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NANOTOXICITY NANOTOXICITY PREVENTIONAND ANTIBACTERIALAPPLICATIONS OFNANOMATERIALS Editedby
SusaiRajendran
PSNACollegeofEngineeringandTechnology,Dindigul,India
AnitaMukherjee
DepartmentofBotany,CentreofAdvancedStudy,UniversityofCalcutta, Kolkata,India
TuanAnhNguyen
InstituteforTropicalTechnology,VietnamAcademyof ScienceandTechnology,Hanoi,Vietnam
ChandraiahGodugu
DepartmentofRegulatoryToxicology,NationalInstituteofPharmaceutical EducationandResearch(NIPER),Balanagar,India
RiteshK.Shukla
SchoolofArts&Sciences,AhmedabadUniversity,Gujarat,India
Elsevier
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BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-12-819943-5
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ListofContributorsix
Forewordxiii
PART1 Basicprinciples
1.Nanoparticle physiologicalmedia interactions3
R.Dorothy,N.Karthiga,S.SenthilKumaran,R.JosephRathish, SusaiRajendranandGurmeetSingh
1.1Introduction3
1.2Recentadvancesontheinteractionof nanoparticleswithbiologicalmedia5 References18
2.Invitromethodstoassessthecellular toxicityofnanoparticles21
KrupaKansaraandAshutoshKumar
2.1Introduction21
2.2Materialsandmethods23
2.3Conclusion38
Acknowledgments38 References38
3.Invivostudies:toxicityand biodistributionofnanocarriersin organisms41
NivyaSharma,MohdAslamSaifi,ShashiBalaSinghand ChandraiahGodugu
Listofabbreviations41
3.1Generaloverview43
3.2Typesofnanocarriers44
3.3Polymericmicelles56
3.4Dendrimers57
3.5Liposomes62
3.6Conclusion63
3.7Futuredirections64 References64
4.Standardbiologicalassaystoestimate nanoparticletoxicityand biodistribution71
JuhiShah,StutiBhagatandSanjaySingh
4.1Introduction71
4.2Invitromethodsfordeterminationof nanoparticletoxicity72
4.3Invivobio-distributionandtoxicityof nanoparticles85
4.4Conclusionandfutureaspects96 Acknowledgments96 Conflictofinterest97 References97
PART2 Toxicityofnanomaterials 5.Toxicityofmetaloxide nanoparticles107
ThodhalYoganandhamSuman,Wei-GuoLiand De-ShengPei
5.1Introduction107
5.2Metaloxidenanoparticles107
5.3Zincoxidenanoparticles108
5.4IronOxide-basedmagneticnanoparticles110
5.5TitaniumdioxideNanoparticles112
5.6Copperoxidenanoparticles114
5.7Toxicitymechanismofmetaloxide nanoparticles115
5.8Conclusion118 Acknowledgments118
Conflictsofinterest118
References119
Furtherreading122
6.Toxicityofsilverandother metallicnanoparticles125
T.Umasankareswari,GurmeetSingh,S.SanthanaPrabha, AbdulhameedAl-Hashem,S.SenthilKumaranand SusaiRajendran
6.1Introduction125
6.2Toxicityofsilvernanoparticles126
6.3Toxicityofgoldnanoparticles128
6.4Toxicityofcoppernanoparticles132
6.5Toxicityofironnanoparticles136
6.6Toxicityofzincnanoparticles137
6.7Conclusion139
Acknowledgment140
References140
7.Recentadvancesinthestudyof toxicityofpolymer-based nanomaterials143
A.SuriyaPrabha,R.Dorothy,S.Jancirani,SusaiRajendran, GurmeetSinghandS.SenthilKumaran
7.1Introduction143
7.2Recentadvancesinthestudyoftoxicityof polymericnanomaterials144
7.3Concludingremarks163 References163
8.Toxicityofpolymeric nanomaterials167
YubinLi,ShaofeiWangandDianwenJu
8.1Introduction167
8.2Classificationofpolymeric nanomaterials168
8.3Invitrotoxicityofpolymeric nanomaterials172
8.4Invivotoxicityofpolymeric nanomaterials174
8.5Mechanismsofpolymericnanomaterialsinducedtoxicity179
Acknowledgments185
Conflictofinterest186
References186
PART3 Preventionofnanotoxicity 9.Generalmethodsfordetectionand evaluationofnanotoxicity195 HaniNasserAbdelhamid
9.1Introduction195
9.2Generalnanotoxicitymethods196
9.3Mechanismofantibacterialactivities198
9.4Methodsfordetectionandevaluationof nanotoxicity198
9.5Conclusionandoutlooks208
Acknowledgment209 References209
10.Safer-by-designfornanomaterials215 L.Reijnders
10.1Introduction215
10.2Hazardandreleasereductionforengineered nanomaterialsinproductionand products217
10.3Reducingreleasestotheenvironmentfrom nanomaterialproductionandprocessing facilities217
10.4Safer-by-designhazardreductionofengineered inorganicandcarbonaceousnanomaterialsfor organisms218
10.5Reducingreleasestotheenvironmentof nanomaterialsfromrelativelylarge nanocompositesandproducts224
10.6Reducinghazardsoffragmentsreleasedfrom nanocomposites227
10.7Conclusions228 References228
PART4 Antibacterialactivityofnanomaterials
11.Antibacterialactivityofmetaloxide nanoparticles241
VojislavStani ´ candSladjanaB.Tanaskovi ´ c
11.1Introduction241
11.2EffectivephysicochemicalpropertiesofMONPsonantibacterialactivity242
11.3Antibacterialactivityofmagnesiumoxideand calciumoxidenanoparticles250
11.4Antibacterialactivityofaluminumoxide nanoparticles253
11.5Antibacterialactivityofsilveroxide nanoparticles254
11.6Antibacterialactivityofcopperoxide nanoparticles255
11.7Antibacterialactivityofzincoxide nanoparticles258
11.8Antibacterialactivityofironoxide nanoparticles261
11.9Antibacterialactivityoftitaniumoxide nanoparticles263 Acknowledgements266 References266
12.Antibacterialactivityofplatinum nanoparticles275
SusaiRajendran,S.SanthanaPrabha,R.JosephRathish,Gurmeet SinghandAbdulhameedAl-Hashem
12.1Platinumnanoparticles275
12.2Antibacterialactivity275
12.3Antibioticsandantimicrobial compounds276
12.4Determinationofthemicrobial activity276
12.5Recenttrendsintheantibacterialactivityof platinumnanoparticles276 References280
13.Antibacterialpropertyofmetal oxide-basednanomaterials283
MdAbdusSubhan
13.1Introduction283
13.2Mechanismofantimicrobialresistance285
13.3MethodstoevaluateMO-NPsantibacterial efficiency285
13.4Antimicrobialeffectofmetalandmetal oxidenanoparticles287
13.5Modeofantimicrobialactionbymetaland metaloxidesnanoparticles288
13.6Nanoparticlecharacteristicsandtheir influenceonantimicrobialactivity292
13.7Metaloxide-basedantibacterial membrane293
13.8Antibacterialfunctionsofmulti-metaloxide nanoparticles294
13.9Magneticbio-metaloxidemagnetosome296
13.10ToxicityconcernsofMO-NPsas antimicrobialagents297
13.11Conclusions,challenges,andfuture perspectives298 References299
14.Antimicrobialpropertiesofcarbon quantumdots301
TheodorosChatzimitakosandConstantineStalikas
14.1Introduction301
14.2Antibacterialpropertiesofcarbon nanodots302
14.3Conclusion313 References313
PART5 Emergingantibacterialandantifungal applications 15.Applicationsofnanotechnologyin agry-foodproductions319
J.L.Castro-Mayorga,L.Cabrera-Villamizar,J.Balcucho-Escalante, M.J.FabraandA.Lo ´ pez-Rubio
15.1Introduction319
15.2Nanoencapsulationtechniquesappliedtofood andagriculture320
