Nanotechnology and the Brain PDF
Preview Nanotechnology and the Brain
INTERNATIONAL REVIEW OF NEUROBIOLOGY VOLUME130 SERIES EDITOR PETER JENNER Division of Pharmacology and Therapeutics GKT School of Biomedical Sciences King's College, London, UK EDITORIAL BOARD ERICAAMODT HUDAAKIL PHILIPPEASCHER MATTHEWJ.DURING DONARDS.DWYER DAVIDFINK MARTINGIURFA BARRYHALLIWELL PAULGREENGARD JONKAAS NOBUHATTORI LEAHKRUBITZER DARCYKELLEY KEVINMCNAUGHT BEAULOTTO JOSE(cid:1)A.OBESO MICAELAMORELLI CATHYJ.PRICE JUDITHPRATT SOLOMONH.SNYDER EVANSNYDER STEPHENG.WAXMAN JOHNWADDINGTON AcademicPressisanimprintofElsevier 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates 525BStreet,Suite1800,SanDiego,CA92101-4495,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 125LondonWall,London,EC2Y5AS,UnitedKingdom Firstedition2016 Copyright©2016ElsevierInc.Allrightsreserved. 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ISBN:978-0-12-804636-4 ISSN:0074-7742 ForinformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/ Publisher:ZoeKruze AcquisitionEditor:KirstenShankland EditorialProjectManager:HannahColford ProductionProjectManager:SuryaNarayananJayachandran CoverDesigner:ChristianBilbow TypesetbySPiGlobal,India CONTRIBUTORS K.T.Al-Jamal InstituteofPharmaceuticalScience,FacultyofLifeSciencesandMedicine,King’sCollege London,London,UnitedKingdom K.Andrieux Universit(cid:1)eParisDescartes,Universit(cid:1)eParis-Sorbonne,UTCBS,UMRCNRS8258, UE1022INSERM,Paris,France E.Araya AdvancedCenterforChronicDiseases(ACCDiS);FacultaddeCienciasExactas, UniversidadAndr(cid:1)esBello,Santiago,Chile E.Barbu SchoolofPharmacyandBiomedicalSciences,UniversityofPortsmouth,Portsmouth, UnitedKingdom G.Battaglia UniversityCollegeLondon,London,UnitedKingdom D.Brambilla InstituteofPharmaceuticalSciences,ETHZurich,Zurich,Switzerland A.L.Cardoso CNC–CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra, Portugal A.M.Cardoso CNC–CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra, Portugal D.Carradori AdvancedDrugDeliveryandBiomaterials,LouvainDrugResearchInstitute,Universit(cid:1)e catholiquedeLouvain,Bruxelles,Belgium R.Costa CNC–CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra, Portugal P.Cunha CNC–CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra, Portugal G.Fullstone UniversityCollegeLondon,London,UnitedKingdom E.Gallardo-Toledo FacultaddeCienciasQu´ımicasyFarmac(cid:1)euticas,UniversidaddeChile;AdvancedCenterfor ChronicDiseases(ACCDiS),Santiago,Chile A.Gaudin YaleUniversity,NewHaven,CT,UnitedStates ix x Contributors R.Gromnicova TheOpenUniversity,MiltonKeynes,UnitedKingdom J.R.Guedes CNC–CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra, Portugal A.Jurado CNC–CenterforNeuroscienceandCellBiology;DepartmentofLifeSciences,University ofCoimbra,Coimbra,Portugal H.Kafa InstituteofPharmaceuticalScience,FacultyofLifeSciencesandMedicine,King’sCollege London,London,UnitedKingdom M.J.Kogan FacultaddeCienciasQu´ımicasyFarmac(cid:1)euticas,UniversidaddeChile;AdvancedCenterfor ChronicDiseases(ACCDiS),Santiago,Chile A.Lalatsa SchoolofPharmacyandBiomedicalSciences,UniversityofPortsmouth,Portsmouth, UnitedKingdom D.Male TheOpenUniversity,MiltonKeynes,UnitedKingdom C.McQuaid TheOpenUniversity,MiltonKeynes,UnitedKingdom C.Morais CNC–CenterforNeuroscienceandCellBiology;DepartmentofLifeSciences,University ofCoimbra,Coimbra,Portugal S.Nyberg UniversityCollegeLondon,London,UnitedKingdom;BiologicalSciences,Sunnybrook ResearchInstitute,Toronto,ON,Canada M.C.PedrosodeLima CNC–CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra, Portugal A.C.Sintov FacultyofEngineeringSciences,BenGurionUniversityoftheNegev,Be’erSheva,Israel X.Tian SchoolofLifeSciences,AnhuiUniversity,Hefei,People’sRepublicofChina C.Velasco-Aguirre FacultaddeCienciasQu´ımicasyFarmac(cid:1)euticas,UniversidaddeChile;AdvancedCenterfor ChronicDiseases(ACCDiS),Santiago,Chile A.T.Viegas CNC–CenterforNeuroscienceandCellBiology;Inter-UniversityDoctoralProgrammein AgeingandChronicDisease,FacultyofMedicine,UniversityofCoimbra,Coimbra, Portugal J.T.