Article(id=1208073009877852439, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208073005197009056, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.05.0511, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1621440000000, receivedDateStr=2021-05-20, revisedDate=null, revisedDateStr=null, acceptedDate=1636041600000, acceptedDateStr=2021-11-05, onlineDate=1765956650466, onlineDateStr=2025-12-17, pubDate=1653667200000, pubDateStr=2022-05-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765956650466, onlineIssueDateStr=2025-12-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765956650466, creator=13701087609, updateTime=1765956650466, updator=13701087609, issue=Issue{id=1208073005197009056, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='5', pageStart='427', pageEnd='532', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765956649350, creator=13701087609, updateTime=1765956710955, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208073263641633510, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208073005197009056, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208073263641633511, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208073005197009056, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=511, endPage=517, ext={EN=ArticleExt(id=1208073010171453738, articleId=1208073009877852439, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress in the treatment of glioblastoma by nose-to-brain delivery, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Glioblastoma (GBM) is a most common primary malignant brain tumor characterized by rapid growth and invasion of surrounding tissues. At present, the standard methods for treatment of GBM include surgical resection, radiotherapy and chemotherapy. Because the existence of blood-brain barrier (BBB) restricts the delivery of anti-cancer drugs into the brain,novel drug deliver approaches are urgently needed to improve the therapeutic effect of GBM. As a non-invasive alternative route for directly targeting the central nervous system (CNS) disease, nose-to-brain delivery could bypass the BBB and reduce the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nanostructured drug delivery systems. The application of nose-to-brain delivery combined with different anticancer drugs or methods in clinical treatment of GBM have been reviewed in present paper.

, correspAuthors=Hai-Long Zhao, authorNote=null, correspAuthorsNote=
*E-mail:
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胶质母细胞瘤(GBM)是最常见的原发性恶性脑肿瘤,其特征是肿瘤快速生长及侵袭周围组织。目前治疗GBM的标准方法包括手术切除、放射疗法和化学药物疗法,由于血脑屏障(BBB)会限制多种抗癌药物进入脑内,因此迫切需要新的给药途径以提高治疗效果。目前,鼻脑给药途径作为一种非侵入性替代途径,能够绕过BBB治疗中枢神经系统(CNS)疾病,并减少全身性不良反应。新近开发的多种新型制剂主要通过纳米结构的药物递送系统来进一步增强鼻脑转运。本文就鼻脑给药途径联合不同抗癌药物或方式在GBM临床治疗中的应用研究进展进行综述。

, correspAuthors=赵海龙, authorNote=null, correspAuthorsNote=
赵海龙,E-mail:
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李吻吻,硕士研究生,主要从事肿瘤细胞微环境和细胞间相互作用的研究

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CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010[J]. Neuro Oncol, 2013, 15(Suppl 2): ii1-ii56., articleTitle=CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010, refAbstract=null), Reference(id=1208073017603760730, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2014, volume=23, issue=10, pageStart=1985, pageEnd=1996, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=Thakkar JP, Dolecek TA, Horbinski C, journalName=Cancer Epidemiol Biomarkers Prev, refType=null, unstructuredReference=Thakkar JP, Dolecek TA, Horbinski C, et al. Epidemiologic and molecular prognostic review of glioblastoma[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(10): 1985-1996., articleTitle=Epidemiologic and molecular prognostic review of glioblastoma, refAbstract=null), Reference(id=1208073017691841119, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2015, volume=4, issue=2, pageStart=55, pageEnd=57, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=Morsy AA, Ng WH, journalName=CNS Oncol, refType=null, unstructuredReference=Morsy AA, Ng WH. Re-do craniotomy for recurrent glioblastoma[J]. CNS Oncol, 2015, 4(2): 55-57., articleTitle=Re-do craniotomy for recurrent glioblastoma, refAbstract=null), Reference(id=1208073017788310115, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2005, volume=352, issue=10, pageStart=987, pageEnd=996, url=null, language=null, rfNumber=[4], rfOrder=3, authorNames=Stupp R, Mason WP, van den Bent MJ, journalName=N Engl J Med, refType=null, unstructuredReference=Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[J]. N Engl J Med, 2005, 352(10): 987-996., articleTitle=Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, refAbstract=null), Reference(id=1208073017880584809, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2018, volume=8, issue=1, pageStart=7222, pageEnd=null, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=Tiek DM, Rone JD, Graham GT, journalName=Sci Rep, refType=null, unstructuredReference=Tiek DM, Rone JD, Graham GT, et al. Alterations in cell motility, proliferation, and metabolism in novel models of acquired temozolomide resistant glioblastoma[J]. Sci Rep, 2018, 8(1):7222., articleTitle=Alterations in cell motility, proliferation, and metabolism in novel models of acquired temozolomide resistant glioblastoma, refAbstract=null), Reference(id=1208073017977053804, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2018, volume=8, issue=null, pageStart=462, pageEnd=null, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=Harder BG, Blomquist MR, Wang J, journalName=Front Oncol, refType=null, unstructuredReference=Harder BG, Blomquist MR, Wang J, et al. Developments in blood-brain barrier penetrance and drug repurposing for improved treatment of glioblastoma[J]. Front Oncol, 2018, 8:462., articleTitle=Developments in blood-brain barrier penetrance and drug repurposing for improved treatment of glioblastoma, refAbstract=null), Reference(id=1208073018073522800, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=18, issue=1, pageStart=34, pageEnd=null, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=Schaffenrath J, Huang SF, Wyss T, journalName=Fluids Barriers CNS, refType=null, unstructuredReference=Schaffenrath J, Huang SF, Wyss T, et al. Characterization of the blood-brain barrier in genetically diverse laboratory mouse strains[J]. Fluids Barriers CNS, 2021, 18(1): 34., articleTitle=Characterization of the blood-brain barrier in genetically diverse laboratory mouse strains, refAbstract=null), Reference(id=1208073018186769011, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2012, volume=32, issue=11, pageStart=1959, pageEnd=1972, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=Pardridge WM, journalName=J Cereb Blood Flow Metab, refType=null, unstructuredReference=Pardridge WM. Drug transport across the blood-brain barrier[J]. J Cereb Blood Flow Metab, 2012, 32(11): 1959-1972., articleTitle=Drug transport across the blood-brain barrier, refAbstract=null), Reference(id=1208073018274849399, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2016, volume=22, issue=9, pageStart=1177, pageEnd=1193, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=Hersh DS, Wadajkar AS, Roberts