Beruflich Dokumente
Kultur Dokumente
AuthorManuscript
NIH-PA Author Manuscript
WileyInterdiscipRevNanomedNanobiotechnol.Authormanuscript;availableinPMC2015
November01.
Publishedinfinaleditedformas:
WileyInterdiscipRevNanomedNanobiotechnol.2014November;6(6):532547.doi:10.1002/wnan.
1282.
Department of NanoEngineering and Moores Cancer Center, University of California, San Diego,
La Jolla, CA 92093, USA
Abstract
Despitethewidesuccessofantibiotics,thetreatmentofbacterialinfectionstillfacessignificant
challenges,particularlytheemergenceofantibioticresistance.Asaresult,nanoparticledrug
deliveryplatformsincludingliposomes,polymericnanoparticles,dendrimers,andvarious
inorganicnanoparticleshavebeenincreasinglyexploitedtoenhancethetherapeutic
effectivenessofexistingantibiotics.Thisreviewfocusesonareaswherenanoparticleapproaches
holdsignificantpotentialtoadvancethetreatmentofbacterialinfection.Theseareasinclude
targetedantibioticdelivery,environmentallyresponsiveantibioticdelivery,combinatorial
antibioticdelivery,nanoparticleenabledantibacterialvaccination,andnanoparticlebased
bacterialdetection.Ineachareawehighlighttheinnovativeantimicrobialnanoparticleplatforms
andreviewtheirprogressmadeagainstbacterialinfections.
Keywords
Nanomedicine;nanoparticles;bacteria;infectiousdiseases;antimicrobialdelivery
1. Introduction
NIH-PA Author Manuscript
Despitetheprofoundsuccessachievedbytheuseofantibioticsagainstinfectiousdiseases,
1,2
bacterialinfectionscontinuetoimposesignificantchallengesonglobalhealthcare .
Eradicationofcertainbacterialinfectionssuchastuberculosisremainsdifficultduetothe
complexmechanismsofthepathogeninsubvertingitshostsimmunesystemaswellasthe
3,4
deliverybarriersthatpreventantibioticsfromreachingsitesofinfection .Highlypotent
antibiotics,includingcertainaminoglycosidesandfluoroquinolones,generatesevereadverse
5,6
effectsandarereservedonlyforseriousinfections .Moresignificantly,theemergenceof
antibioticresistancehasgeneratedalarmingimpact,threateningtosetbacktheprogress
7,8
againstarangeofinfectiousdiseasestothepreantibioticera .Thewidespreaddrug
resistanceisfurtherexacerbatedbytheretreatofthepharmaceuticalsectorfromnew
9
antibioticdevelopment .Thesechallenges,together,highlightthedemandforalternative
andeffectiveantimicrobialstrategies.
Overthelastfewdecades,theapplicationofnanotechnology,particularlytheuseof
10,11
nanoparticlesfordrugdelivery,hasgeneratedsignificantimpactinmedicine
.Various
nanoparticledeliveryplatforms,especiallyliposomes,polymericnanoparticles,dendrimers,
Correspondingauthor:Tel:8582460999,zhang@ucsd.edu.
Gaoetal.
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andinorganicnanoparticles,havereceivedsignificantattention(Figure1).Drugmolecules
loadedintonanocarriersthroughphysicalencapsulation,adsorption,orchemical
conjugationexhibitanimprovedpharmacokineticprofileandtherapeuticindexwhen
12
comparedtotheirfreedrugcounterparts .Otheradvantagesofnanoparticledelivery
systems,includingimproveddrugsolubility,prolongedsystemiccirculation,sustainedand
controlledrelease,precisedrugtargeting,andconcurrentdeliveryofmultipledrugs,have
13
alsobeenvalidatedinvariousstudies .Asaresult,anumberofnanoparticlebaseddrug
deliverysystemshavebeenapprovedforclinicalusetotreatavarietyofinfectiousdiseases,
andmanyotherantimicrobialnanoparticleformulationsarecurrentlyundervariousstages
14
ofpreclinicalandclinicaltests .
Astheabilitytoengineermultifunctionalnanoparticlescontinuallyadvances,numerous
innovativeapproacheshaveemerged,furtherimprovingonnanoparticletherapeuticefficacy
againstbacterialinfection.Inthisreviewarticle,weselectfiveareaswherenanoparticle
approachesholdsignificantpotentialtoimproveuponcurrenttreatments.Theseareasinclude:
(1)targetedantibioticdelivery,(2)environmentallyresponsiveantibioticdelivery,
(3)combinatorialantibioticdelivery,(4)nanoparticleenabledantibacterialvaccination,and
(5)nanoparticlebasedbacterialdetection.Progressesmadeintheseareasoffer
tremendousopportunitiesforalternativeandmoreeffectiveantimicrobialstrategiesthat
alterthepharmacokineticsofexistingantibiotics,producenewantibioticswithnovel
microbialinhibitionmechanisms,orallowformorerapidandsensitivemicrobial
detection.Collectively,theyaddresstheaforementionedchallengesincludingovercoming
antibioticresistance.Herein,werevieweachareawithhighlightsofthecurrentand
forthcomingnanoparticleplatformsagainstbacterialinfections.
