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DrugDiscoveryUpdate Applicationsof NanotechnologyinDrug DiscoveryandDelivery Editedby
ChukwuebukaEgbuna
AfricaCentreofExcellenceinPublicHealthandToxicologicalResearch (ACE-PUTOR),UniversityofPortHarcourt,PortHarcourt,Choba,Nigeria
Mihnea-AlexandruG ˘ aman
FacultyofMedicine,“CarolDavila”UniversityofMedicineandPharmacy, Bucharest,Romania;ClinicalHaematology,DepartmentofHaematology, CentreofHaematologyandBoneMarrowTransplantation,FundeniClinical Institute,Bucharest,Romania
JaisonJeevanandam
CQM-CentrodeQu´ımicadaMadeira,MMRG,UniversidadedaMadeira, CampusdaPenteada,Funchal,Portugal
SeriesEditor
ChukwuebukaEgbuna
Elsevier
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1.Rolesofnanoparticlesindrugdiscoveryanddelivery 3 SaurabhShah,VivekRanjanSinha,ShashiBalaSinghand SaurabhSrivastava 1.1Introduction 3 1.2Typesofnanoparticles 4
1.2.1Lipidnanoparticles4
1.2.2Polymer-basednanoparticles6
1.2.3Inorganiccomponent-basednanoparticles7 1.3Applicationofnanoparticles 8
1.3.1Drugreleaseprofile9
1.3.2Genedelivery10
1.3.3Pulmonarydelivery11
1.3.4Antimicrobialdelivery12
1.3.5Braintargeting13
1.3.6Pharmacokineticsandbiodistribution14
1.3.7Mucoadhesivedelivery14
1.3.8Skindelivery15
1.3.9Macrophageuptake16
1.3.10Nanotheranostics16
1.4Summaryandconclusion 20 References 21 2.Nanoencapsulationofnutraceuticalsanddietary supplementsforeffectivedelivery 27 HuzaifaUmar,MaryamIdris,DogaKavaz,UmarMuhammadGhali, AbdullahiGarbaUsmanandNahitRizaner
2.1Introduction 27 2.2Nutraceuticals 28
2.3Nanoencapsulationofnutraceuticalsanddietary
2.4Nanoencapsulationtechniquesfornutraceuticals
2.4.1Emulsificationtechnique32
2.4.2Nanoprecipitationtechnique33
2.4.3Coacervationtechnique33
2.5Encapsulatednutraceuticalsfordrugdelivery
2.5.1Nanoemulsions36
2.5.2Polymericnanoparticles36
2.5.3Magneticnanoparticles37
2.5.4Nanoliposomes37 2.5.5Nanophytosomes37
3.Nanoformulationofantioxidantsupplements
HabibuTijjani,AhmedOlatunde,MaryamHaladuZangoma, ChukwuebukaEgbuna,AbdulkadirMohammedDanyaro, HafsatAbdulkarim,FatimaAliyuMahmoudand MuhammadMuhammad
3.1Introduction
3.2Nanoformulationsmethods
3.2.1Emulsionsolventevaporationmethod47
3.2.2Solventdisplacementmethod47
3.2.3Supercriticalfluidtechnology47
3.2.4Templatesynthesismethod48
3.2.5Chemicalprecipitationtechnique48
3.2.6Nanoprecipitation48
3.3Nanoformulationsforantioxidants
3.3.1Naturalorplant-derivednanoantioxidants49
3.3.2Chemicalandsyntheticnanoantioxidants53
3.4Antioxidantsinnanomedicine
3.4.1VitaminC58
3.4.2VitaminE59
3.4.3Beta-carotene60
3.4.4Selenium60
3.5Advantagesanddisadvantagesofnanofomulationof antioxidantsupplements
3.6Futureperspectiveandconclusion
4.Nanophytomedicines:naturetomedicines
MithunRudrapal,SugumariVallinayagam, JamesH.Zothantluanga,DipakChetia, ChukwuebukaEgbunaandSanjayG.Walode 4.1Introduction
4.3Therapeuticpotentialsofnanophytomedicine
4.4Nanophytomedicineswithimprovedtargetbinding ability