-W.Wang InstituteofPharmaceuticalScience,FacultyofLifeSciencesandMedicine,King’sCollege London,London,UnitedKingdom PREFACE Central nervous system (CNS) diseases, and more specifically the chronic age-related neurodegenerative disorders, constitute a set of challenging pathologicalconditions,frombothdiagnosticandtherapeuticpointofview. This is particularly true for most of these disorders,due to the lack of early diagnosticbiomarkerstoallowproperfollow-upofdiseaseprogressionand effectivetherapeuticstrategiestoallowapersistentcure.Oncethediseaseis accurately diagnosed, treatment of CNS diseases constitutes another chal- lengemainlyduetothephysicallyandchemicallyprotectedbrainandspinal cord,whencomparedtoperipheralorgans.Theblood–brainbarrier(BBB) maintainsessentialbrainhomeostasisbutsignificantlyrestrictsthedeliveryof mosttherapeuticagentstothebrainparenchyma.Thisisfurthercomplexed by the lack of tissue regenerative properties of the brain cells. The recent advancesinnanotechnologyhaveallowednewfieldsofresearchtoinvestigate cutting-edgebrain-specifictherapiesandtotacklethecomplexbrain-related disorders. Nanoparticles (NPs) provide a flexible platform for conjugating drugsandtargetingligandsandhavebeenextensivelyresearchedtofacilitate BBBcrossingandeffectivedeliverytothebrain. ThisSpecialIssuesoughttobringtogetherresearchersandtheNPsthey use to overcome the big challenge of crossing the BBB. Because the focus was on establishing knowledge to experts from other fields, selective NP examples and targeting strategies are being introduced. Some of the results are novel and not discussed elsewhere. We believe that bringing together expertsinnanotechnology,eachworkingonadifferentclassofNPs,makes this work distinctive in nature. In addition, this volume presents some invitromodelstobeusedforassessingNPstranscytosis,whichisdistinctive fromtransportfromsmallmoleculesduetotheneedforspecializedtransport mechanisms, that is lacking in many existing in vitro BBB testing models. Another topic that needs to be addressed and is introduced in this issue is the different transcytosis routes exploited by a range of NPs. The format of the book is that of stand-alone chapters in the form of a compendium. This way, each chapter can be used as a reference on a par- ticular type of NPs, containing the most updated literature on that topic at the time of publication, in the majority of the chapters. The first chapter Recent Trends in Nanotechnology Toward CNS Diseases: Lipid-Based NanoparticlesandExosomesforTargetedTherapeuticDelivery,byDrs.Cardoso, Guedes, Cardoso, Morais, Cunha, Viegas, Costa, Jurado, and Pedroso de xi xii Preface Lima,startswithanintroductiononstructuralandfunctionalunitsofCNS compositionandtheCNSmicrovessels.Itthendiscussesthelatestadvances employing lipid-based NPs and cell-produced exosomes, as drug and nucleic acid delivery systems. It summarizes some examples of their appli- cations in the context of neurological diseases, with emphasize on success stories in preclinical disease models. Findings from this chapter provide new prospects for further developments using this class of biocompatible nanocarriers, thus enabling researchers to move from the research realm to the clinical arena. DesigningNPsthateffectivelyentertheCNSrapidlyandwithoutalter- ation is one of the major challenges in the use of nanotechnology for the brain.Transcytosis,areceptor-mediatedtransportpathway,permitsendog- enousmacromoleculestoentertheCNSbycrossingtheBBB.Transcytosis