directlystimulatevascularpermeability
.Thesebacterialcomponentsalsoactivate
immunecells,whichinturninteractwithvascularendotheliumthroughmultiple
inflammatoryandvascularmediators,leadingtogapwidening,barrierdysfunction,and
17
eventuallyincreasedpermeability .Moreover,dysfunctionallymphaticdrainagehasalso
beenreportedinbacterialinfection,whichpotentiallypromotesnanoparticleaccumulation
18
atthesitesofinfection .Thesefeaturesofbacterialinfectionsuggestthattheenhanced
permeationandretention(EPR)effectcanbeharnessedbynanoparticlesfortargeted
19
antibioticdelivery .Infact,bothuncoatedliposomesandPEGylatedliposomeshavebeen
showntoaccumulateselectivelyatsofttissueinfectedbyStaphylococcusaureus(S.
2023
aureus),andtheirretentiontimescorrelatedcloselywithsize
.Similarresultswere
observedforsuperparamagneticironoxidenanoparticles(SPIONs)atthesofttissueofrats
24
andinthelungsofmiceinfectedbyS.aureus .
Pathogenicbacteriamaintainanegativesurfacechargeunderphysiologicalconditions.
Therefore,cationicnanoparticlescapableofbindingwithbacteriaviaelectrostatic
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25,26
interactionshavebeenexploredforeffectivebacterialtargeting
.Thisstrategyis
attractiveforitsmultivalenteffectandtheabilitytotargetpolymicrobialinfections.Asa
result,adiverserangeofbactericidalpolymersandpeptideshasbeenincorporatedinto
27
variousnanoparticledesignsforantibacterialapplications .Moreimportantly,
nanoparticleformulationcanincreasethelocalchargeandmassdensitiesofthebactericidal
components,resultinginenhancedtherapeuticindex.Forexample,aselfassembled
cationicpeptidenanoparticlehasshownstrongantimicrobialpropertieswhileinducing
28
minimalsystemictoxicity .Furthermore,improvingthebiodegradabilityofthe
nanoparticlescanfurtherreducecationicchargerelatedtoxicity.Inthisperspective,cationic
nanoparticlesselfassembledfrompolycarbonatebasedblockcopolymerswithhigh
biodegradabilityhavebeenshowntokillbacteriawithoutinducingobvioushemolytic
29
activityandsystemictoxicity .
Activetargetingwithpathogenbindingligandsdirectlyconjugatedtothesurfaceof
nanoparticlesisanotherstrategytotargetbacteria.Forexample,smallmoleculessuchas
30
vancomycinhavebeenconjugatedtothesurfacesofdendrimers ,ironoxide
31
32
33
density,andlengthofthespacerusedinconjugation .Inadditiontosmallmolecules,
lectins,particularlythosewithselectiveagglutinationactivities,havealsobeenusedas
35
ligandstotargetbacteria .Polymericnanoparticlesconjugatedwithmannosespecificor
fucosespecificlectinsshowedenhancedbindingaffinitytothecarbohydratereceptorson
Helicobacterpylori(H.pylori)surfaces,suggestingapromisingapproachforsitespecific
36
andgastroretentivedrugdeliverytotreatH.pyloriinfection .Besideslectins,other
37
38
proteinligandssuchassingledomainantibodies andbacteriophagetailspikeproteins
arehighlyspecifictargetingligandsandtheirconjugationtonanoparticleshasresultedin
targeteddeliveryplatformseffectiveagainstavarietyofbacterialinfections.Furthermore,
aptamershavealsobecomeaclassofattractivetargetingmoietiesowinglargelytothe
advancementinbacteriumbasedaptamerselectiontechniques,whichcontinuallyimprove
aptamerbindingaffinityandspecificity.Thesetargetingmoleculeshavebeenextensively
exploredtotargetnanoparticlestopathogenicbacteriasuchasSalmonellatyphimurium(S.
typhimurium)andMycobacteriumtuberculosis(M.tuberculosis)
39,40
Moreover,bacteriacansurviveingestionbyphagocyticcellssuchasmacrophages,hence
3
evadingtheimmunesystemandthebactericidalactionofantibiotics .Howevermacrophages
41,42
areabletotransportdrugstothesiteofinfectionbyachemotacticmechanism
.