N, journalName=Curr Pharm Des, refType=null, unstructuredReference=Hersh DS, Wadajkar AS, Roberts N, et al. Evolving drug delivery strategies to overcome the blood brain barrier[J]. Curr Pharm Des, 2016, 22(9): 1177-1193., articleTitle=Evolving drug delivery strategies to overcome the blood brain barrier, refAbstract=null), Reference(id=1208073018350346872, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2018, volume=8, issue=6, pageStart=1481, pageEnd=1493, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=Dong X, journalName=Theranostics, refType=null, unstructuredReference=Dong X. Current strategies for brain drug delivery[J]. Theranostics, 2018, 8(6): 1481-1493., articleTitle=Current strategies for brain drug delivery, refAbstract=null), Reference(id=1208073018446815868, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=11, issue=10, pageStart=540, pageEnd=null, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=Hong SS, Oh KT, Choi HG, journalName=Pharmaceutics, refType=null, unstructuredReference=Hong SS, Oh KT, Choi HG, et al. Liposomal formulations for nose-to-brain delivery: Recent advances and future perspectives[J]. Pharmaceutics, 2019, 11(10): 540., articleTitle=Liposomal formulations for nose-to-brain delivery: Recent advances and future perspectives, refAbstract=null), Reference(id=1208073018522313344, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2018, volume=195, issue=null, pageStart=44, pageEnd=52, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=Crowe TP, Greenlee MHW, Kanthasamy AG, journalName=Life Sci, refType=null, unstructuredReference=Crowe TP, Greenlee MHW, Kanthasamy AG, et al. Mechanism of intranasal drug delivery directly to the brain[J]. Life Sci, 2018, 195: 44-52., articleTitle=Mechanism of intranasal drug delivery directly to the brain, refAbstract=null), Reference(id=1208073018614588034, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=9, issue=1, pageStart=2621, pageEnd=null, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=Lochhead JJ, Kellohen KL, Ronaldson PT, journalName=Sci Rep, refType=null, unstructuredReference=Lochhead JJ, Kellohen KL, Ronaldson PT, et al. Distribution of insulin in trigeminal nerve and brain after intranasal administration[J]. Sci Rep, 2019, 9(1): 2621., articleTitle=Distribution of insulin in trigeminal nerve and brain after intranasal administration, refAbstract=null), Reference(id=1208073018702668420, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2013, volume=10, issue=7, pageStart=957, pageEnd=972, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=Pardeshi CV, Belgamwar VS, journalName=Expert Opin Drug Deliv, refType=null, unstructuredReference=Pardeshi CV, Belgamwar VS. Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood–brain barrier:an excellent platform for brain targeting[J]. Expert Opin Drug Deliv, 2013, 10(7): 957-972., articleTitle=Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood–brain barrier:an excellent platform for brain targeting, refAbstract=null), Reference(id=1208073018786554502, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2018, volume=10, issue=3, pageStart=116, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=Ganger S, Schindowski K, journalName=Pharmaceutics, refType=null, unstructuredReference=Ganger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa[J]. Pharmaceutics, 2018, 10(3): 116., articleTitle=Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa, refAbstract=null), Reference(id=1208073018883023497, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2014, volume=5, issue=6, pageStart=709, pageEnd=733, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=Djupesland PG, Messina JC, Mahmoud RA, journalName=Ther Deliv, refType=null, unstructuredReference=Djupesland PG, Messina JC, Mahmoud RA. The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview [J]. Ther Deliv, 2014, 5(6): 709-733., articleTitle=The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview, refAbstract=null), Reference(id=1208073018987881098, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=14, issue=null, pageStart=5895, pageEnd=5909, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=Alexander A, Agrawal M, Uddin A, journalName=Int J Nanomedicine, refType=null, unstructuredReference=Alexander A, Agrawal M, Uddin A, et al. Recent expansions of novel strategies towards the drug targeting into the brain[J]. Int J Nanomedicine, 2019, 14: 5895-5909., articleTitle=Recent expansions of novel strategies towards the drug targeting into the brain, refAbstract=null), Reference(id=1208073019084350093, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=10, issue=7, pageStart=439, pageEnd=null, url=null, language=null, rfNumber=[18], rfOrder=17, authorNames=Trevino JT, Quispe RC, Khan F, journalName=J Clin Trials, refType=null, unstructuredReference=Trevino JT, Quispe RC, Khan F, et al. Non-invasive strategies for nose-to-brain drug delivery[J]. J Clin Trials, 2020, 10(7): 439., articleTitle=Non-invasive strategies for nose-to-brain drug delivery, refAbstract=null), Reference(id=1208073019185013392, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=603, issue=null, pageStart=120714, pageEnd=null, url=null, language=null, rfNumber=[19], rfOrder=18, authorNames=Ferreira NN, de Oliveira Junior E, Granja S, journalName=Int J Pharm, refType=null, unstructuredReference=Ferreira NN, de Oliveira Junior E, Granja S, et al. Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system[J]. Int J Pharm, 2021, 603: 120714., articleTitle=Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system, refAbstract=null), Reference(id=1208073019298259604, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=25, issue=1, pageStart=185, pageEnd=194, url=null, language=null, rfNumber=[20], rfOrder=19, authorNames=Sabir F, Ismail R, Csoka I, journalName=Drug Discov Today, refType=null, unstructuredReference=Sabir F, Ismail R, Csoka I. Nose-to-brain delivery of antiglioblastoma drugs embedded into lipid nanocarrier systems: Status quo and outlook[J]. Drug Discov Today, 2020, 25(1):185-194., articleTitle=Nose-to-brain delivery of antiglioblastoma drugs embedded into lipid nanocarrier systems: Status quo and outlook, refAbstract=null), Reference(id=1208073019361174167, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=10, issue=4, pageStart=1044, pageEnd=1056, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=Upadhaya PG, Pulakkat S, Patravale VB, journalName=Drug Deliv Transl Res, refType=null, unstructuredReference=Upadhaya PG, Pulakkat S, Patravale VB. Nose-to-brain delivery: Exploring newer domains for glioblastoma multiforme management[J]. Drug Deliv Transl Res, 2020, 10(4):1044-1056., articleTitle=Nose-to-brain delivery: Exploring newer domains for glioblastoma multiforme management, refAbstract=null), Reference(id=1208073019436671642, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=17, issue=4, pageStart=1193, pageEnd=1204, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=Ullah I, Chung K, Bae S, journalName=Mol Pharm, refType=null, unstructuredReference=Ullah I, Chung K, Bae S, et al. Nose-to-brain delivery of cancer-targeting paclitaxel-loaded nanoparticles potentiates