s41467-020-19225-7

[58]

Gao D, Li Y, Wu Y, et al. Albumin-consolidated AIEgens for boosting glioma and cerebrovascular NIR-II fluorescence imaging[J]. ACS Appl Mater Interfaces, 2022, 15: 3-13.

[59]

Feczkó T, Piiper A, Ansar S, et al. Stimulating brain recovery after stroke using theranostic albumin nanocarriers loaded with nerve growth factor in combination therapy[J]. J Control Release, 2019, 293: 63-72.

https://doi.org/10.1016/j.jconrel.2018.11.017

[60]

Xue Y, Ding J, Liu Y, et al. Preparation and evaluation of recombinant human erythropoietin loaded Tween 80-albumin nanoparticle for traumatic brain injury treatment[J]. Int J Nanomedicine, 2020, 15: 8495-8506.

https://doi.org/10.2147/IJN.S264025

[61]

Monge-Fuentes V, Biolchi Mayer A, Lima MR, et al. Dopamine-loaded nanoparticle systems circumvent the blood-brain barrier restoring motor function in mouse model for Parkinson's disease[J]. Sci Rep, 2021, 11: 15185.

https://doi.org/10.1038/s41598-021-94175-8

[62]

Rhea EM, Banks WA. Interactions of lipids, lipoproteins, and apolipoproteins with the blood-brain barrier[J]. Pharm Res, 2021, 38: 1469-1475.

https://doi.org/10.1007/s11095-021-03098-6

[63]

Wellington CL, Frikke-Schmidt R. Relation between plasma and brain lipids[J]. Curr Opin Lipidol, 2016, 27: 225-232.

https://doi.org/10.1097/MOL.0000000000000291

[64]

Zhang Y, Sun T, Jiang C. Biomacromolecules as carriers in drug delivery and tissue engineering[J]. Acta Pharm Sin B, 2018, 8: 34-50.

https://doi.org/10.1016/j.apsb.2017.11.005

[65]

Sega EI, Low PS. Tumor detection using folate receptor-targeted imaging agents[J]. Cancer Metastasis Rev, 2008, 27: 655-664.

https://doi.org/10.1007/s10555-008-9155-6

[66]

Rudenko G, Henry L, Henderson K, et al. Structure of the LDL receptor extracellular domain at endosomal pH[J]. Science, 2002, 298: 2353-2358.

https://doi.org/10.1126/science.1078124

[67]

Liang M, Gao C, Wang Y, et al. Enhanced blood-brain barrier penetration and glioma therapy mediated by T7 peptide-modified low-density lipoprotein particles[J]. Drug Deliv, 2018, 25: 1652-1663.

https://doi.org/10.1080/10717544.2018.1494223

[68]

Jonas A, Phillips MC. Lipoprotein structure [M] // Vance DE, Vance JE. Biochemistry of Lipids, Lipoproteins and Membranes. San Diego: Elsevier Science, 2008: 485-506.

[69]

Rensen PC, de Vrueh RL, Kuiper J, et al. Recombinant lipoproteins: lipoprotein-like lipid particles for drug targeting[J]. Adv Drug Deliv Rev, 2001, 47: 251-276.

https://doi.org/10.1016/S0169-409X(01)00109-0

[70]

Fox CA, Moschetti A, Ryan RO. Reconstituted HDL as a therapeutic delivery device[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2021, 1866: 159025.

[71]

Wang R, Wang X, Li J, et al. Lipoprotein-biomimetic nanostructure enables tumor-targeted penetration delivery for enhanced photo-gene therapy towards glioma[J]. Bioact Mater, 2021, 13: 286-299.

[72]

Bell JB, Rink JS, Eckerdt F, et al. HDL nanoparticles targeting sonic hedgehog subtype medulloblastoma[J]. Sci Rep, 2018, 8: 1211.

https://doi.org/10.1038/s41598-017-18100-8

[73]

Chernick D, Zhong R, Li L. The role of HDL and HDL mimetic peptides as potential therapeutics for Alzheimer's disease[J]. Biomolecules, 2020, 10: 1276.

https://doi.org/10.3390/biom10091276

[74]

Zhang H, Zhao Y, Yu M, et al. Reassembly of native components with donepezil to execute dual-missions in Alzheimer's disease therapy[J]. J Control Release, 2019, 296: 14-28.

https://doi.org/10.1016/j.jconrel.2019.01.008

[75]

Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes[J]. Science, 2020, 367: eaau6977.

https://doi.org/10.1126/science.aau6977

[76]

Kandimalla R, Saeed M, Tyagi N, et al. Exosome-based approaches in the management of Alzheimer's disease[J]. Neurosci Biobehav Rev, 2023, 144: 104974.

https://doi.org/10.1016/j.neubiorev.2022.104974

[77]