Therefore,targetingantimicrobialnanoparticlestomacrophagesasopposedtobacteriahas
becomeanattractivestrategyforimprovingantibiotictherapy,particularlytotreat
43
intracellularbacterialinfection .Ithasbeenobservedthatfollowingpassivetargetingtothe
infectionsites,nanoparticlescouldpreferentiallybetakenupbymacrophagesduetothe
spontaneousscavengingfeatureofmacrophages
23,24
.Suchmacrophageuptakecouldbe
furtherenhancedbyattachingtargetingligandsontothenanoparticles
variousligands,includingmannose,maleylatedbovine
44,45
.Inthisregard,
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serumalbuminandOsteroylamylopectin,havebeenappliedtosuccessfully
enhancemacrophageuptakeofnanoparticlesforthetreatmentofintracellular
infection
46,47
potential,andenzymaticactivities .
Amongtheseenvironmentalstimuli,pHgradientshavebeenwidelyusedtodesignnovel,
responsivenanoparticlesforantibioticdelivery.Attheorganlevel,nanoparticleshavebeen
49
designedtorespondtothepHgradientalongthegastrointestinal(GI)tract andtheacidic
50
environmentofhumanskin forsitespecificantibioticdelivery.Attheintracellularlevel,
nanoparticleshavebeenformulatedtorespondtotheacidicpHinsidetheendolysosomal
5153
compartmentsfortriggereddrugrelease
.InadditiontopHgradient,bacterialenzymatic
activities,includingthoseofsecretedtoxins,havealsobeenusedtotriggerthereleaseof
antimicrobialagentstoinhibitthegrowthofthetargetbacteria.
Chargedpolymershavebeenadsorbedontoliposomesurfaceswithoppositechargeto
54,55
stabilizetheliposomes
.SuchstabilizationispHsensitiveandhasbeenextensively
usedtotreatvariousintracellularbacterialinfectionsincludingSalmonellaenterica(S.
56,57
58,59
enterica)
aswellascasesofsepticshock
.Basedonasimilarmechanism,ionic
liposomescanbeemployedtocarryoppositelychargeddrugmoleculesforpHsensitive
drugrelease.Inaddition,loadingliposomeswithmembranedisruptingtoxinssuchas
60
hemolysin andlisteriolysinthatareresponsivetoendosomalacidificationhasalso
61
shownpotentialforthetreatmentofintracellularinfections .
Recently,anewenvironmentresponsivedeliverystrategyhasemergedthatinvolvesthe
attachmentofsmallchargednanoparticlesontoliposomesurfacesforliposomestabilizationand
triggeredantimicrobialdelivery(Figure2).Thenonspecificadsorptionofchargednanoparticles
ontophospholipidbilayersprovidedstericrepulsionthatinhibitedliposomefusion.Italso
reducedliposomesurfacetensionandthusfurtherenhancedliposomestability
62,63
Intriguingly,thechargeandchargedensityofboththenanoparticlestabilizersandtheliposomes
couldbepreciselytailoredtoenablestimulusresponsivebindinganddetachmentofthe
nanoparticles,therebyallowingforanondemandcontroloverliposomefusionactivityfor
smartdrugdelivery.Forinstance,cationicliposomesboundwithnegativelychargedgold
nanoparticlesonlyfusedwithbacteriaatacidicpH,whichmadethemsuitablefortreating
variousskinpathogensthatthriveinacidicinfectionsitessuchasthecasewith
64
Propionibacteriumacnes(P.acnes) .Conversely,anionicliposomesstabilizedbypositively
chargedgoldnanoparticleswerehighlystableingastricacid,butcapableoffusingwithbacteria
65
atphysiologicalpH,makingthemsuitabletotreatgastricpathogenssuchasH.pylori .Even
intheabsenceofsuchstimulusinduceddetachmentofthenanoparticlestabilizers,these
liposomesstillhadasubstantialfractionof
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theirsurfaceareasexposedandhighlyaccessibletobacterialtoxins.Thisfeature
allowedtheliposomestorespondtovariousbacteriasuchasS.aureusthatsecretpore
66
formingtoxinstotriggerdrugreleasefromtheliposomes .Aimedatimprovingthe
topicalapplicationsofnanoparticlestabilizedliposomes,ahydrogelformofthedelivery
systemwasrecentlydeveloped,whichnotonlypreservedthestructuralintegrityofthe
nanoparticlestabilizedliposomes,butalsoallowedforcontrollableviscoelasticityand
67
tunableliposomereleaserate .