antitumor effects in malignant glioblastoma[J]. Mol Pharm, 2020, 17(4):1193-1204., articleTitle=Nose-to-brain delivery of cancer-targeting paclitaxel-loaded nanoparticles potentiates antitumor effects in malignant glioblastoma, refAbstract=null), Reference(id=1208073019507974810, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=36, issue=9, pageStart=131, pageEnd=null, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=de Oliveira Junior ER, Nascimento TL, Salomão MA, journalName=Pharm Res, refType=null, unstructuredReference=de Oliveira Junior ER, Nascimento TL, Salomão MA, et al. Increased nose-to-brain delivery of melatonin mediated by polycaprolactone nanoparticles for the treatment of glioblastoma[J]. Pharm Res, 2019, 36(9):131., articleTitle=Increased nose-to-brain delivery of melatonin mediated by polycaprolactone nanoparticles for the treatment of glioblastoma, refAbstract=null), Reference(id=1208073019579277980, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=597, issue=null, pageStart=120250, pageEnd=null, url=null, language=null, rfNumber=[24], rfOrder=23, authorNames=Qu Y, Li A, Ma L, journalName=Int J Pharm, refType=null, unstructuredReference=Qu Y, Li A, Ma L, et al. Nose-to-brain delivery of disulfiram nanoemulsion in situ gel formulation for glioblastoma targeting therapy[J]. Int J Pharm, 2021, 597: 120250., articleTitle=Nose-to-brain delivery of disulfiram nanoemulsion in situ gel formulation for glioblastoma targeting therapy, refAbstract=null), Reference(id=1208073019667358366, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2013, volume=5, issue=3, pageStart=1020, pageEnd=1048, url=null, language=null, rfNumber=[25], rfOrder=24, authorNames=van Woensel M, Wauthoz N, Rosière R, journalName=Cancers (Basel), refType=null, unstructuredReference=van Woensel M, Wauthoz N, Rosière R, et al. Formulations for intranasal delivery of pharmacological agents to combat brain disease: a new opportunity to tackle GBM?[J]. Cancers (Basel), 2013, 5(3): 1020-1048., articleTitle=Formulations for intranasal delivery of pharmacological agents to combat brain disease: a new opportunity to tackle GBM?, refAbstract=null), Reference(id=1208073019763827360, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2017, volume=6, issue=10, pageStart=92, pageEnd=null, url=null, language=null, rfNumber=[26], rfOrder=25, authorNames=Hewlings SJ, Kalman DS, journalName=Foods, refType=null, unstructuredReference=Hewlings SJ, Kalman DS. Curcumin: A review of its effects on human health[J]. Foods, 2017, 6(10): 92., articleTitle=Curcumin: A review of its effects on human health, refAbstract=null), Reference(id=1208073020959204003, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=689, issue=null, pageStart=108412, pageEnd=null, url=null, language=null, rfNumber=[27], rfOrder=26, authorNames=Wang Z, Liu F, Liao W, journalName=Arch Biochem Biophys, refType=null, unstructuredReference=Wang Z, Liu F, Liao W, et al. Curcumin suppresses glioblastoma cell proliferation by p-AKT/mTOR pathway and increases the PTEN expression[J]. Arch Biochem Biophys, 2020, 689:108412., articleTitle=Curcumin suppresses glioblastoma cell proliferation by p-AKT/mTOR pathway and increases the PTEN expression, refAbstract=null), Reference(id=1208073021034701478, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2017, volume=17, issue=1, pageStart=99, pageEnd=null, url=null, language=null, rfNumber=[28], rfOrder=27, authorNames=Gersey ZC, Rodriguez GA, Barbarite E, journalName=BMC Cancer, refType=null, unstructuredReference=Gersey ZC, Rodriguez GA, Barbarite E, et al. Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species[J]. BMC Cancer, 2017, 17(1): 99., articleTitle=Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species, refAbstract=null), Reference(id=1208073021118587558, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=57, issue=8, pageStart=3391, pageEnd=3411, url=null, language=null, rfNumber=[29], rfOrder=28, authorNames=Sahab-Negah S, Ariakia F, Jalili-Nik M, journalName=Mol Neurobiol, refType=null, unstructuredReference=Sahab-Negah S, Ariakia F, Jalili-Nik M, et al. Curcumin loaded in niosomal nanoparticles improved the anti-tumor effects of free curcumin on glioblastoma stem-like cells: An in vitro study[J]. Mol Neurobiol, 2020, 57(8): 3391-3411., articleTitle=Curcumin loaded in niosomal nanoparticles improved the anti-tumor effects of free curcumin on glioblastoma stem-like cells: An in vitro study, refAbstract=null), Reference(id=1208073021206667944, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2017, volume=51, issue=2, pageStart=467, pageEnd=477, url=null, language=null, rfNumber=[30], rfOrder=29, authorNames=Wang X, Deng J, Yuan J, journalName=Int J Oncol, refType=null, unstructuredReference=Wang X, Deng J, Yuan J, et al. Curcumin exerts its tumor suppressive function via inhibition of NEDD4 oncoprotein in glioma cancer cells[J]. Int J Oncol, 2017, 51(2): 467-477., articleTitle=Curcumin exerts its tumor suppressive function via inhibition of NEDD4 oncoprotein in glioma cancer cells, refAbstract=null), Reference(id=1208073021315719850, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2016, volume=139, issue=12, pageStart=2838, pageEnd=2849, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=Mukherjee S, Baidoo J, Fried A, journalName=Int J Cancer, refType=null, unstructuredReference=Mukherjee S, Baidoo J, Fried A, et al. Curcumin changes the polarity of tumor-associated microglia and eliminates glioblastoma[J]. Int J Cancer, 2016, 139(12): 2838-2849., articleTitle=Curcumin changes the polarity of tumor-associated microglia and eliminates glioblastoma, refAbstract=null), Reference(id=1208073021437354668, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=11, issue=1, pageStart=77, pageEnd=87, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=Machon C, Catez F, Venezia ND, journalName=J Pharm Anal, refType=null, unstructuredReference=Machon C, Catez F, Venezia ND, et al. Study of intracellular anabolism of 5-fluorouracil and incorporation in nucleic acids based on an LC-HRMS method[J]. J Pharm Anal, 2021, 11(1):77-87., articleTitle=Study of intracellular anabolism of 5-fluorouracil and incorporation in nucleic acids based on an LC-HRMS method, refAbstract=null), Reference(id=1208073021533823662, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=111, issue=3, pageStart=283, pageEnd=291, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=Carvalho LA, Teng J, Fleming RL, journalName=J Natl Cancer Inst, refType=null, unstructuredReference=Carvalho LA, Teng J, Fleming RL, et al. Olfactory ensheathing cells: A trojan horse for glioma gene therapy[J]. J Natl Cancer Inst, 2019, 111(3): 283-291., articleTitle=Olfactory ensheathing cells: A trojan horse for glioma gene therapy, refAbstract=null), Reference(id=1208073021634486961, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2012, volume=5, issue=1, pageStart=102, pageEnd=114, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=Zhang J, Stevens MF, Bradshaw TD, journalName=Curr Mol Pharmacol, refType=null, unstructuredReference=Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance[J]. Curr Mol Pharmacol, 2012, 5(1): 102-114., articleTitle=Temozolomide: mechanisms of action, repair and resistance, refAbstract=null), Reference(id=1208073021714178740, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2014, volume=34, issue=5, pageStart=631, pageEnd=635, url=null, language=null, rfNumber=[35], rfOrder=34, authorNames=Li Y, Gao Y, Liu G, journalName=Nan Fang Yi Ke Da Xue Xue Bao, refType=null, unstructuredReference=Li Y, Gao Y, Liu G, et al. Intranasal administration of temozolomide for brain-targeting delivery: Therapeutic effect on glioma in rats[J]. Nan Fang Yi Ke Da Xue Xue Bao, 2014, 34(5):631-635., articleTitle=Intranasal administration of temozolomide for brain-targeting delivery: Therapeutic effect on glioma in rats, refAbstract=null), Reference(id=1208073022100054710, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2015, volume=5, issue=5, pageStart=1580, pageEnd=1593, url=null, language=null, rfNumber=[36], rfOrder=35, authorNames=Chen TC, Fonseca CO, Schönthal AH, journalName=Am J Cancer Res, refType=null, unstructuredReference=Chen TC, Fonseca CO, Schönthal AH. Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy[J]. Am J Cancer Res, 2015, 5(5): 1580-1593., articleTitle=Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy, refAbstract=null), Reference(id=1208073022175552184, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2018, volume=19, issue=12, pageStart=3905, pageEnd=null, url=null, language=null, rfNumber=[37], rfOrder=36, authorNames=Chen TC, da Fonseca CO, Schönthal AH, journalName=Int J Mol Sci, refType=null, unstructuredReference=Chen TC, da Fonseca CO, Schönthal AH. Intranasal perillyl alcohol for glioma therapy: Molecular mechanisms and clinical development[J]. Int J Mol Sci, 2018, 19(12): 3905., articleTitle=Intranasal perillyl alcohol for glioma therapy: Molecular mechanisms and clinical development, refAbstract=null), Reference(id=1208073022276215481, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=3, issue=1, pageStart=vdab005, pageEnd=null, url=null, language=null, rfNumber=[38], rfOrder=37, authorNames=Schönthal AH, Peereboom DM, Wagle N, journalName=Neurooncol Adv, refType=null, unstructuredReference=Schönthal AH, Peereboom DM, Wagle N, et al. Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in adult patients with recurrent glioblastoma[J]. Neurooncol Adv, 2021, 3(1): vdab005., articleTitle=Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in adult patients with recurrent glioblastoma, refAbstract=null), Reference(id=1208073022368490173, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2014, volume=44, issue=6, pageStart=1843, pageEnd=1852, url=null, language=null, rfNumber=[39], rfOrder=38, authorNames=Rieger J, Bahr O, Maurer GD, journalName=Int J Oncol, refType=null, unstructuredReference=Rieger J, Bahr O, Maurer GD, et al. ERGO: A pilot study of ketogenic diet in recurrent glioblastoma[J]. Int J Oncol, 2014, 44(6): 1843-1852., articleTitle=ERGO: A pilot study of ketogenic diet in recurrent glioblastoma, refAbstract=null), Reference(id=1208073022464959167, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=8, issue=1, pageStart=24, pageEnd=null, url=null, language=null, rfNumber=[40], rfOrder=39, authorNames=Klein P, Tyrlikova I, Zuccoli G, journalName=Cancer Metab, refType=null, unstructuredReference=Klein P, Tyrlikova I, Zuccoli G, et al. Treatment of glioblastoma multiforme with "classic" 4:1 ketogenic diet total meal replacement[J]. Cancer Metab, 2020, 8(1): 24., articleTitle=Treatment of glioblastoma multiforme with "classic" 4:1 ketogenic diet total meal replacement, refAbstract=null), Reference(id=1208073022548845249, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=2, issue=null, pageStart=200, pageEnd=null, url=null, language=null, rfNumber=[41], rfOrder=40, authorNames=Mukherjee P, Augur ZM, Li M, journalName=Commun Biol, refType=null, unstructuredReference=Mukherjee P, Augur ZM, Li M, et al. Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma[J]. Commun Biol, 2019, 2: 200., articleTitle=Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma, refAbstract=null), Reference(id=1208073022628537027, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2018, volume=15, issue=1, pageStart=1263, pageEnd=1270, url=null, language=null, rfNumber=[42], rfOrder=41, authorNames=Santos JG, Da Cruz WMS, Schönthal AH, journalName=Oncol Lett, refType=null, unstructuredReference=Santos JG, Da Cruz WMS, Schönthal AH, et al. Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma[J]. Oncol Lett, 2018, 15(1): 1263-1270., articleTitle=Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma, refAbstract=null), Reference(id=1208073022716617413, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2015, volume=3, issue=null, pageStart=3, pageEnd=null, url=null, language=null, rfNumber=[43], rfOrder=42, authorNames=Schwartz K, Chang HT, Nikolai M, journalName=Cancer Metab, refType=null, unstructuredReference=Schwartz K, Chang HT, Nikolai M, et al. Treatment of glioma patients with ketogenic diets: Report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature[J]. Cancer Metab, 2015, 3: 3., articleTitle=Treatment of glioma patients with ketogenic diets: Report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature, refAbstract=null), Reference(id=1208073022775337671, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=24, issue=23, pageStart=4312, pageEnd=null, url=null, language=null, rfNumber=[44], rfOrder=43, authorNames=Bruinsmann FA, Richter Vaz G, de Cristo Soares Alves A, journalName=Molecules, refType=null, unstructuredReference=Bruinsmann FA, Richter Vaz G, de Cristo Soares Alves A, et al. Nasal drug delivery of anticancer drugs for the treatment of glioblastoma: Preclinical and clinical trials[J]. Molecules, 2019, 24(23): 4312., articleTitle=Nasal drug delivery of anticancer drugs for the treatment of glioblastoma: Preclinical and clinical trials, refAbstract=null), Reference(id=1208073022846640841, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=9, issue=3, pageStart=599, pageEnd=null, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=Moretti E, Favero G, Rodella LF, journalName=Cells, refType=null, unstructuredReference=Moretti E, Favero G, Rodella LF, et al. Melatonin's antineoplastic potential against glioblastoma[J]. Cells, 2020, 9(3): 599., articleTitle=Melatonin's antineoplastic potential against glioblastoma, refAbstract=null), Reference(id=1208073022976664267, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=34, issue=2, pageStart=192, pageEnd=199, url=null, language=null, rfNumber=[46], rfOrder=45, authorNames=Neamati F, Asemi Z, journalName=Fundam Clin Pharmacol, refType=null, unstructuredReference=Neamati F, Asemi Z. The effects of melatonin on signaling pathways and molecules involved in glioma[J]. Fundam Clin Pharmacol, 2020, 34(2): 192-199., articleTitle=The effects of melatonin on signaling pathways and molecules involved in glioma, refAbstract=null), Reference(id=1208073023043773133, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=18, issue=3, pageStart=915, pageEnd=927, url=null, language=null, rfNumber=[47], rfOrder=46, authorNames=Wang L, Tang S, Yu Y, journalName=Mol Pharm, refType=null, unstructuredReference=Wang