4.5Nanophytomedicinesandtheiroralbioavailability
4.8Regulatoryaspectsandethicalissuesassociatedwith nanophytomedicine
4.9Challengesencounteredinnanophytomedicine
5.Characterizationofnanoparticles:methodsand techniques
YousefRasmiandNazariV.Mansoureh
5.6X-Raydiffraction
5.7Encapsulationefficiency,drug-loadingcapacity,and percentageofrecovery
5.8Topicalnanoparticlestrategies
5.9Drugreleasestudiesofnanoparticles
5.9.1Drugreleasestudyofnanoparticlesfororaldosage forms109
5.9.2Drugreleasestudyofnanoparticlesfortopical dosageforms109
5.10Solubilityofnanoparticles
5.11Toxicityeffectsofnanoparticles
5.11.1Invitrotoxicityeffect111
5.12Stabilityenhancementofnanoparticles
5.13Futureprojectionandconclusion
6.Applicationsofnanotechnologyinpharmaceutical products 119
JaisonJeevanandam,GenevieveDable-Tupasand MaureenB.DeGuzman
6.1Introduction 119
6.2Comparisonoftraditionalandnanodrugdelivery 120
6.2.1Essentialsofdrugdeliverysystem120
6.2.2Conventionalversusnoveldrugdeliverysystem122
6.2.3Carrier-baseddrugdeliverysystem122
6.2.4Nanodrugdeliverysystemasacarrier-baseddrug deliverysystem123
6.3Pharmaceuticalproductsthroughnanotechnology 125
6.3.1Classificationofnanopharmaceuticalproducts125
6.4Applicationsofnanotechnologyinpharmaceutical processes 127
6.4.1Drugdelivery127
6.4.2Genetherapy132
6.4.3Medicaldiagnosis133
6.4.4Drugdiscovery135
6.4.5Othernovelapplications136
6.5Challengesinnanotechnology-baseddrugdeliverysystem 137
6.6Conclusionandfutureperspectives 138
7.Advancesinnanotechnologyfordrugdiscoveryand design 157
ShashankM.Patil,RamithRamu,PrithviS.Shirahatti, LakshmiV.Ranganatha,NaveenKumar,AbdullahM.Shbeer, MohammedAl-GhorbaniandJagadeepS.Chandra
7.1Introduction 157
7.2Nanomaterials,nanotechnology,andnanobiotechnology 159
7.2.1Nanomaterials159
7.2.2Nanotechnology160
7.2.3Nanobiotechnology161
7.3Roleofnanotechnologyandnanobiotechnologyin biomedicine 161
7.3.1Biopolymernanoparticles162
7.3.2Proteinandpolysaccharidenanoparticles163
7.3.3Liposomes164
7.3.4Polymericmicelles165
7.3.5Nanocrystals166
7.3.6Quantumdots167
7.3.7Dendrimers167
7.3.8Metallicnanoparticles168
7.4Hurdlesandchallenges 169
7.5Futureperspectives 170
7.6Summaryandconclusion 171 References 172 Furtherreading 177
8.Nanomedicinefordiabetesmellitusmanagement 179
AhmedOlatunde,HabibuTijjani,BoluwatifeL.Afolabi, OluwafemiA.Ojo,SundayA.Onikanni,BabatunjiE.Oyinloye, BasiruO.AjiboyeandAbdulwahabLasisi
8.1Introduction 180
8.2Type1diabetesmellitusandnanomedicine 181
8.3Type2diabetesmellitusandnanomedicine 183
8.4Insulindeliveryandnanotechnology 184
8.4.1Polymericnanoparticles184
8.4.2Ceramicnanoparticles185
8.4.3Polymericmicelles186
8.4.4Dendrimers186
8.4.5Liposomes186
8.4.6Othernanoparticles187
8.5Nanopumps 188
8.6Insulindeliveryviainhalation 188
8.7Transplantedpancreaticisletsnanoencapsulation 189
8.8Biologicalmicroelectromechanicalsystemsforinsulin delivery 190