across the BBB involves a number of distinct stages, including receptor binding, endocytosis into a transport vesicle, trafficking of the vesicle to the opposite side of the cell, and finally exocytosis and release of cargo. The second chapter From the Blood to the Central Nervous System: A Nanoparticle’s Journey Through the Blood–Brain Barrier by Transcytosis, by Drs.Fullstone,Nyberg,Tian,andBattaglia,discussesthecurrentknowledge on biological, physiological, and physical factors that influence NP transit through that stage of transcytosis, with implications for NP design. This chapterconcludeswithcurrentprogressmadeindesigningNPsthatexploit transcytosis for CNS delivery. ItisalreadyrecognizedthattheintegrityoftheBBBiscompromisedin some CNS conditions such as brain tumor and inflammatory disorders. The third chapter Application of Nanomedicine to the CNS Diseases, by Drs. Carradori, Gaudin, Brambilla, and Andrieux, discusses in a systematic manner, and in a particular order, the pathophysiology of glioblastoma, Alzheimer’s disease and stroke, conventional treatment options, and the limitations encountered in a disease by disease fashion. This is followed byinsightsonthepreclinicalandclinicalNP-basedapproachesfortreatment of these three conditions, detailing NP advantages and disadvantages. The examples given in this chapter contribute to demonstrate that delivering drugsintothebrainisoneofthepromisingapplicationsofnanotechnology in clinical neuroscience. Carbohydrate-basedNPshavereceivedinterestasBBBdeliverycarriers due to their hydrophilicity, biodegradability, biocompatibility, and ability forlarge-scalemanufacture.Chitosan-basednanocarriers,forexample,have shown ability to deliver drugs, peptides/proteins, and genetic drugs after Preface xiii intravenous, nasal, and oral administration in preclinical proof-of-concept studiesresultinginenhancedbrainlevelsandpharmacodynamicsresponses. The fourth chapter Carbohydrate Nanoparticles for Brain Delivery, by Drs. Lalatsa and Barbu, discussed methods of preparation of carbohydrate- basedNPsandtheassociatedpreclinicalstudieswithmainfindingstabulated. The chapter touches upon some of the novel emerging NPs types which belong to this chemical class. The authors proposes that pullulan, dextran, and cellulose nanocrystals are emerging technologies that warrant further researchtoelicitnoveldeliverysystemsforovercomingtheBBB. SometypesofmetallicNPsholdgreatpotentialfordeliveryoftherapies intotheCNS,withgoldNPsbeingthemoststudiedtype.Thefifthchapter Gold Nanoparticles for Imaging and Drug Transport to the CNS, by Drs. Male, Gromnicova, and McQuaid, discusses how gold NPs with a core size of 2nm, depending on their surface coat, can cross the brain endothelium in vitro by the plasma membrane/cytosolic route (passive transport) or by vesiculartranscytosis(activetransport).GoldNPsarerelativelyeasytosyn- thesizeandcanbemodifiedwithvarioustypesofsurfaceligands.Theirrel- ativelysmallsizesallowthemtopassthroughbrainendotheliuminvitroand in vivo and move rapidly through the brain parenchyma, in neurons and glia, within minutes of infusion. It is considered crucial to improve on the biodistribution of the NPs for CNS drug delivery; smaller gold NPs areremovedrapidlyviathekidney,whilelargerNPsaretakenupbymono- nuclearphagocytesinvarioustissues.ThesixthchapterMetalNanoparticlesas Targeted Carriers Circumventing the Blood–Brain Barrier, by Drs. Sintov Velasco-Aguirre,Gallardo-Toledo,Araya,andKogan,proposestheintrana- saladministrationrouteasawaytocircumventtheBBB.Despiteexploiting this route for nose-to-brain delivery, there is little known about fate of metallic NPs following this route of administration which is one of the aspects this chapter addresses. NPs