L, Tang S, Yu Y, et al. Intranasal delivery of temozolomide-conjugated gold nanoparticles functionalized with anti-EphA3 for glioblastoma targeting[J]. Mol Pharm, 2021, 18(3): 915-927., articleTitle=Intranasal delivery of temozolomide-conjugated gold nanoparticles functionalized with anti-EphA3 for glioblastoma targeting, refAbstract=null), Reference(id=1208073023119270607, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=8, issue=3, pageStart=2001960, pageEnd=null, url=null, language=null, rfNumber=[48], rfOrder=47, authorNames=Hua D, Tang L, Wang W, journalName=Adv Sci (Weinh), refType=null, unstructuredReference=Hua D, Tang L, Wang W, et al. Improved antiglioblastoma activity and BBB permeability by conjugation of paclitaxel to a cell-penetrative MMP-2-cleavable peptide[J]. Adv Sci (Weinh), 2020, 8(3): 2001960., articleTitle=Improved antiglioblastoma activity and BBB permeability by conjugation of paclitaxel to a cell-penetrative MMP-2-cleavable peptide, refAbstract=null), Reference(id=1208073023177990865, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2017, volume=8, issue=1, pageStart=53, pageEnd=null, url=null, language=null, rfNumber=[49], rfOrder=48, authorNames=Pacioni S, D'Alessandris QG, Giannetti S, journalName=Stem Cell Res Ther, refType=null, unstructuredReference=Pacioni S, D'Alessandris QG, Giannetti S, et al. Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts[J]. Stem Cell Res Ther, 2017, 8(1): 53., articleTitle=Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts, refAbstract=null), Reference(id=1208073023253488339, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2017, volume=null, issue=124, pageStart=55845, pageEnd=null, url=null, language=null, rfNumber=[50], rfOrder=49, authorNames=Yu D, Li G, Lesniak MS, journalName=J Vis Exp, refType=null, unstructuredReference=Yu D, Li G, Lesniak MS, et al. Intranasal delivery of therapeutic stem cells to glioblastoma in a mouse model[J]. J Vis Exp, 2017, (124): 55845., articleTitle=Intranasal delivery of therapeutic stem cells to glioblastoma in a mouse model, refAbstract=null), Reference(id=1208073023328985813, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2020, volume=2020, issue=null, pageStart=8889061, pageEnd=null, url=null, language=null, rfNumber=[51], rfOrder=50, authorNames=Chia YC, Anjum CE, Yee HR, journalName=Stem Cells Int, refType=null, unstructuredReference=Chia YC, Anjum CE, Yee HR, et al. Stem cell therapy for neurodegenerative diseases: How do stem cells bypass the blood-brain barrier and home to the brain?[J]. Stem Cells Int, 2020, 2020: 8889061., articleTitle=Stem cell therapy for neurodegenerative diseases: How do stem cells bypass the blood-brain barrier and home to the brain?, refAbstract=null), Reference(id=1208073023383511767, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=2021, issue=null, pageStart=5549381, pageEnd=null, url=null, language=null, rfNumber=[52], rfOrder=51, authorNames=Gutova M, Cheng JP, Adhikarla V, journalName=Stem Cells Int, refType=null, unstructuredReference=Gutova M, Cheng JP, Adhikarla V, et al. Intranasally administered L-Myc-immortalized human neural stem cells migrate to primary and distal sites of damage after cortical impact and enhance spatial learning[J]. Stem Cells Int, 2021, 2021: 5549381., articleTitle=Intranasally administered L-Myc-immortalized human neural stem cells migrate to primary and distal sites of damage after cortical impact and enhance spatial learning, refAbstract=null), Reference(id=1208073023471592153, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=12, issue=1, pageStart=210, pageEnd=null, url=null, language=null, rfNumber=[53], rfOrder=52, authorNames=Zhang YT, He KJ, Zhang JB, journalName=Stem Cell Res Ther, refType=null, unstructuredReference=Zhang YT, He KJ, Zhang JB, et al. Advances in intranasal application of stem cells in the treatment of central nervous system diseases[J]. Stem Cell Res Ther, 2021, 12(1): 210., articleTitle=Advances in intranasal application of stem cells in the treatment of central nervous system diseases, refAbstract=null), Reference(id=1208073023584838363, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2017, volume=23, issue=12, pageStart=2951, pageEnd=2960, url=null, language=null, rfNumber=[54], rfOrder=53, authorNames=Portnow J, Synold TW, Badie B, journalName=Clin Cancer Res, refType=null, unstructuredReference=Portnow J, Synold TW, Badie B, et al. Neural stem cell-based anticancer gene therapy: A first-in-human study in recurrent high-grade glioma patients[J]. Clin Cancer Res, 2017, 23(12):2951-2960., articleTitle=Neural stem cell-based anticancer gene therapy: A first-in-human study in recurrent high-grade glioma patients, refAbstract=null), Reference(id=1208073023689695965, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=21, issue=3, pageStart=213, pageEnd=222, url=null, language=null, rfNumber=[55], rfOrder=54, authorNames=Coccè V, Bonomi A, Cavicchini L, journalName=Curr Cancer Drug Targets, refType=null, unstructuredReference=Coccè V, Bonomi A, Cavicchini L, et al. Paclitaxel priming of TRAIL expressing mesenchymal stromal cells (MSCs-TRAIL)increases antitumor efficacy of their secretome[J]. Curr Cancer Drug Targets, 2021, 21(3): 213-222., articleTitle=Paclitaxel priming of TRAIL expressing mesenchymal stromal cells (MSCs-TRAIL)increases antitumor efficacy of their secretome, refAbstract=null), Reference(id=1208073023756804831, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=10, issue=1, pageStart=88, pageEnd=null, url=null, language=null, rfNumber=[56], rfOrder=55, authorNames=Li M, Sun S, Dangelmajer S, journalName=Stem Cell Res Ther, refType=null, unstructuredReference=Li M, Sun S, Dangelmajer S, et al. Exploiting tumor-intrinsic signals to induce mesenchymal stem cell-mediated suicide gene therapy to fight malignant glioma[J]. Stem Cell Res Ther, 2019, 10(1): 88., articleTitle=Exploiting tumor-intrinsic signals to induce mesenchymal stem cell-mediated suicide gene therapy to fight malignant glioma, refAbstract=null), Reference(id=1208073023857468129, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2019, volume=13, issue=null, pageStart=204, pageEnd=null, url=null, language=null, rfNumber=[57], rfOrder=56, authorNames=Soria B, Martin-Montalvo A, Aguilera Y, journalName=Front Cell Neurosci, refType=null, unstructuredReference=Soria B, Martin-Montalvo A, Aguilera Y, et al. Human mesenchymal stem cells prevent neurological complications of radiotherapy[J]. Front Cell Neurosci, 2019, 13: 204., articleTitle=Human mesenchymal stem cells prevent neurological complications of radiotherapy, refAbstract=null), Reference(id=1208073023941354210, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2021, volume=13, issue=5, pageStart=1169, pageEnd=null, url=null, language=null, rfNumber=[58], rfOrder=57, authorNames=Aguilera Y, Mellado-Damas N, Olmedo-Moreno L, journalName=Cancers (Basel), refType=null, unstructuredReference=Aguilera Y, Mellado-Damas N, Olmedo-Moreno L, et al. Preclinical safety evaluation of intranasally delivered human mesenchymal stem cells in juvenile mice[J]. Cancers (Basel), 2021, 13(5): 1169., articleTitle=Preclinical safety evaluation of intranasally delivered human mesenchymal stem cells in juvenile mice, refAbstract=null), Reference(id=1208073024016851683, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2014, volume=22, issue=1, pageStart=140, pageEnd=148, url=null, language=null, rfNumber=[59], rfOrder=58, authorNames=Balyasnikova IV, Prasol MS, Ferguson SD, journalName=Mol Ther, refType=null, unstructuredReference=Balyasnikova IV, Prasol MS, Ferguson SD, et al. Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors[J]. Mol Ther, 2014, 22(1): 140-148., articleTitle=Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors, refAbstract=null), Reference(id=1208073024071377636, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208073009877852439, doi=null, pmid=null, pmcid=null, year=2012, volume=1, issue=12, pageStart=866, pageEnd=873, url=null, language=null, rfNumber=[60], rfOrder=59, authorNames=Reitz M, Demestre M, Sedlacik J, journalName=Stem Cells Transl Med, refType=null, unstructuredReference=Reitz M, Demestre M, Sedlacik J, et al. Intranasal delivery of neural stem/progenitor cells: A noninvasive passage to target intracerebral glioma[J]. 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经鼻脑给药途径治疗胶质母细胞瘤研究进展
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李吻吻 1 , 赖睿 2 , 刘淇 3 , 赵海龙 1, *
解放军医学杂志 | 综述 2022,47(5): 511-517
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解放军医学杂志 | 综述 2022, 47(5): 511-517
经鼻脑给药途径治疗胶质母细胞瘤研究进展
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李吻吻1, 赖睿2, 刘淇3, 赵海龙1, *
作者信息
  • 1遵义医科大学基础医学院病理生理学教研室,贵州遵义 563000
  • 2遵义医科大学第一临床学院,贵州遵义 563000
  • 3遵义医科大学口腔医学院,贵州遵义 563000
  • 李吻吻,硕士研究生,主要从事肿瘤细胞微环境和细胞间相互作用的研究

通讯作者:

赵海龙,E-mail:
Research progress in the treatment of glioblastoma by nose-to-brain delivery
Wen-Wen Li1, Rui Lai2, Qi Liu3, Hai-Long Zhao1, *
Affiliations
  • 1Department of Pathophysiology, School of Preclinical Medicine, Zunyi Medical University, Zunyi, Guizhou 563000, China
  • 2First Clinical College, Zunyi Medical University, Zunyi, Guizhou 563000, China
  • 3School of Stomatology, Zunyi Medical University, Zunyi, Guizhou 563000, China
出版时间: 2022-05-28 doi: 10.11855/j.issn.0577-7402.2022.05.0511
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胶质母细胞瘤(GBM)是最常见的原发性恶性脑肿瘤,其特征是肿瘤快速生长及侵袭周围组织。目前治疗GBM的标准方法包括手术切除、放射疗法和化学药物疗法,由于血脑屏障(BBB)会限制多种抗癌药物进入脑内,因此迫切需要新的给药途径以提高治疗效果。目前,鼻脑给药途径作为一种非侵入性替代途径,能够绕过BBB治疗中枢神经系统(CNS)疾病,并减少全身性不良反应。新近开发的多种新型制剂主要通过纳米结构的药物递送系统来进一步增强鼻脑转运。本文就鼻脑给药途径联合不同抗癌药物或方式在GBM临床治疗中的应用研究进展进行综述。

鼻腔输送  /  胶质母细胞瘤  /  血脑屏障  /  鼻脑给药  /  干细胞

Glioblastoma (GBM) is a most common primary malignant brain tumor characterized by rapid growth and invasion of surrounding tissues. At present, the standard methods for treatment of GBM include surgical resection, radiotherapy and chemotherapy. Because the existence of blood-brain barrier (BBB) restricts the delivery of anti-cancer drugs into the brain,novel drug deliver approaches are urgently needed to improve the therapeutic effect of GBM. As a non-invasive alternative route for directly targeting the central nervous system (CNS) disease, nose-to-brain delivery could bypass the BBB and reduce the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nanostructured drug delivery systems. The application of nose-to-brain delivery combined with different anticancer drugs or methods in clinical treatment of GBM have been reviewed in present paper.

nasal delivery  /  glioblastoma  /  blood-brain barrier  /  nose-to-brain delivery  /  stem cells
李吻吻, 赖睿, 刘淇, 赵海龙. 经鼻脑给药途径治疗胶质母细胞瘤研究进展. 解放军医学杂志, 2022 , 47 (5) : 511 -517 . DOI: 10.11855/j.issn.0577-7402.2022.05.0511
Wen-Wen Li, Rui Lai, Qi Liu, Hai-Long Zhao. Research progress in the treatment of glioblastoma by nose-to-brain delivery[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (5) : 511 -517 . DOI: 10.11855/j.issn.0577-7402.2022.05.0511
胶质母细胞瘤(glioblastoma,GBM)是成人最常见、最致命的原发性恶性脑肿瘤,其发病率随年龄增长而增高,75~84岁时达到峰值,但在85岁后下降,且男性发病率高于女性[1]。目前GBM的临床治疗手段主要为外科手术、放射疗法(简称放疗)和化学药物疗法(简称化疗),其中最大程度的手术切除是最有效的方法之一[2]。然而术后GBM患者的预后普遍较差,中位生存期仅15个月,且复发率高于90%[3]。目前,临床上GBM最常用的化疗药物是替莫唑胺(temozolomide,TMZ),其在体内自发水解为烷基化代谢物从而抑制肿瘤。临床中使用放疗联合TMZ治疗可使患者中位生存期延长2.5个月[4],但TMZ易产生耐药性,且入脑后靶向性较差,不良反应较多[5]。大部分抗癌药物由于血脑屏障(blood brain barrier,BBB)的低通透性而不易入脑[6],临床上需要提高药物剂量才能在脑中获得有效治疗浓度,从而限制了其临床应用。虽然目前可使用聚焦超声(BBB的机械破坏)、血管活性肽(BBB的化学破坏)等方式予以克服,但在一定程度上会对BBB造成破坏,且药物疗效不佳[6]。因此迫切需要一种新的给药方法,既能跨过BBB的阻碍,又能保证药物疗效。最近一种新的非侵入性给药方法,即鼻脑给药途径,可作为递送药物活性分子的替代途径。经鼻入脑的给药方式可使药物绕过BBB直接入脑,且能够保证药物到达肿瘤组织对具有有效浓度,是一种有效的新型药物输送策略。本文就鼻脑给药途径联合不同抗癌药物或方式在GBM治疗中的应用研究进展进行综述。
BBB是脑组织与血液之间的屏障,由内皮细胞、星形胶质细胞、周细胞、基底膜和细胞外基质组成,可阻止机体血液中的大分子、毒素和药物进入脑组织,从而维持脑组织稳态[7]。BBB通常只允许分子量小于400 ku的小亲脂性分子通过[8]。因此,使用药物治疗中枢神经系统(central nervous system,CNS)疾病时必须克服BBB的障碍。目前主要通过脑室内或鞘内注射来实现脑内直接给药[9],但脑室内或鞘内注射是侵入性方式,容易引发感染等并发症。因此,如何跨过BBB实现脑内给药是大部分CNS疾病(包括脑肿瘤)临床治疗最常见的障碍或困难[10]
鼻腔由前庭区域、呼吸区域和嗅觉区域等三个区域组成[11]。前庭区域是鼻腔入口,主要由鳞状上皮细胞组成;呼吸区域是鼻腔最大的区域,含有丰富的血管与神经[12],其中的三叉神经与脑内CNS相连[13];嗅觉区域由嗅上皮细胞组成,该处存在连接脑组织与外部环境的有孔毛细血管,是BBB最薄弱的部位,被认为是经鼻途径药物的主要吸收部位[14]
由于鼻腔黏膜对小分子药物和生物类药物具有很好的吸收和渗透性,同时多肽等大分子物质及干细胞也能通过嗅觉区域进入脑内,因此鼻腔非常适合药物输送入脑[15]。药物经鼻入脑主要通过嗅觉神经和三叉神经通路[16]。当药物从鼻腔到达嗅觉区域时,会通过嗅觉神经和三叉神经进入脑内的嗅球,然后进入脑脊液,进一步到达大脑的不同区域,从而达到绕过BBB的目的[17]
虽然滴鼻剂、喷雾剂等形式已广泛使用,并已被证实对鼻内给药更有效[18];但由于药物会经历黏液纤毛清除、酶促降解过程,其生物利用度降低且停留时间短,可能会限制鼻内吸收[19]。同时,可喷入鼻腔的药物量有限,长期接触含有细胞毒性的制剂会导致纤毛毒性、鼻黏膜损伤和刺激,甚至引起过敏[20-21]。为克服这些障碍以提高鼻腔给药的有效性,利用吸收促进剂、黏膜黏附剂、酶抑制剂和纳米载体等方法延长鼻腔停留时间,降低黏膜纤毛清除率,可改善药物的吸收情况[19,22-23]。新型药物制剂主要包括纳米颗粒、水凝胶、微球或基于脂质的纳米制剂,药物被封装到适当的载体系统中以控制释放和增强药物向CNS的靶向递送,从而提高鼻黏膜对药物的吸收利用[19,22-24]
总之,鼻脑给药途径是利用连接大脑与外部环境之间的独特解剖结构,从而绕过BBB的给药方式。与其他CNS给药方式相比,鼻脑给药途径作为一种简单的、非侵入性给药替代途径,具有生物利用度高、创伤性小、不良反应少等优势,且可防止胃肠道反应和首过效应[19]。因此,鼻脑给药途径在GBM等脑部肿瘤的药物治疗中具有一定的应用前景[25]。长期鼻腔给药会对鼻腔黏膜和纤毛产生毒副作用,而纳米药物递送系统可控制释放并增强药物向CNS的靶向递送,增强鼻黏膜对药物的吸收,同时降低药物对鼻腔的毒副作用。
CC是一类源自姜黄根状茎的天然活性化合物,具有广泛的抗癌、抗肿瘤、抗氧化和抗炎作用[26]。近年来研究发现,CC可调节多种细胞信号通路及分子靶点如p53、磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol 3 kinase/protein kinase B,P13K/Akt)、Janus激酶/信号转导和转录激活因子(Janus kinase/signal transducer and activator of transcription,JAK/STAT)以及核转录因子κB (nuclear transcription factor-κB,NF-κB)等,从而抑制GBM肿瘤细胞的迁移、侵袭、增殖等[27-29]。此外,CC还可特异性抑制GBM肿瘤干细胞的增殖并选择性诱导肿瘤细胞凋亡,从而保护正常脑组织[28,30]。Mukherjee等[31]发现,CC经GBM特异性抗体耦联修饰后,在GBM模型动物中经鼻腔给药,能够靶向GBM细胞产生显著的抑制效果,表明CC可通过鼻脑给药途径有效治疗GBM。
5-FU是天然尿嘧啶的类似物,在细胞内代谢活化生成靶向DNA和RNA等的核苷和核苷酸代谢物,可发挥细胞毒性作用,目前广泛用于治疗各种肿瘤[32]
近期研究发现,嗅鞘细胞(olfactory ensheathing cell,OEC)具有迁移到损伤部位的能力和抗炎特性,经鼻脑给药途径入脑后可以靶向脑肿瘤[33]。Carvalho等[33]研究发现,体外培养的OEC可过表达酵母胞嘧啶脱氨酶(cytosine deaminase,CD)和尿嘧啶磷酸核糖转移酶(uracil phosphoribosyltransferase,UPRT),然后利用其自身对脑肿瘤的靶向性,在脑肿瘤部位特异地将前药5-氟胞嘧啶(5- fluorocytosine,5-FC)转化为细胞毒剂5-FU,进而抑制肿瘤细胞的核苷酸合成并诱导其死亡。该研究结果表明,利用OEC载体可实现5-FU经鼻脑给药途径靶向杀伤GBM细胞的目的。
TMZ具有一定的脂溶性,可跨越BBB,是目前临床治疗GBM的常规性化疗药物。TMZ可在DNA的嘌呤和嘧啶中添加一个甲基,从而导致碱基错配、细胞损伤及细胞凋亡[34]。但在临床上,TMZ的使用以口服为主,在药物生效过程中需要克服酶降解、首过效应和BBB等障碍,容易产生耐药性。近年来有研究发现,在使用TMZ对GBM模型动物进行治疗的过程中,相较静脉注射和灌胃,鼻脑给药途径能够显著抑制GBM的生长、减小肿瘤体积并延长动物中位生存期。Li等[35]研究发现,TMZ经鼻脑给药能够有效治疗GBM,且有效药物剂量较小,可作为新的GBM治疗策略。
POH是一种从香菜、薰衣草、薄荷、芹菜籽等植物精油中分离出来的天然单环萜烯[36]。由于POH半衰期较短,临床上常通过口服胶囊的方式治疗GBM,但需要每天连续多次给药,易导致消化系统不良反应,如恶心、疲倦和呕吐等[37]
目前研究发现,POH经鼻脑给药可有效延长患者生存期,且不良反应少[38]。Schönthal等[38]研究发现,经鼻脑途径给予不同剂量的POH均具有良好的耐受性,未报告严重不良事件。同时,6个月无进展生存率(progression free survival-6,PFS-6)为33%,12个月总生存率(overall survival-12,OS-12)为55%,中位总生存期为15个月。该研究结果表明,POH经鼻脑给药治疗GBM具有一定的安全性,且可有效降低复发率。