8.9Nanotechnologyinnoninsulinremedy 190
8.9.1Artificialpancreas191
8.9.2Nanoporeimmunoisolationtools191
8.9.3Nanorobotics191
8.10Nanotechnologyapplicationsinthemanagementof diabetes-relatedcomplications 192
8.10.1Nanotechnologyindiabeticretinopathy192
8.10.2Nanotechnologyindiabetes-inducedfootulcers192
8.10.3Nanotechnologyinotherdiabetes-associated complications192
8.11Advantagesofusingnanotechnologyindiabetesmellitus management 193
8.12Limitationsinusingnanotechnologyindiabetesmellitus management 193
8.13Conclusion 194 References 194
Contents
9.Nanotechnologicalapplicationofpeptide-and protein-basedtherapeutics 205
ChinazaGodswillAwuchi,MohammadAkram,IfeanyiClifford Owuamanam,ChikaC.Ogueke,ChibuezeGospelAwuchiand HanningtonTwinomhwezi
9.1Introduction 206
9.2Benefitsofpeptideandproteintherapeuticsin biomedicine 209
9.3Challengeswithpeptide-andprotein-based therapeutics 210
9.4Excipientsusedinsynthesisofproteinandpeptide nanoparticles 210
9.5Therapeuticanddiagnosticapplicationsofprotein-based therapeuticsnanomaterials 216
9.5.1Therapeuticapplication216
9.5.2Diagnosticapplications219
9.6Improvingstabilityusingprotein-basedtherapeutics nanoparticles 221
9.6.1Physicalstabilityenhancement222
9.6.2Biologicalstabilityimprovement222
9.7Evaluationparametersandformulationtechniquesfor protein/peptidenanoparticles 223
9.7.1Emulsificationmethod223
9.7.2Desolvationmethod224
9.7.3Electrospraymethod224
9.7.4Complexcoacervationmethod224
9.8Biomedicalapplicationsofnanoparticlesofproteinsand peptides 225
9.8.1Routes225
9.8.2Antibiotics226
9.8.3Deliveryofnonviralgene226
9.8.4Immunologicaladjuvant226
9.8.5Treatmentofdiseases226
9.9Concernsaboutpeptide-andprotein-based nanoparticles 230
9.10Futureprospects 230 9.11Conclusion 230 Abbreviations 231 References 231
10.Nanodrugdeliverysystemsincancertherapy
AndrewG.Mtewa,JonathanT.Bvunzawabayaand FanuelLampiao 10.1Introduction
10.5Proteinnanoparticles
10.6Anticancernanoparticledrugs
10.7Applicationofnanodrugdeliverysystems
11.Nanotechnologyinterventionsinneuroscience: currentperspectivesandstrategies
AshwinKumarN,GowriAnnasamy,PavaniRekulapally, SureshSNandSaravananKrishnan
11.1Introduction
11.5Nanotechnology-basedtherapeuticinterventionsfor neuraldisorders
11.5.1Organicnanoparticles270 11.5.2Inorganicnanoparticles271
11.5.3Impactofnanomaterialsinneuroscience: clinicaltrialsandcasestudies272 11.5.4Neuropsychiatricdrugs274
11.6Futureperspectives
12.Nanotechnologyapplicationforeffectivedeliveryof antimalarialdrugs
HabibuTijjani,MaryamHaladuZangoma,AhmedOlatunde, AdamuAbdullahi,ChukwuebukaEgbunaand AbdulkadirMohammedDanyaro
12.1Introduction
12.2Nanotechnologyapproachesforantimalarial
12.3Nano-baseddrugpreparationmaterials
12.3.1Lipidnanoemulsion295
12.3.2Polymericmicelles295
12.3.3Lipid-baseddeliverysystems295
12.3.4Lipidnanoparticles296
12.3.5Liposomes296
12.4Nano-baseddrugdeliveryformalarialtreatment 296
12.5Nanocarriersforantimalarialdrug