Meanwhile,polymericnanoparticleshavebeenextensivelystudiedforresponsiveantibiotic
delivery.Forexample,triblockcopolymernanoparticlescomposedofpoly(lacticco
glycolicacid)(PLGA),poly(Lhistidine)andpoly(ethyleneglycol)(PEG)havebeen
68
reportedforacidresponsiveantibioticdelivery .Thesenanoparticlesmaintaineda
negativechargeatneutralpH;however,whenexposedtoanacidicpH,theprotonationof
theimidazolegroupsswitchedthesurfacechargetoapositiveone,resultinginenhanced
bacterialbindingandimprovedantibacterialefficacy.Asanotherexample,heparinand
chitosanhavebeenappliedtoformbasesensitivenanoparticlesfortreatinggastric
pathogenssuchasH.pylori.ThepolymersselfassembledtoformnanoparticlesatpH1.2
2.5;however,uponcontactwithH.pyloriatthegastricepitheliumwithphysiologicalpH,
thechitosandeprotonated,causingnanoparticledisassemblyandreleaseofdrugsfor
69
bacteriakilling .Moreover,bytailoringthepKaofamphiphiliccopolymers,awiderange
ofpolymericnanoparticleshasbeenengineered,whichpreciselyrespondtothesubtle
changesofpHalongtheGItractforsitespecificantibioticdelivery.Enzymesensitive
polymericnanoparticleshavealsobeendevelopedforintracellulardeliveryinmacrophages.
Forexample,atriplelayerednanogelformulationhasbeenreported,whichcontaineda
bacteriallipasesensitivepoly(caprolactone)interlayerbetweenthecrosslinked
70
polyphosphoestercoreandthePEGshell .Followingmacrophageuptake,thepresenceof
bacterialphosphataseorphospholipasetriggeredrapiddrugrelease,whichsubsequently
47
inhibitedthegrowthofS.aureus .
Combiningtwoormoredistinctantibioticsrepresentsacommonstrategyintreating
bacterialinfectionswiththeaimtobroadentheantimicrobialspectrum,generatesynergistic
effects,andcounteractantibioticresistance.However,varyingpharmacokinetics,
biodistributions,toxicityprofiles,andmembranetransportpropertiesamongdifferentdrug
compoundscomplicatedosingandschedulingoptimization,whichinturncompromisedrug
71
synergyinvivo .Inthisregard,nanoparticlesofferuniquepropertiestoenhance
combinatorialantibioticdeliveryandnumerousapplicationshavebeeninvestigatedto
addressavarietyofbacterialinfections(Table1).
Liposomesareahighlyversatileplatformforcombinatorialdelivery.Hydrophilicdrugscan
bedirectlyencapsulatedintheaqueouscompartmentsofliposomes,whilehydrophobic
72
drugscanbeincorporatedintothelipidbilayermembranes .Forexample,isoniazidand
rifampicin,firstlineantituberculardrugs,havebeenloadedintheaqueouscompartment
andthelipidbilayer,respectively.Theresultingliposomalformulationhasshownincreased
efficacycomparedtofreedrugcounterpartsatthesamedosages
7375
.Liposomal
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formulationcanalsoreducedrugtoxicitytothehostcells,therebyallowingforcodelivery
ofcombinatorialantibioticsthatareotherwisetootoxicintheirfreeforms.Forexample,
drugcompoundssuchasgallium(Ga)andbismuthderivativesareantibioticsthatinhibit
bacterialgrowthbyinterruptingtheirironuptake.Althoughtheyhaveshownsynergetic
effectsincombinationwithotherantibiotics,theirusagehasbeenlimitedbysevere
76
3+
resistantPseudomonasaeruginosa(P.aeruginosa) .Similarly,bismuthethanedithiol
(BiEDT)wasencapsulatedtogetherwithtobramycinintoliposomes,resultinginthe
eliminationofBiEDTstoxiceffectonhumanlungcellswhileincreasingitsantibacterial
7880
efficacyagainstP.aeruginosaandBurkholderiacepacia(B.cepacia)
.Arecentin
vivostudyshowedthatthesamedrugcombinationinaliposomeformulationenhanced
81
efficacyinreducingbacterialburdeninratschronicallyinfectedwithP.aeruginosa .