15.3Nanosensorsinfoodandagriculture328
15.4Nanotechnologyappliedtoenvironmental remediation331
15.5Manufactureofprotectiveclothesforfarm workers332
15.6Conclusionandoutlooks333 References333 Furtherreading340
16.Nanoparticleapplicationsin sustainableagriculture,poultry,andfood: trendsandperspective341
N.ChandraMohana,P.R.Mithun,H.C.YashavanthaRao, C.MahendraandS.Satish
16.1Introduction341
16.2Nanoparticleapplicationsinagriculture342
16.3Nanoparticleapplicationsinpoultry347
16.4Nanoparticleapplicationsinfood347
16.5Nano-biosensorssustainableagriculture, poultry,andfood348
16.6Regulatoryaspectsofnanotechnologyin agriculture,poultry,andfood348
16.7Conclusionandfutureperspectives350 Conflictsofinterest351 References351
17.Antibacterialnanocomposite coatings355
TienVietVu,VanThangNguyen,PhuongNguyen-Tri,TheHuu Nguyen,ThienVuongNguyenandTuanAnhNguyen
17.1Introduction355
17.2Inorganicnanocompositecoating356
17.3Organicnanocompositecoating357
17.4Environmentalbenefitsandimpactsof antibacterialnanocompositecoatings360 References360
18.Antimicrobialnanomaterialsforwater disinfection365
NidhiVerma,SachinVaidh,GajendraSinghVishwakarmaand AlokPandya
18.1Introduction365
18.2Significanceofnanotechnology366
18.3Antibacterialmetaloxidesandmetal nanoparticles367
18.4Mechanismsfornanoparticle-mediated microbialdisinfection373
18.5Advancedtechnologiesfornanoparticle-based waterdisinfection375
18.6Somecommercializedproductsandtheir information377
18.7Currentstatusoftechnologytransfer,scaleup, andchallenges378 Acknowledgment379 References379
19.Nanomaterialsforantifungal applications385
K.Kavitha,N.Vijaya,A.Krishnaveni,M.Arthanareeswari,Susai Rajendran,AbdulhameedAl-HashemandA.Subramania
19.1Introduction385
19.2Recenttrendsinthestudyofantifungal activitiesofnanoparticles387 References397
20.Antibacterialnanocoatings399 MajidMontazerandTinaHarifi
20.1Introduction399
20.2Novelandsmartantibacterialnanocoating approaches400
20.3Applicationsofantibacterial nanocoatings403
20.4Safetyandtoxicologicalissues409
20.5Conclusion410 References411 Furtherreading413
21.Emergingantibacterialandantifungal applicationsofnanomaterialsonfood products415
DılhunKerimanArserim-Uc¸arandBurcuC¸abuk
21.1Introduction415
21.2Organicnanomaterialapplications417
21.3InorganicNanomaterialApplications435
21.4Conclusion439 References440 Furtherreading453
Index455
ListofContributors HaniNasserAbdelhamid AdvancedMultifunctionalMaterialsLaboratory,Department ofChemistry,AssiutUniversity,Assiut,Egypt
AbdulhameedAl-Hashem PetroleumResearchCentre,KuwaitInstituteforScientific Research,Safat,Kuwait
DılhunKerimanArserim-Uc¸ar FoodEngineeringDepartment,FacultyofEngineering andArchitecture,Bingo ¨ lUniversity,Bingo ¨ l,Turkey
M.Arthanareeswari PGandResearchDepartmentofChemistry,SRMUniversity, Chennai,India
J.Balcucho-Escalante NanobiotechnologyandAppliedMicrobiologyResearchGroup (NANOBIOT),UniversityoftheAndes,Bogota ´ ,Colombia
StutiBhagat DivisionofBiologicalandLifeSciences,SchoolofArtsandSciences, AhmedabadUniversity,Ahmedabad,Gujarat,India
L.Cabrera-Villamizar NanobiotechnologyandAppliedMicrobiologyResearchGroup (NANOBIOT),UniversityoftheAndes,Bogota ´ ,Colombia
BurcuC¸abuk GastronomyandCulinaryArtsDepartment,ArtsandDesignFaculty, AlanyaHamdullahEminPa¸saUniversity,Antalya,Turkey
J.L.Castro-Mayorga NanobiotechnologyandAppliedMicrobiologyResearchGroup (NANOBIOT),UniversityoftheAndes,Bogota ´ ,Colombia
TheodorosChatzimitakos LaboratoryofAnalyticalChemistry,Departmentof Chemistry,UniversityofIoannina,Ioannina45110,Greece
R.Dorothy DepartmentofEEE,AMETUniversity,Chennai,India
M.J.Fabra FoodSafetyandPreservationDepartment,InstituteofAgrochemistryand FoodTechnology(IATA-CSIC),Valencia,Spain
ChandraiahGodugu DepartmentofRegulatoryToxicology,NationalInstituteof PharmaceuticalEducationandResearch(NIPER),Hyderabad,India
TinaHarifi DepartmentofTextileEngineering,FunctionalFibrousStructures& EnvironmentalEnhancement(FFSEE),AmirkabirUniversityofTechnology,Tehran, Iran
S.Jancirani PGandResearchDepartmentofChemistry,MVMGovernmentCollegefor Women,Dindigul,India
DianwenJu DepartmentofMicrobiologicalandBiochemicalPharmacy;TheKey LaboratoryofSmartDrugDelivery,MinistryofEducation,SchoolofPharmacy,Fudan University,Shanghai,P.R.China
KrupaKansara DivisionofBiologicalandLifeSciences,SchoolofArtsandSciences, AhmedabadUniversity,Ahmedabad,India
N.Karthiga DepartmentofChemistry,SBMCollegeofEngineering,Dindigul,India
K.Kavitha PGandResearchDepartmentofChemistry,NationalCollege,Trichy,India
A.Krishnaveni DepartmentofChemistry,YadavaCollege,Madurai,India
AshutoshKumar DivisionofBiologicalandLifeSciences,SchoolofArtsandSciences, AhmedabadUniversity,Ahmedabad,India
S.SenthilKumaran SchoolofMechanicalEngineering,VITUniversity,Vellore,India
Wei-GuoLi CollegeofLifeScience,HenanNormalUniversity,Xinxiang,P.R.China
YubinLi DepartmentofNeurology,XinqiaoHospital,ThirdMilitaryMedical University,Chongqing,P.R.China;DepartmentofDermatology,PerelmanSchoolof Medicine,UniversityofPennsylvania,Philadelphia,PA,UnitedStates;Corporal MichaelJ.CrescenzVAMedicalCenter,Philadelphia,PA,UnitedStates
A.Lo ´ pez-Rubio FoodSafetyandPreservationDepartment,InstituteofAgrochemistry andFoodTechnology(IATA-CSIC),Valencia,Spain
C.Mahendra DepartmentofStudiesinBotany,UniversityofMysore,Mysore,India
P.R.Mithun ElexesMedicalConsultingPvtLtd.,Bengaluru,India
N.ChandraMohana MicrobialDrugsLaboratory,DepartmentofStudiesin Microbiology,UniversityofMysore,Mysore,India
MajidMontazer DepartmentofTextileEngineering,FunctionalFibrousStructures& EnvironmentalEnhancement(FFSEE),AmirkabirUniversityofTechnology,Tehran, Iran
TheHuuNguyen FacultyofChemicalTechnology,HanoiUniversityofIndustry,Hanoi, Vietnam
ThienVuongNguyen InstituteforTropicalTechnology,VietnamAcademyofScience andTechnology,Hanoi,Vietnam
TuanAnhNguyen InstituteforTropicalTechnology,VietnamAcademyofScienceand Technology,Hanoi,Vietnam
VanThangNguyen FacultyofChemicalTechnology,HanoiUniversityofIndustry, Hanoi,Vietnam
PhuongNguyen-Tri DepartmentofChemistry,UniversityofMontreal,Montreal,QC, Canada
AlokPandya DepartmentofPhysicalScience,InstituteofAdvancedResearch, Gandhinagar,India
De-ShengPei CollegeofLifeScience,HenanNormalUniversity,Xinxiang,P.R.China; ChongqingInstituteofGreenandIntelligentTechnology,ChineseAcademyofSciences, Chongqing,P.R.China
S.SanthanaPrabha PSNACollegeofEngineeringandTechnology,Dindigul,India