此外,Rieger等[39]发现,在POH鼻脑给药的基础上,给予生酮饮食可有效治疗复发性GBM。酮体会抑制GBM细胞的活力,但不会影响正常细胞的活力[40],因此,利用低碳水化合物、高脂肪的生酮饮食联合鼻脑给药POH可增加血酮体水平以治疗GBM,且能够降低药物毒性、保证疗效[41]。相较于单纯鼻脑给药POH,结合生酮饮食可明显降低GBM的复发率,这可能与患者的血脂和低密度脂蛋白胆固醇水平降低有关[42]。因此,POH经鼻脑给药能够有效治疗GBM,且与生酮饮食结合可明显提高疗效,具有巨大的潜在临床应用前景[43]
总之,CC、5-FU、TMZ、POH等抗癌药物可通过鼻脑给药途径直接进入大脑,从而治疗GBM。
治疗GBM的新型药物递送系统正在开发中,最近纳米颗粒(nanoparticles,NP)受到了极大的关注,NP、纳米乳剂和基于脂质的纳米制剂等主要用于鼻脑递送研究[44]
聚合物NP在药物传递方面显示出了巨大的潜力。最近有学者提出了用于鼻内给药治疗GBM的负载褪黑素聚己内酯纳米颗粒(MLT-NP)[23]。褪黑素(melatonin,MLT)是一种由松果体合成和分泌的吲哚类激素[45],具有抗炎和抗氧化活性,可调节生物节律并抑制GBM细胞的增殖[46]。但MLT半衰期短、口服生物利用度低、溶解性差、首过效应明显,从而较难达到治疗浓度,限制了其临床应用[23]。de Oliveira Junior等[23]研究发现,MLT-NP制剂对GBM细胞具有很强的细胞毒性作用,与鼻内或口服途径给药的游离MLT相比,由于NP可从鼻腔直接到达大脑,因此MLT-NP鼻内给药增加了大脑中MLT的浓度,一定程度上提高了GBM的治疗效果[23]
研究发现,与游离姜黄素(CM)相比,姜黄素负载纳米颗粒(CM-NP)对脑肿瘤切除后GBM干细胞(GSCs)的增殖、迁移和侵袭具有明显抑制作用,同时可诱导GSCs细胞周期阻滞和凋亡的发生[29]。该研究结果表明,CM-NP可有效地靶向GSCs,发挥较强的抗肿瘤作用。
目前TMZ虽然是GBM临床治疗的一线药物,但存在靶向性差、不良反应多和易产生耐药性等问题,限制了其在临床的应用。Wang等[47]研究发现,采用EphA3抗体和NP对TMZ进行修饰(抗EphA3-TMZ@GNPs)后,辅以鼻脑给药方式能够有效治疗GBM。与游离TMZ相比,抗EphA3-TMZ@GNPs可绕过BBB并靶向GBM细胞,产生较强的细胞毒性作用诱导凋亡发生,最终提高在GBM模型动物中的抗GBM效果,延长其生存期。
紫杉醇(paclitaxel,PTX)也是临床治疗GBM的常用药物,但由于其溶解度低并具有脱靶细胞毒性,临床应用时可能会引起多种不良反应[48]。Ullah等[22]研究发现,PTX结合NP并经过精氨酸-甘氨酰-天冬氨酸三肽(RGD)修饰(RGD-NP-PTX)后,能够通过鼻脑给药途径靶向进入GBM区域,并抑制肿瘤细胞的生长。此外,RGD-NP-PTX治疗仅对快速分裂的GBM有效,而对无法分裂的正常脑细胞没有明显伤害作用。因此,RGD-NP-PTX在治疗GBM方面具有良好的临床价值和应用前景。
由于干细胞对肿瘤组织具有特异倾向性且能够穿过BBB,目前临床上已尝试使用干细胞治疗GBM[49-51]。此外,干细胞对损伤区域具有倾向性。有研究发现,神经干细胞(neural stem cells,NSCs)可迁移到神经系统的损伤部位,从而改善患者的认知功能,促进认知恢复[52];人脐带间充质干细胞(mesenchymal stem cells,MSCs)具有恢复神经细胞数量和减轻脑炎症的神经保护作用[53]。Portnow等[54]研究发现,NSCs本身具有较好的GBM治疗作用和安全性;Coccè等[55]研究发现,MSCs在体外可通过促进肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor related apoptosis inducing ligand,TRAIL)的过表达而诱导GBM细胞凋亡。目前临床上常用的干细胞主要为具有自我更新能力的多能干细胞,如NSCs和MSCs等[56]
胶质瘤模型小鼠在放疗后经鼻脑递送MSCs可延长小鼠的寿命。Soria等[57]研究证实,鼻脑递送hMSCs可促进辐射诱导的脑损伤修复,改善神经功能。此外,MSCs治疗可防止机体炎症、氧化应激的发生,促进辐射后脑损伤修复并改善小鼠的神经功能,继而保证小鼠正常的生物学功能和主要器官的组织结构完整[58]。此外,鼻脑递送MSCs能够向颅内GBM区域迁移,并通过表达TRAIL促进GBM细胞凋亡,最终明显延长GBM模型动物的存活时间;同时配合放疗,可使CXC趋化因子配体12(CXC chemokine ligand 12,CXCL12)表达上调,增强MSCs向颅内肿瘤部位迁移的能力[59]。Reitz等[60]研究发现,通过鼻脑给药途径输送NSCs入脑可有效治疗GBM,且不良反应少、创伤性小;滴鼻6h后,NSCs通过嗅觉途径迁移入脑,并在GBM肿瘤部位发生特异性聚集,24 h细胞数量到达顶峰,表明NSCs对GBM肿瘤有一定的倾向性。
在干细胞通过鼻脑给药途径治疗GBM的过程中,应用纤维蛋白胶或甲巯咪唑(methimazole,MT)可以显著延长干细胞在鼻腔中的停留时间,从而提高干细胞的靶向治疗效果。例如,在NSCs鼻脑给药过程中应用MT可显著提高GBM模型小鼠的存活率[61]
总之,干细胞对肿瘤的生长具有抑制作用,可诱导肿瘤消退。干细胞经鼻脑给药途径治疗GBM是一种安全、简单且有效的非侵入性方式,可最大程度地减轻放疗引起的不良反应,且干细胞对肿瘤组织的倾向性可提高治疗的靶向性,因此干细胞经鼻脑给药途径治疗GBM具有一定的临床应用价值。
由于GBM具有浸润生长的特性,手术不能完全切除肿瘤组织,同时由于BBB会限制大部分药物入脑,化疗药物的治疗效果不佳,最终导致GBM患者预后较差,生存率较低。通常情况下,口服给药被认为是一种最方便的治疗方式。然而,治疗GBM的药物(如TMZ)要以其生物活性形式到达大脑必须通过BBB,在此过程中药效降低。
目前,在GBM的治疗中,鼻脑途径是可绕过BBB的一种非侵入性给药方法,较其他方法具有潜在的优势。本文主要探讨了通过鼻脑途径给予抗癌药物CC、5-FU、TMZ和POH等对GBM的治疗作用。鼻脑给药后药物具有更好的生物分布和更高的治疗效果(图1)。鼻脑给药POH在临床试验中表现出较好的耐受性和较高的患者依从性。临床应用的干细胞(如NSCs和MSCs等)对GBM具有倾向性,使其通过鼻脑给药途径能够保证较强的靶向性且不良反应较少。在鼻脑给药递送方面,已经设计和研究了包裹在纳米结构载体(纳米乳液、微乳、聚合物和脂质纳米粒)中的药物,以提高鼻腔到大脑的药物输送效率。其中新型制剂提供了表面修饰的纳米载体,能够靶向GBM细胞输送特定药物,同时减轻对鼻黏膜的毒副作用。尽管目前针对GBM的鼻脑给药方式研究较少,但该给药方式已在临床上配合部分新型药物或成熟药物用于GBM的初期治疗,未来可为GBM患者带来新的治疗选择。
  • 国家自然科学基金(31701007)
  • 国家自然科学基金(82060503)
  • 遵义医科大学研究生科研基金项目(ZYK024)
  • 贵州省科技计划项目(黔科合基础[2019]1334号)()
  • 贵州省卫健委科学技术基金(gzwjkj2019-1-033)
  • 贵州省教育厅青年科技人才成长项目(QJHKYZ-2017-198)
参考文献 引证文献
排序方式:
[1]
Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010[J]. Neuro Oncol, 2013, 15(Suppl 2): ii1-ii56.
[2]
Thakkar JP, Dolecek TA, Horbinski C, et al. Epidemiologic and molecular prognostic review of glioblastoma[J]. Cancer Epidemiol Biomarkers Prev, 2014, 23(10): 1985-1996.
[3]
Morsy AA, Ng WH. Re-do craniotomy for recurrent glioblastoma[J]. CNS Oncol, 2015, 4(2): 55-57.
[4]
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[J]. N Engl J Med, 2005, 352(10): 987-996.
[5]
Tiek DM, Rone JD, Graham GT, et al. Alterations in cell motility, proliferation, and metabolism in novel models of acquired temozolomide resistant glioblastoma[J]. Sci Rep, 2018, 8(1):7222.
[6]
Harder BG, Blomquist MR, Wang J, et al. Developments in blood-brain barrier penetrance and drug repurposing for improved treatment of glioblastoma[J]. Front Oncol, 2018, 8:462.
[7]
Schaffenrath J, Huang SF, Wyss T, et al. Characterization of the blood-brain barrier in genetically diverse laboratory mouse strains[J]. Fluids Barriers CNS, 2021, 18(1): 34.
[8]
Pardridge WM. Drug transport across the blood-brain barrier[J]. J Cereb Blood Flow Metab, 2012, 32(11): 1959-1972.
[9]
Hersh DS, Wadajkar AS, Roberts N, et al. Evolving drug delivery strategies to overcome the blood brain barrier[J]. Curr Pharm Des, 2016, 22(9): 1177-1193.
[10]
Dong X. Current strategies for brain drug delivery[J]. Theranostics, 2018, 8(6): 1481-1493.
[11]
Hong SS, Oh KT, Choi HG, et al. Liposomal formulations for nose-to-brain delivery: Recent advances and future perspectives[J]. Pharmaceutics, 2019, 11(10): 540.
[12]
Crowe TP, Greenlee MHW, Kanthasamy AG, et al. Mechanism of intranasal drug delivery directly to the brain[J]. Life Sci, 2018, 195: 44-52.
[13]
Lochhead JJ, Kellohen KL, Ronaldson PT, et al. Distribution of insulin in trigeminal nerve and brain after intranasal administration[J]. Sci Rep, 2019, 9(1): 2621.
[14]
Pardeshi CV, Belgamwar VS. Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood–brain barrier:an excellent platform for brain targeting[J]. Expert Opin Drug Deliv, 2013, 10(7): 957-972.
[15]
Ganger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa[J]. Pharmaceutics, 2018, 10(3): 116.
[16]
Djupesland PG, Messina JC, Mahmoud RA. The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview [J]. Ther Deliv, 2014, 5(6): 709-733.
[17]
Alexander A, Agrawal M, Uddin A, et al. Recent expansions of novel strategies towards the drug targeting into the brain[J]. Int J Nanomedicine, 2019, 14: 5895-5909.
[18]
Trevino JT, Quispe RC, Khan F, et al. Non-invasive strategies for nose-to-brain drug delivery[J]. J Clin Trials, 2020, 10(7): 439.
[19]
Ferreira NN, de Oliveira Junior E, Granja S, et al. Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system[J]. Int J Pharm, 2021, 603: 120714.
[20]
Sabir F, Ismail R, Csoka I. Nose-to-brain delivery of antiglioblastoma drugs embedded into lipid nanocarrier systems: Status quo and outlook[J]. Drug Discov Today, 2020, 25(1):185-194.
[21]
Upadhaya PG, Pulakkat S, Patravale VB. Nose-to-brain delivery: Exploring newer domains for glioblastoma multiforme management[J]. Drug Deliv Transl Res, 2020, 10(4):1044-1056.
[22]
Ullah I, Chung K, Bae S, et al. Nose-to-brain delivery of cancer-targeting paclitaxel-loaded nanoparticles potentiates antitumor effects in malignant glioblastoma[J]. Mol Pharm, 2020, 17(4):1193-1204.
[23]
de Oliveira Junior ER, Nascimento TL, Salomão MA, et al. Increased nose-to-brain delivery of melatonin mediated by polycaprolactone nanoparticles for the treatment of glioblastoma[J]. Pharm Res, 2019, 36(9):131.
[24]
Qu Y, Li A, Ma L, et al. Nose-to-brain delivery of disulfiram nanoemulsion in situ gel formulation for glioblastoma targeting therapy[J]. Int J Pharm, 2021, 597: 120250.
[25]
van Woensel M, Wauthoz N, Rosière R, et al. Formulations for intranasal delivery of pharmacological agents to combat brain disease: a new opportunity to tackle GBM?[J]. Cancers (Basel), 2013, 5(3): 1020-1048.
[26]
Hewlings SJ, Kalman DS. Curcumin: A review of its effects on human health[J]. Foods, 2017, 6(10): 92.