Moreover,liposomalformulationofcombinatorialantibioticsenablesratiometriccontrol
overthedrugsandthusunifiesthepharmacokineticsofdifferentdrugmoleculesandensures
paralleltissuedistribution.Theseadvantagesservetoenhancetheantimicrobialefficacyof
thedrugs.Forexample,usingthedosageanddosingschedulederivedfrominvitrostudies,
thecoadministrationofgentamicinandceftazidimeonlyresultedinanadditiveeffectina
82
ratmodelofanacuteunilateralKlebsiellapneumoniae(K.pneumoniae)infection .In
contrast,thecorrespondingliposomalformulationencapsulatingbothgentamicinand
ceftazidimeshowedasynergisticeffectthatledtoashortercourseoftreatmentatlower
83
cumulativedoses .Thebenefitofratiometricdeliveryusingliposomeswasalsoreported
84,85
inothercombinationtherapiesintreatingS.aureus
Mycobacteriumavium(M.avium)
86,87
,andH.pylori
,M.tuberculosis
73,74
88,89
Polymericnanoparticlesrepresentanotheremergingplatformforcombinatorialantibiotic
deliverytotreatbacterialinfection.Ingeneral,drugmoleculescanbedirectlyencapsulatedinto
thepolymericcores.Forpreciseratiometricloadingandcontrolleddrugrelease,multipledrugs
canbecovalentlyconjugatedtothepolymerbackbonefollowedbynanoparticlepreparation
90
92
.Inaddition,usingemulsiontechniques,bothhydrophobicandhydrophilicdrugmolecules
93,94
canbecoencapsulatedintothepolymericcores
.Asaresult,severalpolymeric
nanoparticlesystemshavebeenreportedfordeliveringantibioticcombinations.Forexample,the
combinationofrifampinandazithromycinwasdeliveredwithPLGAnanoparticlesandshowed
95
betterefficacyinvitrocomparedtofreedrugsintreatingpersistentchlamydialinfection .
Nanoparticlesmadeofgliadin,avegetalproteincommonlyderivedasafractionofwheatgluten,
wereusedtocoencapsulateclarithromycinandomeprazole,whichachievedbetterefficacy
againstH.pyloribacteriainrats
96,97
.Thegliadinnanoparticleswerefurtherconjugatedwith
98
lectinandusedintripletherapywithamoxicillin,clarithromycin,andomeprazole ,resultingin
superiorinvivoclearanceofH.pyloricomparedtothenonconjugatedformulationandfree
drugs.Moreover,PLGAnanoparticleswerealsousedfororaldeliveryofantituberculosisdrugs
99,100
(ATDs)
.In8)thesestudies,threeorfourfrontlineATDs,includingrifampicin,isoniazid,
pyrazinamideandethambutol,werecoencapsulatedinsidePLGAnanoparticlesthroughan
emulsion
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technique,andtheresultingnanoparticleformulationimprovedbacterialclearancein
M.tuberculosisinfectedmiceandguineapigsviaoraladministration.
consideredasthemosteffectivepublichealthinterventioneverachieved
.The
vaccinestrategyalsoholdsthepromisetohaltantibioticresistancebyreducingthe
103,104
exposureofbacteriatowidelyusedantimicrobialagents
.However,themajorityof
existingvaccinespredominantlydrivethegenerationofneutralizingoropsonizing
antibodiesagainstpathogens,amechanismthatisineffectiveagainstanumberof
105
infections .Vaccinedevelopmentagainstthesediseasesisfurtherhamperedby
incompleteunderstandingoftheenormouslycomplexhumanimmunesystemandthe
underlyingmechanismsofprotection
106
.Toaddressthesechallenges,nanoparticlesoffer
uniqueadvantagesforimmunemodulationagainstbacterialinfections
107,108
Nanoparticleshavebeenextensivelyexploredtoovercometheinstability,undesirable
systemicbiodistribution,andtoxicityfrequentlyassociatedwiththeadministrationofsoluble
molecules
109,110
.Ithasbeenreportedthatconjugationofantigenstonanoparticlesurfaces
facilitatedBcellactivation
111
,duetoahigherquantityofantigensthatweredeliveredto
112
antigenpresentingcells(APCs) .Withtheadvancementinnanoparticleengineering,
fabricationtechniqueslongestablishedformanufacturingnanoparticlebaseddrugdelivery
systemsincludinglayerbylayerassembly
113,114
,facilespraydryingprocess
115
,andsoft
116
lithographybasedPRINTtechnology havealsobeenincreasinglyappliedtoimproveon
antigenloading.Recently,naturalcellularmembranecoatednanoparticleshavealsobeen
showntodetainmembranedamagingtoxinsanddivertthemawayfromtheircellular
117,118
targets
.Suchatoxindetainmentstrategywasappliedtosafelydeliverintact
staphylococcalhemolysintoAPCsandinducedsuperiorprotectiveimmunityagainsttoxin
mediatedadverseeffectsinmicewhencomparedtovaccinationwithheatdenaturedtoxins
119
(Figure3) .Thisapproachmaintainedafaithfulantigenicpresentationwhileremoving
toxinvirulence,thereforeavoidingthetradeoffbetweenefficacyandsafetythatremainsa
majorchallengeofcurrenttoxoiddevelopment.