SusaiRajendran CorrosionResearchCentre,StAntony’sCollegeofArtsandSciences forWomen,AmalaAnnaiNagar,Dindigul,India;PSNACollegeofEngineeringand Technology,Dindigul,India;CorrosionResearchCentre,DepartmentofChemistry,St Antony’sCollegeofArtsandSciencesforWomen,Dindigul,India;Departmentof Chemistry,St.Antony’sCollegeofArtsandSciencesforWomen,Dindigul,India
H.C.YashavanthaRao DepartmentofBiochemistry,IndianInstituteofScience, Bengaluru,India
R.JosephRathish PSNACollegeofEngineeringandTechnology,Dindigul,India
L.Reijnders IBED,UniversityofAmsterdam,Amsterdam,TheNetherlands
MohdAslamSaifi DepartmentofRegulatoryToxicology,NationalInstituteof PharmaceuticalEducationandResearch(NIPER),Hyderabad,India
S.Satish DepartmentofStudiesinMicrobiology,Manasagangotri,UniversityofMysore, Karnataka,India
JuhiShah DivisionofBiologicalandLifeSciences,SchoolofArtsandSciences, AhmedabadUniversity,Ahmedabad,Gujarat,India
NivyaSharma DepartmentofRegulatoryToxicology,NationalInstituteof PharmaceuticalEducationandResearch(NIPER),Hyderabad,India
GurmeetSingh PondicherryUniversity,Puducherry,India
SanjaySingh DivisionofBiologicalandLifeSciences,SchoolofArtsandSciences, AhmedabadUniversity,Ahmedabad,Gujarat,India
ShashiBalaSingh DepartmentofRegulatoryToxicology,NationalInstituteof PharmaceuticalEducationandResearch(NIPER),Hyderabad,India
ConstantineStalikas LaboratoryofAnalyticalChemistry,DepartmentofChemistry, UniversityofIoannina,Ioannina45110,Greece
VojislavStani ´ c Vin ˇ caInstituteofNuclearSciences,LaboratoryofRadiationand EnvironmentalProtection,UniversityofBelgrade,Belgrade,Serbia
MdAbdusSubhan DepartmentofChemistry,ShahJalalUniversityofScienceand Technology,Sylhet,Bangladesh
A.Subramania CentreforNanoSciences&Technology,MadanjeetSchoolofGreen EnergyTechnologies,PondicherryUniversity,Puthucherry,India
ThodhalYoganandhamSuman CollegeofLifeScience,HenanNormalUniversity, Xinxiang,P.R.China;ChongqingInstituteofGreenandIntelligentTechnology,Chinese AcademyofSciences,Chongqing,P.R.China;EcotoxicologyDivision,CentreforOcean Research,SathyabamaInstituteofScienceandTechnology,Chennai,TamilNadu,India
A.SuriyaPrabha DepartmentofChemistry,MountZionCollegeofEngineeringand Technology,Pudukkottai,India
S.SanthanaPrabha PSNACollegeofEngineeringandTechnology,Dindigul,India
SladjanaB.Tanaskovi ´ c FacultyofPharmacy,DepartmentofGeneralandInorganic Chemistry,UniversityofBelgrade,Belgrade,Serbia
T.Umasankareswari DepartmentofChemistry,RajapalayamRajusCollege, Rajapalayam,India
SachinVaidh DepartmentofBiologicalScienceandBiotechnology,Instituteof AdvancedResearch,Gandhinagar,India
NidhiVerma DepartmentofPhysicalScience,InstituteofAdvancedResearch, Gandhinagar,India
N.Vijaya DepartmentofChemistry,VellalarCollegeforWomen,Thindal,India
GajendraSinghVishwakarma DepartmentofBiologicalScienceandBiotechnology, InstituteofAdvancedResearch,Gandhinagar,India
TienVietVu FacultyofChemicalTechnology,HanoiUniversityofIndustry,Hanoi, Vietnam
ShaofeiWang DepartmentofCellularandGeneticMedicine,SchoolofBasicMedical Sciences,FudanUniversity,Shanghai,P.R.China
Foreword Ihavealwaysenjoyedmultidisciplinaryscientificmeetingsastheyarethemeltingpot forideas.Asmostknow,theprogressinsciencenowadaysisverydependentuponhaving aninputfromdifferentskillsets.Nowhereisthismoreimportantatthispointintime thanthefieldofnanotechnology.TheRoyalMicroscopicalSociety(RMS)isonesuchmultidisciplinarygroup—physicists,chemists,biologists,engineers,medics,etc.However,in the1990sRMSmeetingsoftenresultedinparallelsessionswithgroupsofspecialistsonly talkingamongstthemselves.DuringmypresidencyoftheRMSIwaschargedwithfinding atopictowhichallstrandsofthesocietycouldcontribute.Thetopicthatquicklysuggesteditselfwasthehealtheffectsoffineparticles—itneedshighresolutionmicroscopy, sophisticatedchemical,andphysicalanalysisofminuteamountsofmaterial,biological experimentation,andobservanceofhealthoutcomes.Themeetingledtoamultiauthor book, ParticulateMatter:PropertiesandEffectsUponHealth [1].Thisappearedjustpriorto theemergenceofsocietalknowledgeoftheexistenceofthenanotechnologyindustryand wasofacertainamountofinfluenceinframingthesubsequentnanotoxicologydebate.
Thisbookaddressesatopicofcrucialimportance.Itiswidelyknownthattheprofligate useofantibioticsinhumanmedicineandanimalhusbandryoverthepast50 1 yearshas ledandcontinuestoleadtotheemergenceofstrainsofbacteriathatareresistanttoall knownantibiotics.Societyhashadlessthanacentury’sbenefitfromthistechnologyand duringthattimewehavecometoexpectthatthewondersofmodernsurgeryandthe perinatalsurvivalofmostofouroffspringwillcontinue.Butnowthebugsarefighting backviaDarwinianevolutionandwestandtolosemuchofthebenefit.
Nanotechnologyholdsouttheprospectofbeingabletotargetmedicinesmoreprecisely withinthebody.Withthatcomesthetemptingideathatwemaybeabletodevise mechanismsofdeliveringantimicrobialtherapiesmoredirectlytofociofinfectionor indeedtospecifictypesofbacteriadirectly.Thereisaworldofdifferencebetweenacceptingatherapyunderinformedconsentandhavingsomethingthrustuponyou,without consent,viatheenvironment.Ifyouhaveaseriousenoughillness,cancerforexample, youmayconsideracceptingquitepotentiallydangerousoreventotallyexperimentaltherapies.Andyetweknowthatsomemedicinesortheirmetabolitescanbepassedontothe environmentinbodilyeffluviaandcausesubsequentproblems.Thesecretwithnanomedicinesisgoingtobetoachievetheformerandavoidthelatter.
Nanoparticleshavetoxicologicalpropertiesassociatedwiththeirenhancedsurface chemistryandabilitytomoveeasilythroughthebodyandtheenvironment [2].There havealsobeensomeindicationsthattheymaycauseecologicalproblems [3,4].Thenanotechnologyindustryhassofarbeenanexampleofcollaborationbetweensociety,industry, andsciencetoapplytheprecautionaryprincipletothedevelopmentofnanomedicines.It isnotcleartowhatextentthiswasduetothejuxtapositionofemergingknowledgeofthe
negativeeffectsofparticlesonhealthwiththearrivalofabrandnewindustryor,onthe otherhand,totheapplicationofethicalself-governance.Itisprobablyabitofboth.The outcome,however,isgoodbecauseitappearstobemakingproductdevelopersperform thoughtexperimentstolookatwhatmightgowrongandtestforthatbeforegoinginto fullproduction.Historyislitteredwithexampleswherethisapproachhasnotbeen heeded(simplylookatthecostscurrentlybeingincurredbythechemicalindustry becauseofPCBsintheenvironmentforagoodexample).Acomprehensivelistofsuch pooroutcomesisdescribedintheEuropeanEnvironmentAgency’slatelessonsfromearly warningsseries [5].