[27]
Wang Z, Liu F, Liao W, et al. Curcumin suppresses glioblastoma cell proliferation by p-AKT/mTOR pathway and increases the PTEN expression[J]. Arch Biochem Biophys, 2020, 689:108412.
[28]
Gersey ZC, Rodriguez GA, Barbarite E, et al. Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species[J]. BMC Cancer, 2017, 17(1): 99.
[29]
Sahab-Negah S, Ariakia F, Jalili-Nik M, et al. Curcumin loaded in niosomal nanoparticles improved the anti-tumor effects of free curcumin on glioblastoma stem-like cells: An in vitro study[J]. Mol Neurobiol, 2020, 57(8): 3391-3411.
[30]
Wang X, Deng J, Yuan J, et al. Curcumin exerts its tumor suppressive function via inhibition of NEDD4 oncoprotein in glioma cancer cells[J]. Int J Oncol, 2017, 51(2): 467-477.
[31]
Mukherjee S, Baidoo J, Fried A, et al. Curcumin changes the polarity of tumor-associated microglia and eliminates glioblastoma[J]. Int J Cancer, 2016, 139(12): 2838-2849.
[32]
Machon C, Catez F, Venezia ND, et al. Study of intracellular anabolism of 5-fluorouracil and incorporation in nucleic acids based on an LC-HRMS method[J]. J Pharm Anal, 2021, 11(1):77-87.
[33]
Carvalho LA, Teng J, Fleming RL, et al. Olfactory ensheathing cells: A trojan horse for glioma gene therapy[J]. J Natl Cancer Inst, 2019, 111(3): 283-291.
[34]
Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance[J]. Curr Mol Pharmacol, 2012, 5(1): 102-114.
[35]
Li Y, Gao Y, Liu G, et al. Intranasal administration of temozolomide for brain-targeting delivery: Therapeutic effect on glioma in rats[J]. Nan Fang Yi Ke Da Xue Xue Bao, 2014, 34(5):631-635.
[36]
Chen TC, Fonseca CO, Schönthal AH. Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy[J]. Am J Cancer Res, 2015, 5(5): 1580-1593.
[37]
Chen TC, da Fonseca CO, Schönthal AH. Intranasal perillyl alcohol for glioma therapy: Molecular mechanisms and clinical development[J]. Int J Mol Sci, 2018, 19(12): 3905.
[38]
Schönthal AH, Peereboom DM, Wagle N, et al. Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in adult patients with recurrent glioblastoma[J]. Neurooncol Adv, 2021, 3(1): vdab005.
[39]
Rieger J, Bahr O, Maurer GD, et al. ERGO: A pilot study of ketogenic diet in recurrent glioblastoma[J]. Int J Oncol, 2014, 44(6): 1843-1852.
[40]
Klein P, Tyrlikova I, Zuccoli G, et al. Treatment of glioblastoma multiforme with "classic" 4:1 ketogenic diet total meal replacement[J]. Cancer Metab, 2020, 8(1): 24.
[41]
Mukherjee P, Augur ZM, Li M, et al. Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma[J]. Commun Biol, 2019, 2: 200.
[42]
Santos JG, Da Cruz WMS, Schönthal AH, et al. Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma[J]. Oncol Lett, 2018, 15(1): 1263-1270.
[43]
Schwartz K, Chang HT, Nikolai M, et al. Treatment of glioma patients with ketogenic diets: Report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature[J]. Cancer Metab, 2015, 3: 3.
[44]
Bruinsmann FA, Richter Vaz G, de Cristo Soares Alves A, et al. Nasal drug delivery of anticancer drugs for the treatment of glioblastoma: Preclinical and clinical trials[J]. Molecules, 2019, 24(23): 4312.
[45]
Moretti E, Favero G, Rodella LF, et al. Melatonin's antineoplastic potential against glioblastoma[J]. Cells, 2020, 9(3): 599.
[46]
Neamati F, Asemi Z. The effects of melatonin on signaling pathways and molecules involved in glioma[J]. Fundam Clin Pharmacol, 2020, 34(2): 192-199.
[47]
Wang L, Tang S, Yu Y, et al. Intranasal delivery of temozolomide-conjugated gold nanoparticles functionalized with anti-EphA3 for glioblastoma targeting[J]. Mol Pharm, 2021, 18(3): 915-927.
[48]
Hua D, Tang L, Wang W, et al. Improved antiglioblastoma activity and BBB permeability by conjugation of paclitaxel to a cell-penetrative MMP-2-cleavable peptide[J]. Adv Sci (Weinh), 2020, 8(3): 2001960.
[49]
Pacioni S, D'Alessandris QG, Giannetti S, et al. Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts[J]. Stem Cell Res Ther, 2017, 8(1): 53.
[50]
Yu D, Li G, Lesniak MS, et al. Intranasal delivery of therapeutic stem cells to glioblastoma in a mouse model[J]. J Vis Exp, 2017, (124): 55845.
[51]
Chia YC, Anjum CE, Yee HR, et al. Stem cell therapy for neurodegenerative diseases: How do stem cells bypass the blood-brain barrier and home to the brain?[J]. Stem Cells Int, 2020, 2020: 8889061.
[52]
Gutova M, Cheng JP, Adhikarla V, et al. Intranasally administered L-Myc-immortalized human neural stem cells migrate to primary and distal sites of damage after cortical impact and enhance spatial learning[J]. Stem Cells Int, 2021, 2021: 5549381.
[53]
Zhang YT, He KJ, Zhang JB, et al. Advances in intranasal application of stem cells in the treatment of central nervous system diseases[J]. Stem Cell Res Ther, 2021, 12(1): 210.
[54]
Portnow J, Synold TW, Badie B, et al. Neural stem cell-based anticancer gene therapy: A first-in-human study in recurrent high-grade glioma patients[J]. Clin Cancer Res, 2017, 23(12):2951-2960.
[55]
Coccè V, Bonomi A, Cavicchini L, et al. Paclitaxel priming of TRAIL expressing mesenchymal stromal cells (MSCs-TRAIL)increases antitumor efficacy of their secretome[J]. Curr Cancer Drug Targets, 2021, 21(3): 213-222.
[56]
Li M, Sun S, Dangelmajer S, et al. Exploiting tumor-intrinsic signals to induce mesenchymal stem cell-mediated suicide gene therapy to fight malignant glioma[J]. Stem Cell Res Ther, 2019, 10(1): 88.
[57]
Soria B, Martin-Montalvo A, Aguilera Y, et al. Human mesenchymal stem cells prevent neurological complications of radiotherapy[J]. Front Cell Neurosci, 2019, 13: 204.
[58]
Aguilera Y, Mellado-Damas N, Olmedo-Moreno L, et al. Preclinical safety evaluation of intranasally delivered human mesenchymal stem cells in juvenile mice[J]. Cancers (Basel), 2021, 13(5): 1169.
[59]
Balyasnikova IV, Prasol MS, Ferguson SD, et al. Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors[J]. Mol Ther, 2014, 22(1): 140-148.
[60]
Reitz M, Demestre M, Sedlacik J, et al. Intranasal delivery of neural stem/progenitor cells: A noninvasive passage to target intracerebral glioma[J]. Stem Cells Transl Med, 2012, 1(12):866-873.
[61]
Spencer D, Yu D, Morshed RA, et al. Pharmacologic modulation of nasal epithelium augments neural stem cell targeting of glioblastoma[J]. Theranostics, 2019, 9(7): 2071-2083.
2022年第47卷第5期
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doi: 10.11855/j.issn.0577-7402.2022.05.0511
  • 接收时间:2021-05-20
  • 首发时间:2025-12-17
  • 出版时间:2022-05-28
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  • 收稿日期:2021-05-20
  • 录用日期:2021-11-05
基金
National Natural Science Foundation of China(31701007)
国家自然科学基金(31701007)
National Natural Science Foundation of China(82060503)
国家自然科学基金(82060503)
Postgraduate Research fund Project of Zunyi Medical University(ZYK024)
遵义医科大学研究生科研基金项目(ZYK024)
Science and Technology Program of Guizhou Province(QKHJZ-2019-1334)()
贵州省科技计划项目(黔科合基础[2019]1334号)()
Science and Technology Fund Project of Guizhou Health Commission(gzwjkj2019-1-033)
贵州省卫健委科学技术基金(gzwjkj2019-1-033)
Development Project of Science and Technology Talents Supported by Education Department of Guizhou Province(QJHKYZ-2017-198)
贵州省教育厅青年科技人才成长项目(QJHKYZ-2017-198)
作者信息
    1遵义医科大学基础医学院病理生理学教研室,贵州遵义 563000
    2遵义医科大学第一临床学院,贵州遵义 563000
    3遵义医科大学口腔医学院,贵州遵义 563000

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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