Besidesdeliveringantigens,nanoparticlescanconcurrentlycarryadjuvantstomimicnatural
120,121
microbesforenhancedvaccinationefficacy
.Particularly,varioustolllikereceptor(TLR)
ligandsincludingsmallmolecules,carbohydrates,DNAs,andRNAs,togetherwithantigenshave
beendeliveredusingnanoparticles,resultinginequivalentimmuneresponsescomparedto
122125
solubleantigenformulationsbutatsignificantlyreduceddosages
.Moreimportantly,
nanoparticlesallowforprogrammablepresentationofadjuvantsandantigenstoimmunecellsfor
desirableresponses.Forexample,combinationsofTLRagonists,asopposedtoasingleadjuvant,
havebeenconcurrentlyloadedintonanoparticlestomimicthecombinatorialTLRactivationthat
126128
occursinnaturalinfections,thereforeresultinginmorevigorousimmuneresponses
.In
addition,nanoparticlesallowforthesequentialpresentationofantigensandadjuvantstobe
programmedforoptimalimmuneresponses.Forexample,encapsulationofantigensandTLR
agonistsintothesamenanoparticleshasshown
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advantagesfortheinductionofeffectorTcellresponses
antigenprocessingoccursindendriticcells
130,131
124,129
duetothemannerinwhich
.Incontrast,deliveryofantigensandTLR
132
agonistsinseparatenanoparticlesseemedtobenefitantibodyresponses .Recentadvancement
incontrollingtheintrananoparticlearchitectureandadjuvantdistributionhasprovided
133
additionalcapabilityforprogrammingnanoparticlebasedimmunemodulation .Forexample,
whenaninterbilayercrosslinkedmultilamellarvesicleswereusedassyntheticvaccines,the
TLR4agonistmonophosphoryllipidA(MPLA)wasincorporatedthroughoutthevesiclelayers
andelicitedstrongerserumIgGtitresascomparedtothevesiclescarryingthesameamountof
MPLAbutattachedonlyonthevesiclesurfaces(Figure4)
134
Targetingvaccinestodesiredsitesforsafeandeffectiveimmuneresponsesisanother
advantageofusingnanoparticlesforvaccinedelivery.Forexample,acationicnanogel
loadedwithasubunitfragmentofClostridiumbotulinum(C.botulinum)typeAneurotoxin
hasbeenshowntofacilitatepersistentantigenadherencetothenasalepitheliumand
135
effectiveuptakebymucosaldendriticcells .Thisplatformnotonlyelicitedstrong
systemicandmucosalimmuneresponses,butalsopreventedexposureoftheupper
respiratorytractandthecentralnervoussystemtotoxicantigens.Asanotherexample,
nanoparticlesresponsivetothepHgradientoftheGItracthavebeenabletoprotectantigens
whileinthestomachbutreleasetheminthelowerGItractforsubsequenttranslocation
acrosstheintestinalepithelium
136
.Asimilarstrategyhasalsoshownpromisefortargeting
137
antigentranscytosingMcellsoverlyingPeyerspatchesforfurtherenhancedimmunity .
Inaddition,nanoparticlebasedvaccineplatformscaneffectivelytargetlymphnoderesiding
immunecells.Ithasbeenshownthatsmallernanoparticlestransportfastertothelymph
138
139
designedtoescapeendosomesfollowingtheiruptakebyAPCs
.Thesenanoparticles
specificallydepositedvaccinepayloadsintothecytosolandshowedpromisetoenhance
CD8+Tcellpriming.
Rapidandsensitivebacterialdetectioniscrucialforidentificationoftheinfectionsource,
allowingfortreatmentwiththeappropriateantibioticsandthuspreventingthespreadofthe
143,144
disease
.Bacterialcultureandbiochemicalstainingremainthecurrentgoldstandard
intheclinicdespitelaboriousprocessing,longproceduraltimesandlimitationsin
identifyingcertainpathogenicspecies.Amongthevariousexistingdiagnosticapproaches,
thosebasedonpolymerasechainreaction(PCR)andsequencinghaveshownparticular
145,146
promiseashighlysensitivetoolsformicrobialidentification
.However,quantitative
realtimePCRbasedsystemsareoftentooexpensiveinresourcelimitedsettings,andthe
147,148
currentsequencingtechniquesstilllackpracticalapplicabilityforpatientcare
.In
thisregard,nanoparticlesofferuniqueopportunitiesforgeneric,accurateandpointofcare
detectionofpathogens
149,150
Usingconventionalorganicfluorophoresforbacterialdetectionislimitedbythe
moleculesshortlifetimeandlowsensitivity.Toovercomethesechallenges,silica
nanoparticleshave
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beenusedtoencapsulatethousandsoffluorescentmoleculesinasingleparticle,resultingin
151
significantlystrongerfluorescencesignals .Thisstrategyhasresultedinultrasensitive
bacterialdetectionatasinglecelllevel.Meanwhile,semiconductorquantumdots(QDs)have
alsoemergedasapromisingclassoffluorophoresforbacterialdetection.Comparedtoorganic
fluorephores,QDsarebrighterandmorestable;theyalsoexhibitbroadabsorptionandnarrow
152
emissionspectra,apropertyusefulforsimultaneousexcitationanddetection .Ligand
conjugatedQDshavebeenextensivelyexploredforthedetectionofvariousbacteria,including
Escherichiacoli(E.coli),S.typhimurium,Mycobacteriumbovis(M.bovis),andoral
153155
bacteria
.Additionalstrategieshavebeenexploredtofurtherimprovethesensitivityof
QDbasedbacterialdetectionsystems.Forexample,thebindingaffinityofQDscoatedwith
zinc(II)dipicolylaminecoordinationcomplexes,abacterialligand,hasbeenshowntocorrelate
156
tothesizeoftheQDs .Basedonthisobservation,QDswithtailoredsizeshavebeen
developedtodistinguishdifferentmutantsofthesamebacterialspecies.Asanotherexample,
streptavidincoatedQDshavebeenusedtolabelengineeredbacteriophagesfollowinganinvivo
157
amplificationandbiotinylationprocess .Thismethodenabledspecificdetectionofasfewas
10bacteriapermilliliterintestingsamples.