Societyreallydoesneedsomesortofthoughtexperimentthinktanktobeappliedin manyareasofcurrenttechnologicaldevelopment,particularlywherethetechnologyisboth powerfulandhastheabilitytobepervasiveintheenvironment.Mycurrentreadingofthe situationisthatthenanomedicineindustrymayprovideagoodtemplateforsuchacollaborationbetweensocietyandindustry—andfromthatrespectitisaverywelcomedevelopment.Thisbookmirrorsthatapproachinthatitcoversmanyoftheareasofconcerninthe realmsoftoxicologyandecotoxicologywhilealsodemonstratingtheingenuityandtechnologicalskillthatisbeingappliedtothefieldofnanomedicine.Icommendittoyou.
C.VyvyanHoward
NanoSystemsBiology,CentreforMolecularBioscience, UniversityofUlster,Coleraine,UnitedKingdom
References [1] R.L.Maynard,C.V.Howard(Eds.),ParticulateMatter:PropertiesandEffectsUponHealth,BiosScientific Publishers,OxfordUK,1999.ISBN1-85996-172-X.
[2] A.Elsaesser,C.V.Howard,Toxicologyofnanoparticles,Adv.DrugDeliv.Rev.64(2012)129 137.
[3] K.VanHoecke,J.K.Quik,J.Mankiewicz-Boczek,K.C.Deschamphelaere,A.Elsaesser,P.Vandermeeren, etal.,FateandeffectsofCeO2 nanoparticlesinaquaticecotoxicitytests,Environ.Sci.Technol.43(2009) 4537 4546.
[4] K.VanHoecke,K.A.C.DeSchamphelaere,Z.Ali,F.Zhang,A.Elsaesser,P.RiveraGil,etal.,Ecotoxicityand uptakeofpolymercoatedgoldnanoparticles,Nanotoxicology7(1)(2013)37 47.
[5]EuropeanEnvironmentAgencyReport22/2001,Latelessonsfromearlywarnings:theprecautionaryprinciple 1896 2000,ISBN:92-9167-323-4. https://www.eea.europa.eu/publications/environmental_issue_report_ 2001_22.
1 Nanoparticle physiologicalmedia interactions R.Dorothy1,N.Karthiga2,S.SenthilKumaran3, R.JosephRathish4,SusaiRajendran 4 andGurmeetSingh5
1DepartmentofEEE,AMETUniversity,Chennai,India 2DepartmentofChemistry,SBM CollegeofEngineering,Dindigul,India 3SchoolofMechanicalEngineering,VITUniversity, Vellore,India 4PSNACollegeofEngineeringandTechnology,Dindigul,India 5PondicherryUniversity,Puthucherry,India
1.1Introduction Nanoparticlesaresurroundedbyproteinscalledthecorona,whichhasbeeninvestigatedbymanytechniques.Thecoronaisusedindrugdeliveryanddiagnosis.When nanoparticles(NPs)enterintoabiologicalsystemmanyinterestingincidentscanoccur. Someoccurrencesareknown,butthemajorityareunknown.
1.1.1Particle cellinteractionsinphysiologicalmedia Particle cellinteractionsinphysiologicalmediaaresignificantindeterminingthefate andtransportofNPsandthebiologicalresponsestothem.Theseinteractionsareassessed inrealtimeusingmanytechniquesincludingatomicforcemicroscopy-(AFM)based platform.
1.1.2Engineerednanoparticlesinmanycommercialproducts Engineerednanoparticles(ENPs)areinvolvedinmanyindustrialprocesses.Henceenvironmental [1],occupational [2,3],andconsumerexposureareinevitable [4,5].Nano-enabled technologiesarepresentlyusedinvariousbiomedicalapplications.Theyareusedinpreventingthetransmissionofinfectiousdiseases [6,7] andtheranosticapplications [8]
1.1.3Nanoparticle-mediatedtherapies Nanoparticle-mediatedtherapieshavebeenintroducedinmanyfields.Theycaneither enhancecurrentdiagnosticmethods likemagneticresonanceimaging(MRI) [9] andX-rays [10], orintroducenewmethodssuchasphoto-acoustictomography [11].
1.1.4Proteincorona Thepotentialadversehealtheffectsandtheefficacyoftheranosticsdependonthe nanoparticle cellinteractionsandparticleuptakefromcells [12].Thereisaplethoraof publishedliteraturedocumentingENPsandtheirabilitytopenetratebiologicalbarriers andinitiateacascadeofevents,whichprobablyleadtoadversehealtheffects [13].When NPsenterphysiologicalmedia,thereisaninstantaneousformationofaproteincoating, generallyknownastheproteincorona(PC) [14] (Fig.1.1).ThePCisresponsiblefor undesirablebiologicalaspects,tunabledrugdeliverysystems,andnovelmedical applications.
ThebehaviorandthefateoftheNPsinbiologicalsystemsaregovernedbythePC [15] ThePChasinfluenceoftheiragglomerationpotential [16],theNPadhesiontothecell membrane [17],andpotentialcelluptakeandpossibletoxicity [18].Becauseoftheimportanceofthecoronainthenanoparticle cellinteractions,numerousstudieshavefocused ontheidentificationof(1)parametersinfluencingtheadsorptionofproteinsonthesurface ofNPsinvariousphysiologicalfluids [19] and(2)theroleofthecoronaontheNPcell uptake [20]
1.1.5Quantificationofparticleuptake Eventhoughthesestudieshaveinvestigatedthenanoparticle cellinteractions,theyare donesoindirectlybyobservingsecondaryfeaturessuchasthecelladhesion/viability,
FIGURE1.1 Nanoparticlewithproteincorona.
morphology,metabolicactivity,oxidativestress,andparticleuptake.Theyarelaterrelated toNPpropertiessuchassize,shape,andsurfacechemistry/modifications [21].Themost frequentlyusedmetricisthequantificationofparticleuptake [22,23].
1.1.6Flowcytometry
FlowcytometryisthemostsignificantmethodusedfortheNPuptakequantification. ThisrequiresfluorescenceENPs [24].Neverthelessthefluorescentdyesmayalterthe chemistryandaffectthenanoparticle cellinteractions [25].
1.1.7Useofplasmonicproperties
Wangetal.usedtheplasmonicpropertiesofgoldnanoparticles(AuNPs)tostudythe intracellularlocalizationofNPstorecreateathree-dimensional(3D)mappingoftheirdistribution [26].However,thisapproachislimitedtoasmallnumberofENPswithintrinsic particleproperties.
1.1.8Othermethodsusedtoquantifythenanoparticleuptake
Conventionalmethodslikeinductivelycoupledmassspectrometry [27] havebeenusedto quantifytheNPuptake.Jamesetal.employedX-rayfluorescencemicroscopytomapZnO particlesdistributioninTHP-1cells [28].Thisisconsideredaverysophisticatedmethod. Recently,moleculardynamicsimulationshavebeenusedtoinvestigatetheseinteractions [12]
1.1.9Limitationsoftheabovemethods
Theabovementionedmethodshavethefollowinglimitations.
• Theydonotprovideadirectquantificationofthenanoparticle cellinteractions.
• Theydependonintrinsicparticleproperties(e.g.,fluorescence,plasmonicresonance, etc.).Thislimitstheirapplicabilitytoonlyafewparticlesystems.
• Theyrequirehighlyspecializedequipment.
1.1.10Useofatomicforcemicroscopy
RecentlyAFMhasbeenusedtoinvestigatenanoparticle nanoparticleinteractions [29] AFMhasbeenwidelyusedinmaterialscienceforsurfaceimaging [30] andcorrosioninhibitionstudy [31]
1.2Recentadvancesontheinteractionofnanoparticleswithbiologicalmedia
RecentadvancesontheinteractionofNPswithbiologicalmediaarediscussedinthis section.