Li C, Guan N, Liu F. T7 peptide-decorated exosome-based nanocarrier system for delivery of galectin-9 siRNA to stimulate macrophage repolarization in glioblastoma[J]. J Neurooncol, 2023, 162: 93-108.

https://doi.org/10.1007/s11060-023-04257-y

[78]

Qi Y, Guo L, Jiang Y, et al. Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles[J]. Drug Deliv, 2020, 27: 745-755.

https://doi.org/10.1080/10717544.2020.1762262

[79]

Nguyen VH, Lee BJ. Protein corona: a new approach for nanomedicine design[J]. Int J Nanomedicine, 2017, 12: 3137-3151.

https://doi.org/10.2147/IJN.S129300

[80]

Tenzer S, Docter D, Kuharev J, et al. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology[J]. Nat Nanotechnol, 2013, 8: 772-781.

https://doi.org/10.1038/nnano.2013.181

[81]

Schöttler S, Becker G, Winzen S, et al. Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers[J]. Nat Nanotechnol, 2016, 11: 372-377.

https://doi.org/10.1038/nnano.2015.330

[82]

Zhang Z, Guan J, Jiang Z, et al. Brain-targeted drug delivery by manipulating protein corona functions[J]. Nat Commun, 2019, 10: 3561.

https://doi.org/10.1038/s41467-019-11593-z

[83]

Gupta MN, Roy I. How corona formation impacts nanomaterials as drug carriers[J]. Mol Pharm, 2020, 17: 725-737.

https://doi.org/10.1021/acs.molpharmaceut.9b01111

[84]

Yallapu MM, Chauhan N, Othman SF, et al. Implications of protein corona on physico-chemical and biological properties of magnetic nanoparticles[J]. Biomaterials, 2015, 46: 1-12.

https://doi.org/10.1016/j.biomaterials.2014.12.045

[85]

Zhang Z, Guan J, Jiang Z, et al. Brain-targeted drug delivery by manipulating protein corona functions[J]. Nat Commun, 2019, 10: 3561.

https://doi.org/10.1038/s41467-019-11593-z

[86]

Zhang ZA, Xin X, Liu C, et al. Novel brain-targeted nanomicelles for anti-glioma therapy mediated by the ApoE-enriched protein corona in vivo[J]. J Nanobiotechnol, 2021, 19: 453.

https://doi.org/10.1186/s12951-021-01097-8

[87]

Savenkova DA, Makarova AA, Shalik IK, et al. miRNA pathway alteration in response to non-coding RNA delivery in viral vector-based gene therapy[J]. Int J Mol Sci, 2022, 23: 14954.

https://doi.org/10.3390/ijms232314954

[88]

Chan KY, Jang MJ, Yoo BB, et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems[J]. Nat Neurosci, 2017, 20: 1172-1179.

https://doi.org/10.1038/nn.4593

[89]

Chen W, Yao S, Wan J, et al. BBB-crossing adeno-associated virus vector: an excellent gene delivery tool for CNS disease treatment[J]. J Control Release, 2021, 333: 129-138.

https://doi.org/10.1016/j.jconrel.2021.03.029

[90]

Lentz TL, Burrage TG, Smith AL, et al. Is the acetylcholine receptor a rabies virus receptor?[J]. Science, 1982, 215: 182-184.

https://doi.org/10.1126/science.7053569

[91]

Lafon M. Rabies virus receptors[J]. J Neurovirol, 2005, 11: 82-87.

https://doi.org/10.1080/13550280590900427

[92]

Yang YJ, Zhao PS, Wu HX, et al. Production and characterization of a fusion peptide derived from the rabies virus glycoprotein (RVG29)[J]. Protein Expr Purif, 2014, 104: 7-13.

https://doi.org/10.1016/j.pep.2014.09.001

[93]

Xin X, Liu W, Zhang ZA, et al. Efficient anti-glioma therapy through the brain-targeted RVG15-modified liposomes loading paclitaxel-cholesterol complex[J]. Int J Nanomedicine, 2021, 16: 5755-5776.

https://doi.org/10.2147/IJN.S318266

[94]

Wu H, Liu Y, Chen L, et al. Combined biomimetic MOF-RVG15 nanoformulation efficient over BBB for effective anti-glioblastoma in mice model[J]. Int J Nanomedicine, 2022, 17: 6377-6398.

https://doi.org/10.2147/IJN.S387715

2023年第58卷第8期

PDF下载

480

215

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2023-0549

接收时间：2023-05-03
首发时间：2025-11-21
出版时间：2023-08-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2023-05-03
修回日期：2023-06-05

基金

作者信息

中国医学科学院、北京协和医学院药物研究所, 药物传输技术与新型制剂北京市重点实验室, 北京 100050

通讯作者:

*黄伟, Tel: 86-10-63026505, E-mail: huangwei@imm.ac.cn

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2023-0549

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

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

关闭全屏

BibTeX
EndNote
RefWorks
TxT