Besidesfluorescencebaseddetectiontechniques,ironoxidenanoparticleshavereceived
158,159
muchattention,owinglargelytotheirintrinsicmagneticproperties
.Ironoxide
nanoparticlescoatedwithpathogenspecificantibodieshavebeenwidelyusedtoisolate
160,161
livingbacteriafromhumanbloodsamplesunderamagneticfield
.Morerecently,
thistechniquehasbeencoupledwithmicrofluidictechnologyandhasresultedinhigh
162164
throughputbacterialdetectionundervariousclinicalsettings
.Meanwhile,
paramagneticironoxidenanoparticlesthatallowforsignalreadoutwithmagnetic
resonanceimaging(MRI)systemshavebecomeanattractivenewoptionforultrasensitive
bacterialdetection.Forinvitrodiagnosis,ironoxidenanoparticleswithadiameterof21nm
havebeencoupledwithaDNAhybridizationtechniquetoenhancethecapturingof
bacterial16SrRNAswithaminiaturizedmicroNMRsystem,resultinginrapidandspecific
165
pathogenprofilinginclinicalsamples(Figure5) .Forinvivodiagnosis,ironoxide
nanoparticleshavealsobeenexploredtodetectavarietyofpathogenicbacteriainanimal
models,wherethehighspatialresolutionandexcellentsofttissuecontrastofMRIprovided
informationonbothbacteriallocalizationandcorrespondinghostresponses
166
Goldnanoparticlesareanotheremergingnanoparticleplatformforbacterialdetection.These
nanoparticlespossessstronglightscatteringpropertiesandchangetheirplasmonresonance
spectrumuponaggregation.Thisphenomenonhasbeenwidelyexploredforthedetectionof
167
bacteriaspecificDNAs,proteins,andlivebacteria .Forexample,individualgold
nanoparticleshavebeenpreciselycrosslinkedwithswitchablelinkers,whichweredesignedto
168
breakinthepresenceoftargetsubjects .Asaresult,thisdesignamplifiedthepathogen
inducednanoparticleaggregationdispersionprocessandallowedforvisibledetectionofE.coli
ataconcentrationof100CFU/mL.Inaddition,goldnanoparticlescannonspecificallyquench
fluorescentmolecules.Basedonthisphenomenon,afluorophoredisplacementstrategyhasbeen
169
developedforbacterialdetection .Inthisstrategy,goldnanoparticlesadsorbedwith
fluorescentpolymerssuchaspoly(paraphenyleneethynylene)andpolylysineselectively
interactedwithbacteriaandreleasedtheboundfluorescentpolymerswhichwere
WileyInterdiscipRevNanomedNanobiotechnol.Authormanuscript;availableinPMC2015November01.
Gaoetal.
Page10
initiallyquenchedbythegoldnanoparticles.Therecoveredpolymerfluorescenceallowed
fortheeffectiveidentificationofbacteriawithinminutes.
Recently,rapidprogresshasbeenmadebyintegratingnanoparticlebasedmicrobial
detectionintominiaturizeddevicessuchasmicrofluidicsystemsandlabonachipfor
broaderapplications
170
.Thesedevicespotentiallyperformassayswithadequate
163,171
sensitivity,specificityandreproducibility,yetdemandlittleuserinput
.The
combinationofnanoparticlebaseddetectionprincipleswithsuchdevicesprovide
unprecedentedopportunitiesinunderdevelopedregionstoperformroutinetests,detectthe
presenceofaninfectiousagentwithepidemicpotential,andprovideguidanceforthe
regionaldiseasecontrol.