1.2.1Dynamicalmodelingofmanipulationprocessintrolling-modeatomic forcemicroscopy
Dynamicalbulgedmodelingoftrolling-modeAFMinmanipulationofbio-samplesis presented.ThecombinationofhighaccuracyandcompatibilitywithphysiologicalconditionsmakesAFMauniquetoolforstudyingbiologicalmaterialsinliquidmedium. However,AFMmicrocantileverundergoesrigoroussensitivitydegradationandnoise amplificationwhileoperatinginliquid;thelargehydrodynamicpullbetweenthecantilever andthesurroundingliquidoverwhelmsthetip-sampleinterfaceforcesthataresignificantin controllingtheprocess.Consequently,asuitablenanoneedleshouldbelongenoughtomaintainthecantileveroutofliquidmediumandshortenoughtobeabletotransmittherequired forcetopushNP.Nevertheless,alongnanoneedlemaydeflectundertheapproachingforce; therefore,itsbendingdeflectionshouldbeaccountedforingoverningequations.Moreover, analyticalandfiniteelementstressanalysis ofnanoneedleandcantileveriscarriedoutto assureabouttheirselectedmaterialandgeometry.Johnson Kendall Robertstheoryisused tomodelcontactmechanicsbetweentheneedle/surfaceandtheparticle.Pullandmeniscus forcesareutilizedtomodeltheliquidmedia.GoverningequationsaresolvedusingODE45 andthesystembehaviorissimulated.Criticalconditionsofdescendingincludingcriticaltime andforceareproduced,andchangesofpushingforce,needledeflection,andindentation depthsareillustrated.Also,effectsofvelocityvariationsareobserved.Then,diverseheights fornanoneedlearetestedandanappropriateoneispreferredforourpurpose(tokeepthe needleoutofliquidandtransmittheforceappropriately).Thesimulationisrepeatedfora varietyofbiologicalparticlesandtheirbehaviorsarestudied.Attheend,thepresentsimulationisvalidatedthroughcomparingtheresultswithanearlierwork.Thiscomparisonshows thatthesimulationisreliablefortheproposedpurpose [32].
1.2.2Limitsoftheeffectivemediumtheoryinparticleamplifiedsurface plasmonresonancespectroscopybiosensors
Theresonantwavemodesinmonomodalandmultimodalplanarsurfaceplasmonresonance(SPR)sensorsandtheirresponsetoabidimensionalarrayofAuNPsareinvestigated boththeoreticallyandexperimentally,toexaminetheparametersthatrulethecorrectNP countingintheemergingmetalnanoparticle-amplifiedsurfaceplasmonresonance(PA-SPR) spectroscopy.Withnumericalsimulationsbasedonthefiniteelementmethod,wecalculate theerrorexecutedinthedeterminationofthesurfacedensityofNPs σ whentheMaxwellGarnetteffectivemediumtheoryisusedforfastdataprocessingoftheSPRreflectivity curvesuponNPdetection.Thevariationincreasesdirectlywiththedemonstrationsofnonnegligiblescatteringcross-sectionofthesingleNP,dipole dipoleinteractionsbetweenadjacentAuNPsanddipolarinteractionswiththemetalsubstrate.Nearfieldsimulationsshow clearlytheset-upofdipolarinteractionswhenthedielectricthicknessissmallerthan10nm andconfirmthatthestrangedispersionusuallyobservedexperimentallyisduetothefailureoftheeffectivemediumtheories.UsingcitratestabilizedAuNPswithanominaldiameterofabout15nm,weexpressexperimentallythatdielectricloadedwaveguidescanbe usedascorrectnanocountersintherangeofsurfacedensitybetween20and200NP/μm 2 ,
openingthewaytotheuseofPA-SPRspectroscopyonsystemsmimickingthephysiological cellmembranesonSiO2 supports [33].
1.2.3Aromaticnitrogenmustard-basedautofluorescentamphiphilicbrush copolymeraspH-responsivedrugdeliveryvehicle
Thedeliveryofclinicallyacceptednonfluorescentdrugsischallengedduetohowharditis tomonitortheintracellulardrugdeliverywithoutincorporatinganyintegratedfluorescence moietyintothedrugcarrier.ThepresentinvestigationreportsthesynthesisofapH-responsive autofluorescentpolymericnanoscaffoldfortheadministrationof nonfluorescentaromaticnitrogenmustardchlorambucil(CBL)drugintothecancercells.Copolymerizationofpoly(ethylene glycol)(PEG)attachedstyreneandCBLconjugatedN-substitutedmaleimidemonomersallows theformationofwell-definedluminescentalternatingcopolymer.Theseamphiphilicbrush copolymersself-organizedinaqueousmediuminto25 68nmNPs,wheretheCBLdrugis enclosedintothecoreoftheself-assembledNPs.Invitrostudiesexposed B70%drugwas retainedunderphysiologicalconditionsatpH7.4and37 C.AtendolysosomalpH5.0,90%of theCBLwasreleasedbythepH-inducedcleavage ofthealiphaticesterlinkagesconnecting CBLtothemaleimideunit.AlthoughthenascentNP(withoutdrugconjugation)isnonhazardous,thedrugconjugatedNPconfirmedhighertoxicityandbettercellkillingcapabilityincervicalcancer(HenriettaLacks)cellsratherthaninnormalcells.Interestingly,thecopolymer withoutanypredictablechromophoreexhibitedphotoluminescenceunderultraviolet(UV)light irradiationduetothepresenceof“through-space” π π interactionbetweentheC 5 Ogroup ofmaleimideunitandtheadjacentbenzenering ofthestyrenicmonomer.Thispropertyused intracellulartrackingofCBLconjugatedautofluorescentnanocarriersthroughfluorescence microscopeimaging.Finally,the4-(4-nitrobenzyl)pyridinecolorimetricassaywasexecutedto examinetheabilityofCBL-basedpolymeric nanomaterialstowardalkylationofDNA [34].
1.2.4Dynamicchangesofproteincoronacompositionsonthesurfaceofzinc oxidenanoparticleincellculturemedia
Thepotentialfunctionsofnanomaterialsusedinnanomedicineasconstituentsindrug deliverysystemsandinotherproductscontinuetoexpand.Whennanomaterialsareintroducedintophysiologicalenvironmentsanddrivenbyenergetics,theyreadilyassociate proteinsformingaPContheirsurface.ThisPCcouldresultinamodificationofthenanomaterial’ssurfacecharacteristics,disturbingtheirinteractionwithcellsduetoconformationalchangesinadsorbedproteinmolecules.However,ourcurrentunderstandingof nanobiologicalinteractionsisstillverylimited.Utilizingaliquidchromatography mass spectroscopy/massspectroscopytechnologyandaCytoscapeplugin(ClueGO)approach, westudiedthecompositionofthePCforasetofzincoxidenanoparticles(ZnONP)from cellculturemediacharacteristicallyandfurtheranalyzedthebiologicalinteractionofrecognizedproteins,respectively.Intotal,36and33commonproteinswereexaminedas beingboundtoZnONPat5and60min,respectively.Theseproteinswerefurtherstudied withClueGO,whichprovidedgeneontologyandthebiologicalinteractionprocessesof identifiedproteins.ProteinsboundtothesurfaceofNPsthatmaychangethestructure,
thereforethefunctionoftheadsorbedproteincouldaccordinglyaffectthedifficult biologicalprocesses [35].