explored over the past decades are spherical in nature. Recent advances in nanotechnology allow fabrication NPs of high aspect ratios (>3) such as rod-shaped gold NPs and carbon nanotubes (CNTs). CNTs exhibitseveralattractivecharacteristicsallowingtheiruseinthebrainenvi- ronment.Thepropertiesincludetheabilitytoefficientcrossingofbiological membranes,multiplecellinternalizationpathways,andtheirintrinsicphys- icalproperties,eg,theirinfraredabsorptionandself-heatingproperties.The seventhchapterCurrentPerspectiveofCarbonNanotubesApplicationinNeurol- ogy, by Drs. Kafa, Wang, and Al-Jamal, discusses major advances in using CNTsfortreatingbraintumoranddegenerativediseaseswithspecialfocus xiv Preface ontheirabilitiestocrosstheBBBfollowingsystemicadministration,which is the major obstacle for most other NPs. Collectively,thisSpecialIssueprovidessomeexamples,andisnotexclu- sive, of the types of the NPs that have been explored preclinically in brain delivery. It is clear that from the material presented here that there is real progress in the understanding of the physiology of the BBB and the types ofnanotechnology-basedcarriersthatneedtobeusedtoovercomethisbar- rier. The advances in chemical modification approaches of these nanocarriers helped to improve their in vivo performance. The choice of theinvitroBBBmodelsiscritical;thereisaneedforatightpolarizedmodel. Thecoculturewithcellsthatcouldserveininductionofpolarizationandact as a target cell is reasonable idea. We need to find powerful imaging tools, ie, real time to understand mechanisms for transcytosis. Correlation of invitrofindingswithinvivodistributionandfunctionneedstobeconsid- eredasoneofthefar-reachingobjectivesduringthestudydesign. Thereis clearly a future perspective for a wider range of drug delivery options. Finally,despitethepromisenanotechnologyholdsinbraindeliveryand imaging,itisimportantnottoforgetaddressingotherissuesthatmayariseas aconsequence.Some arethefate ofthese NPsandthechallenges encoun- teredbeforetheirclinicaltranslationcanbeachieved.Itisoursincerehope thatthereaderswillbemotivatedtocontinuesearchingfornewtechnology toolsorevenoptimizeontheexistingonestoovercomethebarrierstobrain delivery. Some technologies such as sonoporation, which relieson tempo- rarilyopeningthetightjunctionsoftheBBB,althoughnotcoveredinthis volume,holdgreatpromise.ThenumberofCNSdisordersandbraincancer is on a steep increase and success in the field of brain disease diagnosis and therapy will no doubt create a huge societal and economic impact. I would like to thank all of the contributing authors for their excellent contributions to this volume. I also thank my research team members, namely, Drs. Pedro Costa and Julie Wang, and Mrs. Kuo-Ching Mei and Izzat Suffian, for their assistance and helping me editing this book. I also thankProf.PeterJenner,aneditoroftheInternationalReviewofNeurobiology bookseries,forhiskindinvitation.WealsothankMs.PoppyGarrawayand Ms. Hannah Colford and all of the other fine people at Elsevier for their assistance andsupportinbringingthisvolumeto fruition.Ithasbeen great pleasureworkingwithallofyou.Youmademytasksimpleandenjoyable. KHULOUD T. AL-JAMAL King’s College London July 2016 CHAPTER ONE Recent Trends in Nanotechnology Toward CNS Diseases: Lipid-Based Nanoparticles and Exosomes for Targeted Therapeutic Delivery A.M. Cardoso*, J.R. Guedes*, A.L. Cardoso*, C. Morais*,†, P. Cunha*, A.T. Viegas*,{, R. Costa*, A. Jurado*,†, M.C. Pedroso de Lima*,1 *CNC–CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra,Portugal †DepartmentofLifeSciences,UniversityofCoimbra,Coimbra,Portugal {Inter-UniversityDoctoralProgrammeinAgeingandChronicDisease,FacultyofMedicine,Universityof Coimbra,Coimbra,Portugal 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction 2 2. Lipid-BasedNanoparticlesforNucleicAcidandDrugDeliverytotheCNS 7 2.1 IschemicStroke 8 2.2 NeuropathicPain 12 2.3 Alzheimer'sDisease 14 2.4 Parkinson'sDisease 17 2.5 Machado–JosephDisease 18 2.6 MultipleSclerosis 19 2.7 CNSTumors 20 2.8 OtherNeurologicalDisorders 26 3. ExosomesasDeliverySystemsforCNSDiseases 27 4. Conclusions 31 Acknowledgments 32 References 32 Abstract Centralnervoussystem(CNS)diseasesconstituteasetofchallengingpathologicalcon- ditionsconcerningdiagnosisandtherapeutics.Formostofthesedisorders,thereisa lack of early diagnosis, biomarkers to allow proper follow-up of disease progression andeffectivetherapeuticstrategiestoallowapersistentcure.Thepoorprognosisof most CNS diseases is, therefore, a global concern, especially regarding chronic age- relatedneurodegenerativedisorders,whicharealreadyconsideredproblemsofpublic healthduetotheincreasingaverageoflifeexpectancy. InternationalReviewofNeurobiology,Volume130 #2016ElsevierInc. 1 ISSN0074-7742 Allrightsreserved. http://dx.doi.org/10.1016/bs.irn.2016.05.002 2 A.M.Cardosoetal. ThedifficultiesassociatedwiththetreatmentofCNSdiseasesareowed,atleastin part, to very specific characteristics of the brain and spinal cord, when compared to peripheral organs. In this regard, the CNS is physically and chemically protected by theblood–brainbarrier(BBB),which,whilemaintainingessentialbrainhomeostasis,sig- nificantlyrestrictsthedeliveryofmosttherapeuticagentstothebrainparenchyma.On theotherhand,regenerativepropertiesofthetissuearelacking,meaningthataCNS insultresultinginneuronaldeathisapermanentphenomenon. ApproachesfortransposingtheBBBaimingtotreatCNSdiseases,relyingonspecific propertiesofnanosystems,havebeenreportedfortherapeuticdeliverytoCNSwithout interferingwiththenormalfunctionofthebrain.Inthischapter,weaddressthelatest advances concerning the principles of such approaches, employing lipid-based nanoparticlesandcell-producedexosomesasdrugandnucleicaciddeliverysystems, andsummarizerecentexampleofapplicationsinthecontextofneurologicaldiseases. Majorachievementsobtainedinpreclinicalstudiesandthetrendsidentifiedbythese studiesareemphasizedtoprovidenewprospectsforfurtherdevelopmentsinthisarea, thusenablingustomovefromtheresearchrealmtotheclinicalarena. 1. INTRODUCTION The nervous system is one of the most complex and mysterious sys- temsofallorganisms.Itisusuallydividedintoperipheralandcentralnervous system (CNS), the latter being composed of the brain and spinal cord that constitute the operation control center of the body, regulating all life pro- cessesfromconsciousactionstohomeostaticfunctions.Themainstructural and functional unit of the nervous system is the neuron, a highly polarized cell type that participates in neuronal circuits, allowing the transmission of information across brain regions and the guidance of electrical impulses to peripheral organs in order to control their function. For decades, it was thought that the production of new neurons was confined to the period ofembryonicdevelopment.However,neuronalstemcells(NSCs)localized in NSC niches, such as the subventricular zone of the lateral ventricles (Lois & Alvarez-BuyIIa, 1994), were shown to present persistent neuro- genesisproperties,indicatingthatneuronaldivisionisaslowbutnaturalpro- cess in adulthood (Reynolds, Tetzlaff, & Weiss, 1992). In addition to neurons, several other cell types also found in the nervous system play important roles in the maintenance of the electrical and chemical balances that allow the successful operation of neuronal circuits. The main non- neuronal cells of the brain parenchyma are astrocytes, oligodendrocytes, and microglia. While astrocytes contribute to physical scaffolding and to
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