7. Conclusions
Theadventofnanotechnology,particularlynanoparticleengineering,togetherwiththe
accumulationofknowledgeoninfectiousdiseases,hasallowedforsignificantadvancement
inthefieldofantibacterialdrugdelivery.Majoreffortshavebeendevotedtodeveloping
variousnanoparticlebaseddeliveryplatformsincludingliposomes,polymericnanoparticles,
dendrimers,andinorganicnanoparticles.Thesenanoparticleapproacheshaveshown
excellentoutcomesintreatinganddetectingbacterialpathogensbyenablingtargeted,
responsive,andcombinatorialdeliveryofantibiotics,effectiveantibacterialvaccination,and
rapiddetectionofbacteria.Itisexpectedthatnanotechnologywillcontinuebringing
improvementstoantimicrobialdeliverysystemsforefficacious,patientcompliant,andcost
effectivetherapeuticsaswellasthespecificandsensitivedetectionofvariousinfectious
diseases.
Acknowledgments
ThisworkissupportedbytheNationalInstituteofDiabetesandDigestiveandKidneyDiseasesofthe
NationalInstitutesofHealthunderAwardNumberR01DK095168.
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Figure1.
Schematicillustrationofmajornanoparticlebaseddeliveryplatformsfortreating
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inorganicnanoparticle.
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Figure2.
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Page21
Schematicpreparationofnanoparticledetainedtoxins,denotednanotoxoid,consistingof
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Page22
Schematicillustrationofinterbilayercrosslinkedmultilamellarvesicles(ICMVs)for
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Gaoetal.
Page23
Figure5.
MagnetoDNAassayforthedetectionofbacterial16SrRNA.TotalRNAisextractedfrom
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byhybridizingwithMNPstoformamagneticsandwichcomplex.Samplesaresubsequently
analyzedusingaminiaturizedmicroNMR(NMR)system.Reproducedwithpermission
fromreference165.
Wile
yInterdiscipRevNanomedNanobiotechnol.Authormanuscript;availableinPMC2015November01.
Gaoetal.
Page24
Table 1
Combinatorialnanoparticlesforantibacterialdrugdelivery
Platform
Formulation
DrugCombination
Targetedbacteria
References
DPPC,DMPGand
cholesterol
Galliumandgentamicin
P.aeruginosa
[77]
DSPCandcholesterol
Bismuthethanedithiol(BiEDT)and
tobramycin
P.aeruginosaandB.
cenocepacia
[78]
PEGylatedliposome
Daptomycinandclarithromycin
MRSA
[85]
PG,PCandcholesterol
Clarithromycinandofloxacin
M.avium
[86]
PC,SA,andcholesterol
Ciprofloxacinandvancomycin
MRSA
[84
PC,PEGDSPE,and
cholesterol
Gentamicinandceftazidime
K.pneumoniae
[83]
DPPCandcholesterol
Isoniazidandrifampicin
M.turberculosis
[75]
PG,PCandcholesterol
Streptomycinandandciprofloxacin
M.avium
[87]
PC,PE,SAandcholesterol
Amoxicillintrihydrateandranitidine
bismuthcitrate
H.pylori
[88]
PAA,PAH,PC,and
cholesterol
Amoxicillinandmetronidazole
H.pylori
[89]
PLGA
Rifampinandazithromycin
C.trachomatisandC.
pneumoniae
[95]
PLGA
Rifampicin,isoniazid,pyrazinamide,
andethambutol.
M.tuberculosis
[99]
Sodiumalginateandchitosan
Rifampicin,isoniazid,pyrazinamide,
andethambutol.
M.tuberculosis
[100]
Chitosanandglutamicacid
Amoxicillin,clarithromycin,and
omeprazole
H.pylori
[97]
GliadinandPluronicF68
Clarithromycinandomeprazole
H.pylori
[98]
Gliadin,lectinandPluronic
F68
Amoxicillin,clarithromycinand
omeprazole
H.pylori
[96]
Liposomes
Polymericnanoparticles
Acronyms:
DPPC:1,2dipalmitoylsnglycero3phosphocholine,
DMPG:1,2dimyristoylsnglycero3phosphoglycerol
DSPC:1,2distearoylsnglycero3phosphocholine
DSPE1,2distearoylsnglycero3phosphoethanolamine
DPPC:dipalmitoylphosphatidylcholine
PG:eggyolkphosphatidylglycerol
PE:phosphatidylethanolamine
PC:phosphatidylcholine
SA:stearylamine
PLGA:poly(lacticacidcoglycolicacid)
PAA:poly(acrylicacid)
PAH:poly(allylaminehydrochloride)
WileyInterdiscipRevNanomedNanobiotechnol.Authormanuscript;availableinPMC2015November01.