1.2.5Invitromethodsforassessingnanoparticletoxicity
Asaresultoftheirincreaseinannualproductionandwidespreaddistributioninthe environment,NPspotentiallycauseanimportantpublichealthrisk.Thesought-aftercatalyticactivityapprovedbytheirphysiochemicalpropertiesdoublesasahazardtophysiologicalprocessesfollowingexposurethroughinhalation,oral,transdermal,subcutaneous, andintravenousuptake.Uponuptakeintothebody,theirsize,morphology,surfacecharge, coating,andchemicalcompositionsupplementtheresponseofbiologicalsystemstothe materialsandincreasetheirtoxicity.Recognitionofeachpropertyisessentialtopredict theharmimposedbyforeignnanomaterialsinthebody.Assaymethodsrangingfromendotoxinandlactatedehydrogenasesignalingtoapoptosisandoxidativestressdetectionsupply valuabletechniquesforexposingbiomarkersofNP-inducedcellulardamage.Spectroscopic investigationofepithelialbarrierpenetrationanddistributionwithinlivingcellsrevealsthe proclivityofNPstoenterthebody’snaturalprotectiveboundariesanddepositthemselves incytotoxiclocations.Combinationofthevariouscharacterizationmethodologiesandassays isrequiredforeverynewnanoparticulatesystemdespitepreexistingdataforsimilarsystemsduetothelackofdeterministictrendsamonginvestigatedNPs.Thepropensityof nanomaterialstodenatureproteinsandoxidizesubstratesintheirlocalenvironmentproducessignificantconcernfortheapplicabilityofseveraltraditionalinvitroassays,andthe alterationofsusceptibleapproachesintonovelmethodssuitablefortheevaluationofNPs comprisesthefocusoffutureworkcenteredonNPtoxicityanalysis [36].
1.2.6Nanoparticlestargetingretinalandchoroidalcapillariesinvivo
ThefunctionalizationofNPswithexactreceptorligandsenablestheiraccumulationin targetedtissuesandcanbeusedtherapeuticallytotransportdrugsorfordiagnosticpurposes(Parveenetal.,Nanomedicine8:147 166,2012).Targetingendothelialcellsinretinal andchoroidalcapillariescanberealizedevenunderphysiologicalconditionsusingquantumdotsasmodelNPsfunctionalizedwithanintegrin-bindingpeptide(Pollingeretal., Proc.Natl.Acad.Sci.110:6115 6120,2013).Eventhoughthechemistryisstandardand waswell-explainedintheliterature,thatweusedwaswell-explainedintheliterature, thereareanumberofpreparationstepsthataredelicateanddeservespecialnotice.Itis, therefore,ourgoaltodescribestepbystepthesignificantmethodsofligandimmobilizationonquantumdotsurfacestoassistthereadertoreproduceourwork.Herewedescribe thechemicalalterationofquantumdotswithcasatargetingpeptidethatallowsthe resultingmodifiedNPstoadheretoendothelialcellsalsointheretinaltissue.Wedemonstratethepropertiesoftheresultingparticlesbyshowingsomeoftheinvitroresultsfrom ourpreviousstudies.Doingso,weconcurrentlyencouragethereadertocheckparticles intendedfortargetingcellsinvivofirstbyextensiveinvitroanalysisofparticleinteraction withcellsbythemeansofflowcytometryandconfocalmicroscopytoprovethesuccessful functionalization.Onlythentheapplicationoffunctionalizedquantumdotsintothe
systemiccirculationofmiceledtotheprefer redlocalizationofNPsintheretinaland choroidalbloodvessels [37] .
1.2.7DistributionofsuperparamagneticAu/Fenanoparticlesinanisolated guineapigbrainwithanintactblood brainbarrier
Diagnosisandtreatmentofbraindisorders,suchasepilepsy,neurodegenerativediseases, andtumors,promotefrominnovativeapproachestodelivertherapeuticordiagnosticcompoundsintothebrainparenchyma,witheitherahomogeneousoratargetedlocalizeddistributionpattern.ToevaluatethemechanisticfeatureofdiffusionofNPsintothebrainparenchyma, acomplex,yetcontrolledandfacilitatedenvironmentwasused:theisolatedguineapigbrain maintainedinvitrobyarterialperfusion.Inthisuniquepreparationtheblood brainbarrier andtheinteractionsbetweenvascularandneuronalsectionsaremorphologicallyandfunctionallyconserved.Inthisstudy,superparamagneticAu/Fenanoparticles(MUS:OTAu/FeNPs), recentlystudiedasapromisingmagneticresonanceT2contrastagentwithhighcellular penetration,werearteriallyperfusedintotheinvitroisolatedbrainandshowedhighand homogeneouspenetrationthroughtranscytosisintothebrainparenchyma.Ultramicroscopy investigationoftheinvitroisolatedbrainsectionsbytransmissionelectronmicroscope(TEM) analysisoftheelectron-densecenteroftheMUS:OTAu/FeNPswasconductedtounderstand NPs’brainpenetrationthroughtheblood brainbarrierafterinvitroarterialperfusionand theirdistributionintheparenchyma.ThedatashowsthatMUS:OTAu/FeNPsenterthebrain usingaphysiologicalrouteandthereforecanbedevelopedasbrainpenetratingnanomaterials withpotentialcontrastagentandtheranosticscapabilities [38]
1.2.8Long-termreal-timetrackinglivestemcells/cancercellsinvitro/invivo throughhighlybiocompatiblephotoluminescentpoly(citrate-siloxane) nanoparticles
Long-termlivecelltrackingisdesirableandessentialtounderstandthedynamicsand complexityofbiologicalinteractionsinstemcellsandcancercells.Conventionallivecells fluorescencetrackersaregenerallynondegradableandshowincreasedtoxicityconcerns duringthelong-standingapplication.Previouslywedevelopedecofriendlyfluorescent poly(citrate)-basedhybridelastomersforboneregenerationapplications.Here,wefabricatedthephotoluminescentpoly(citrate-siloxane)nanoparticles(PCSNPs)throughanoil/ wateremulsionmethodandconfirmedtheirlong-termlivestemcells/cancercellsimaging applications.PCSNPsshowedauniformsizedistribution(meandiameter120nm)and highlystabledispersability(above30days)indifferentphysiologicalmedium,aswellas outstandingfluorescentpropertiesandphotostability.PCSNPspossessexcellentcellular biocompatibility,whichcouldbeefficientlyinternalizedbycellsandselectivelyimagethe celllysosomewithahighphotostability.ComparedwithcommercialCellTrackerGreen andCellTrackerRed,theadipose-derivedmesenchymalstemcellsorhumanhepatoma cellswerestablylabeledbyPCSNPsforover14daysastheygrewanddeveloped(seven passages).Additionally,PCSNPscapablytrackedcellsupto7daysinvivothroughanoninvasivewaycomparedwith1dayofcommercialtracker.Thisstudydemonstratesan
importantapproachtodesignbiodegradablemultifunctionaldeliveryplatformsfor biomedicalapplicationssuchaslong-termbioimaging [39] .
1.2.9Theeffectofsilicananoparticlesstabilityinbiologicalmedia
ThestabilityandlevelofaggregationofNPsinphysiologicalconditionsordifferent mediaaresignificantforbiomedicalapplications.TheinteractionofNPsindifferent mediacouldchangethephysicochemicalpropertiesofNPs.Inthisstudy,twodissimilar sizesofamorphoussilicananoparticles(SiNPs)encapsulateddyeweresynthesizedusing themicelleentrapmentmethod.TheSiNPsencapsulateddyessuspensionwasblended withadifferentconcentrationofsaltsolution,NaClandmouseserumandprotectedat 37 CtomimicthehumanbodyenvironmentinordertostudytheinteractionofSiNPs encapsulateddyesinphysiologicalconditions.Particlesagglomerationoraggregationof SiNPsencapsulateddyesinNaClsolutionandmouseserumwereexaminedandanalyzed.Theabsorbancespectraandthestabilityefficiencywererecordedandcalculated usingultraviolet visible(UV Vis)spectrometer,whiletheparticlesizewasmeasured usingZetasizerparticleanalysisandTEM.Theresultsshowedthat53nmofSiNPswas morestablecomparedto30nmbothinNaClsolutionandinmouseserum [40]
1.2.10Experimentalchallengesregardingtheinvitroinvestigationofthe nanoparticle-biocoronaindiseasestates
ToxicologicalevaluationofNPsrequirestheutilizationofinvitrotechniquesduetotheir numberanddiverseproperties.Cellculturesystemsareoftendeficientintheiraptitudeto carryoutcomparativetoxicityevaluationduetodosimetryissuesandcapabilitytosimulate invivoenvironments.Uponencounteringaphysiologicalenvironment,NPsbecomecoated withbiomoleculesformingabiocorona(BC),influencingfunction,biodistribution,andtoxicity.Disease-inducedalterationsinthebiologicalmilieucanalterBCformation.Thisstudy evaluatestheroleoflow-densitylipoprotein(LDL)inchangingmacrophageresponsesto ironoxide(Fe3O4)NPs.BCswereformedbyincubatingFe3O4NPsinserum-freemedia,or 10%fetalbovineserumwithorwithoutLDLpresent.Followingexposurestoanormalized dose(25 μg/mL),macrophageassociationofFe3O4NPswithaLDL-BCwasenhanced.TNFα mRNAexpressionandproteinlevelsweredifferentiallystimulatedduetoBCs.CellsurfaceexpressionofSR-B1wascondensedfollowingallFe3O4NPsexposures,whileonlyNPs withanLDL-BCenhancedmitochondrialmembranepotential.Thesefindingsproposethat elevationsinLDLmaygivetodistinctBCformationtherebyinfluencingNP-cellularinteractionsandresponse.Further,ourstudyhighlightschallengesthatmayariseduringthe invitroevaluationofdisease-relatedvariationsintheNP-BC [41].
1.2.11Effectofionicstrengthonshear-thinningnanoclay polymercomposite hydrogels
Nanoclay polymershear-thinningcompositesare designedforabroadrangeofbiomedicalapplications,includingtissueengineering,drugdelivery,andadditivebiomanufacturing.
Despitetheadvancesinclay-polymerinjectablenanocomposites,colloidalpropertiesof layeredsilicatesarenotfullyconsideredinevaluatingtheinvitroperformanceofshearthinningbiomaterials(STBs).Here,asamodelsystem,weinvestigatetheeffectofionson therheologicalpropertiesandinjectabilityofnanoclay gelatinhydrogelstoknowtheir behaviorwhenpreparedinphysiologicalmedia.Inparticular,welearntheeffectofsodium chloride(NaCl)andcalciumchloride(CaCl2),commonsaltsinphosphatebufferedsaline (PBS)andcellculturemedia(e.g.,Dulbecco’sModifiedEagle’sMedium),onthestructural organizationofnanoclay(LAPONITEXLG-XR,ahydrouslithiummagnesiumsodiumsilicate)-polymercomposites,responsiblefortheshear-thinningpropertiesandinjectability ofSTBs.Theformationofnanoclay polymeraggregatesduetotheion-inducedshrinkage ofthedisperseddoublelayerandfinallytheliquid-solidphaseseparationdecreasesthe resistanceofSTBagainstelasticdeformation,decreasingtheyieldstrain.Accordingly,the straincorrespondingtotheonsetofstructuralbreakdown(yieldzone)isregulatedby theiontypeandconcentration.TheseresultsareindependentoftheSTBcompositionand candirectlybeconvertedintothephysiologicalconditions.Theexfoliatednanoclayundergoesvisuallyundetectableaggregationuponmixingwithgelatininphysiologicalmedia, resultinginheterogeneoushydrogelsthatphasedivideunderstress.Thisworkgivesfundamentalinsightsintonanoclay polymerinteractionsinphysiologicalenvironments,pavingthewayfordesigningclay-basedinjectablebiomaterials [42]
1.2.12TheeffectofsurfacechargeandpHonthephysiologicalbehaviorof cobalt,copper,manganese,antimony,zinc,andtitaniumoxidenanoparticles invitro
ThereisinadequateknowledgeregardingvariousinteractionsofmetalNPsinaliving organism.Assumingly,metalscanconnecttonucleicacids,peptides,andproteins(e.g., enzymes),andchangethefunctioningofvitalcellularsectionsafterenteringtheorganism. Thepredictivefactorsforquantitativenanostructure activityrelationshipanalysiscould enhanceefficientandharmlessusageofNPsintheindustryaswellinthemedicine.The studiesvaluethecompositionoftheNPcoronadeterminedbytime,temperature,and sourceofproteinwhichhasbeenfoundtoimplicatethephysiologicalbehaviorofNPs. Onehaslargelybeenignored:theNPsspecificisoelectricpoint(IEP)andpHatthestate ofmeasurement.Herein,thisstudyinvestigatestheeffectofpHandsurfacechargeofsix metaloxide(MeOx)NPsontimedependencyofcytotoxicity.Severalaspectsofthecharacterizationofultrafineparticlesintheactualtestsystem,whichisthemostrelevantforthe explanationofthetoxicologicaldata,arereferred:(1)thedifferenceofpHintheroom temperatureandintheincubationconditions;(2)thedifferenceofdispersionsinMilliQ andcompletecellmedia;(3)theneedtodemonstratethepHandIEPwhenthehydrodynamicsizeismeasured;(4)thesignificanceoftimeduetothetime-dependentequilibrationandchangesofNPscorona.Thesurfacechargedeterminestheformationofcorona andcouldbemodifiedbypH.MeOxNPswithoutfullychargeequilibratedcoronamight playthemainroleofMeOxNPsenteringintothecellandaccordinglythetime-dependent materializationofthecellulareffect [43]
1.2.13Sweetstrategiesinprostatecancerbiomarkerresearch:focusona prostate-specificantigen
Aclarioncallforearlydiagnosisofprostatecancer(PCa)canbeaddressedusingnew approachessuchasabnormalproteinglycosylation.Proteinsarenaturallyaffectedby numerousposttranslationalmodifications,mainlybyglycosylationwhichisassociated withphysiologicalandpathologicaltransformationparticipatinginthegrowthofdiseases suchasvarioustypesofcancer,butalsoneurodegenerativedisorders,endocrineabnormalities,AIDS,etc.Therefore,glycoproteinsplayavitalroleincancerbiomarkerresearch, anddeterminationofglycosylationisnowadaysoneofthekeyanalyticaltasks.Thepredominantlyusedapproachbasedonaffinityassaysusinglectinsasglycorecognitionelementshasbecomeanessentialpartinthebiomedicalresearchasitshowsgreatprospects intheclinicaldiagnostics.Duetotheirabilitytounderstandsaccharidestructures,lectins canbeappliedforbindingtodifferentmoleculesandsubstratessuchasproteins,lipids, cellwallsaswellasinbiologicalmaterials,includingstemcellsandmicroorganisms.In ordertoimprovethediagnosticpotentialofwell-knowncancerbiomarkers,lectin-based biosensorsandbiochipsarebeingwidelyusedforthefindingofglycoproteins.Inthis review,wewillfocusonvariousbioassaystrategiesforglycoprofilingofaprostatespecificantigen(PSA)withanemphasisonmodernandpotentialtechniquessuitablefor theanalysisofPSAglycanpatternsbiosensors,biochips,andmassspectrometrymethods. Allmentionedmethodsaresuitableforapplicationsinresearch,diagnosis,andtherapyof PCa [44].
1.2.14Ironoxidecolloidalnanoclustersastheranosticvehiclesandtheir interactionsatthecellularlevel
Advancesinsurfactant-assistedchemicalapproacheshaveledthewayfortheutilizationofnanoscaleinorganicparticlesinmedicaldiagnosisandtreatment.Inthisfield, magnetically-drivenmultimodalnanotoolsthatperformbothdetectionandtherapy,welldesignedinsize,shape,andcomposition,arehighlyadvantageous.Suchatheranostic material—whichentailsthecontrolledassemblyofsmaller(maghemite)nanocrystalsina secondarymotifthatishighlydispersibleinaqueousmedia—isdiscussedhere.Thesesurfacefunctionalized,pomegranate-likeferrimagneticnanoclusters(40 85nm)aremadeof nanocrystalsubunitsthatshowaremarkableMRIcontrastefficiency,whichisbetterthan thatofthesuperparamagneticcontrastagentEndorem.Goingbeyondthisfeatureand withtheirdemonstratedlowcytotoxicityinhand,westudythecriticalinteractionofsuch nanoprobeswithcellsatdifferentphysiologicalenvironments.Thetime-dependentinvivo scintigraphicimagingofmiceexperimentalmodels,combinedwithabiodistributionstudy, revealedtheaccretionofnanoclustersinthespleenandliver.Moreover,theinvitroproductionofspleencellsandcytokineproductionwitnessedasize-selectiveregulationofimmune systemcells,inferringthatsmallerclustersinducemainlyinflammatoryactivities,while largeronesstimulateanti-inflammatoryactions.Thepreliminaryfindingscorroboratethat themodularchemistryofmagneticFe3O4 nanoclustersstimulatesunknownpathwaysthat couldbedeterminedtomodifytheirfunctioninfavorofhealthcare [45].
1.2.15Assemblyofcarboxylatedzincphthalocyaninewithgoldnanoparticlefor colorimetricdetectionofcalciumion
Aseriesofwater-solublecarboxylatedzinc phthalocyanine(ZnPc-COOH)wereobtained fromafacilehydrolyzationofterminatingnitrilesgroupsofzincphthalocyaninesynthesized viabisphthalonitrilebasedprecursor.After theAuNPswithpositivelychargedsurfactant cetrimoniumbromidewereaddedtoas-preparedZnPc-COOHsolution,theelectronicinteractionbetweenthemwouldcontributetothetunableconjugateofAuNPs/ZnPc-COOHand directtoared-shiftedabsorptionpeakinUV Visspectrum.Particularly,boththeamountof phthalocyanineringsandconcentrationsofZnPc-COOHwouldcreatealargedifferencein theinteractionwithAuNPs.Inthepresenceofdifferentmetalions,theZnPc-COOH/AuNPs aqueoussolutionrevealedaselectiveresponsetoCa21,leadingtoanincreasedaggregation extent,whilethenakedeyevisualizedcolorchange.Thefurtherexperimentexposedthatthe red-shiftwasavailableinawideconcentrationrangeofCa21,andthered-shiftdegreewas proportionaltotheconcentrationofCa21 intherangeof2 8 μMwithalimitofdetection definedas1 μM.CombingthephotosensitivityofZnPc-COOHandlocalizedsurfaceresonanceplasmonofAuNPs,thislabel-freesearchwouldgiveapotentialapplicationincolorimetricdetectionandphotosensitizationunderaphysiologicalenvironment [46].
1.2.16Developingthenextgenerationofgraphene-basedplatformsforcancer therapeutics
Graphenehasahopefulfutureinapplicationssuchasdiseaseidentification,cancertherapy, drug/genedelivery,bioimaging,andantibacterialapproachesduetographene’sdistinctive physical,chemical,andmechanicalpropertiesalongsideminimaltoxicitytonormalcells,and photostability.However,theseuniquefeatures andbioavailabilityofgraphenearefraughtwith uncertaintiesandconcernsforenvironmentalandoccupationalexposure.Changesinthephysicochemicalpropertiesofgrapheneinfluencebiologicalresponsesincludingreactiveoxygenspecies(ROS)production.LessproductionofROSbycurrentlyavailabletheranosticagents,for example,magneticnanoparticles(MNP),carbonnanotubes,goldnanostructuresorpolymeric NPs,controlstheirclinicalapplicationincancertherapy.Oxidativestressmadebygraphene accumulatedinlivingorgansisowingtoacellularfactors,whichmayaffectphysiologicalinteractionsbetweengrapheneandtargettissuesandcells.Acellularfactorsincludeparticlesize,shape, surfacecharge,surfacecontainingfunctionalgroups,andlightactivation.Cellularresponses suchasmitochondrialrespiration,graphene cellinteractionsandpHofthemediumarealso determinantsofROSproduction.ThemechanismsofROSproductionbygrapheneandtherole ofROSforcancertreatmentareinadequatelyunderstood.Theaimofthisstudyistosetthetheoreticalbasisforfurtherresearchingrowinggraphene-basedtheranosticplatforms [47].
1.2.17pH-Responsivemorphology-controlledredoxbehaviorandcellular uptakeofnanoceriainfibrosarcoma
Mehmoodetal.reportedonstructural/microstructuralassociationswithbiologicalperformanceforthreenanoceriamorphologies,aimingtoexplainthemajorfactorsintheir
interactionswithfibrosarcoma [48].TheseincludethepHoftheinvitromediumandthe crystallinities,stoichiometries,surfaceareasandchemistries,andmaximaloxygenvacancy concentrations([VO••]Max).Althoughthe[VO••]Maxisdominantintheredoxbehavior, theroleofthemorphologywasmarkedintheorderofusefulnessoftheredoxregulation, whichwasnanocubes(NC) , nanorods(NR) , nanooctahedra(NO).TheproposedmechanismillustratestheroleofVO•• inexplainingantioxidantbehavioratphysiologicalpH7.4 andprooxidantbehaviorinthetumormicroenvironmentpH6.4.CellularuptakeatpH7.4 wasdominatedbythemorphologyoftheNP,demonstratingtheorderNO , NC , NR. Controlofthe[VO••]Max,morphology,anddependentstructuralandmicrostructuralparameterscanbeusedtooptimizetheuptakeandredoxperformanceofnanoceria [48].
1.2.18pH-andthermo-sensitiveMTX-loadedmagneticnanocomposites: synthesis,characterization,andinvitrostudiesonA549lungcancercelland
MRimaging Farshbafetal.haveproposed [49] asimplisticmethodforfabricationofmultifunctional pH-andthermo-sensitivemagneticnanocomposites(MNCs)asatheranosticagentforuse intargeteddrugdeliveryandMRI.Tothisend,theinvestigatorsdecoratedFe3O4 MNPs with N,N-dimethylaminoethylmethacrylateand N-isopropylacrylamide,bestknownfor theirpH-andthermo-sensitiveproperties,respectively.Theinvestigatorsalsoconjugated mesoporoussilicananoparticles(MSNs)topolymermatrixactingasadrugcontainerto increasethedrugencapsulationefficiency.Methotroxate(MTX),asamodeldrug,was effectivelyloadedinMNCs(M-MNCs)viasurfaceadsorptionontoMSNsandelectrostatic interactionbetweendrugandcarrier.ThepH-andtemperature-triggeredliberateofMTX wasconcludedthroughtheestimationofinvitroreleaseatbothphysiologicalandsimulatedtumortissueconditions.Basedoninvitrocytotoxicityassayresults,M-MNCssignificantlyexposedhigherantitumoractivitycomparedtofreeMTX.InvitroMRsusceptibility experimentshowedthatM-MNCsrelativelypossessedhightransverserelaxivity(r2)of about0.15/mM/msandalinearrelationshipbetweenthetransverserelaxationrate(R2), andtheFeconcentrationintheM-MNCswasalsodemonstrated.Therefore,thedesigned MNCscanpotentiallybecomeanelegantdrugtransporter,whiletheyalsocanbeapromisingMRInegativecontrastagent [49].
1.2.19Monitoringthedynamicsofcell-derivedextracellularvesiclesatthe nanoscalebyliquid-celltransmissionelectronmicroscopy
Cell-derivedextracellularvesicles(EVs)circulatinginbodyfluidsholdassuresasbioactivetherapeuticagentsandasbiomarkerstodetectanextensiverangeofdiseases. However,nano-imagingmethodsarerequiredtocharacterizethesecomplexandheterogeneoussoftmaterialsintheirnativewetenvironment.Theinvestigatorsexploitliquid-cell transmissionelectronmicroscopy(LCTEM)tocharacterizethemorphologyanddynamic behaviorofEVsinphysiologicalmediawithnanometerresolution.Thebeam-induced controlledgrowthofAuNPsonbilayermembranesisusedasanoriginalinsitustaining methodtoadvancethecontrastofEVsandartificialliposomes.LCTEMprovides