12.5.1Mesoporoussilicaasananocarrierforantimalarialdrugs297
12.5.2Liposomesasananocarrierforantimalarialdrugs299
12.5.3Solidlipidnanoparticles304
12.5.4Nanostructuredlipidcarriers307
12.5.5Microemulsionsandnanoemulsions309
12.5.6Polymericnanoparticles312
12.7Challengesofnanotechnologyforantimalarialdrugs
12.8Conclusionandfutureprospects
AnjaliB.Thakkar,RamalingamB.Subramanian, VasudevR.ThakkarandParthThakor
14.Toxicityofnanomaterialsindrugdelivery
BushraAkhtar,FaqirMuhammad,AliSharifandTahiraAslam
14.4Toxicityofnanomaterialsinbiologicalsystems:potential exposureroutes 351
14.4.1Toxicityofnanomaterialsinthenervoussystem351
14.4.2Toxicityofnanomaterialsintheliver353
14.4.3Toxicityofnanomaterialsinthepulmonarysystem354
14.4.4Toxicityofnanomaterialsinthekidney355
14.4.5Toxicityofnanomaterialsintheintegumentarysystem356
14.5Potentialmechanismsofnanomaterialstoxicityin biologicalsystems 358
14.5.1Generationofreactiveoxygenspeciesand oxidativestress359
14.5.2Inflammation359 14.5.3DNAdamage359
14.6Futureperspectiveandconclusion 360 References 360
15.Invitroandinvivotoxicityofmetalnanoparticles andtheirdrugdeliveryapplications 367 JaisonJeevanandamandYenSanChan
15.1Introduction
15.2.1Goldnanoparticles369
15.2.2Silvernanoparticles372
15.2.3Coppernanoparticles373
15.2.4Othermetalnanoparticles375
15.2.5Novelmetalnanoparticles376
15.3Invitrotoxicanalysisofmetalnanoparticles 377
15.3.1Goldandsilvernanoparticles377 15.3.2Metaloxidenanoparticles379
15.3.3Novelmetalnanoparticles380
15.4Invivotoxicanalysisofmetalnanoparticles 382
15.4.1Mousemodels382
15.4.2Zebrafish383
15.4.3Drosophila383 15.4.4Otheranimalmodels384
15.5Drugdeliveryapplicationsofmetalnanoparticles 384
15.5.1Cancertreatment385
15.5.2Diabetesandneurodegenerativediseases385
15.5.3Otherdiseases386
15.6Futureperspective 387
Listofcontributors HafsatAbdulkarim DepartmentofBiochemistry,BauchiStateUniversity,Gadau, BauchiState,Nigeria
AdamuAbdullahi DepartmentofBiochemistry,BauchiStateUniversity,Gadau, BauchiState,Nigeria
BoluwatifeL.Afolabi Phytomedicine,NaturalProducts,DrugandBiochemical ToxicologyGroup,DepartmentofBiochemistry,LandmarkUniversity,Omu-Aran, KwaraState,Nigeria
BasiruO.Ajiboye PhytomedicineandMolecularToxicologyResearchLaboratory, DepartmentofBiochemistry,FederalUniversityOye-Ekiti,EkitiState,Nigeria
BushraAkhtar DepartmentofPharmacy,UniversityofAgriculture,Faisalabad, Pakistan
MohammadAkram DepartmentofEasternMedicineandSurgery,Government CollegeUniversityFaisalabad,Faisalabad,Pakistan
MohammedAl-Ghorbani DepartmentofChemistry,CollegeofScienceandArts, TaibahUniversity,Madina,SaudiArabia;DepartmentofChemistry,Collegeof Education,ThamarUniversity,Thamar,Yemen
GowriAnnasamy BiomedicalStream,DeptofSciencesandHumanities,IIITDM Kancheepuram,TamilNadu,India
TahiraAslam InstituteofPhysiologyandPharmacology,UniversityofAgriculture, Faisalabad,Pakistan
ChibuezeGospelAwuchi DepartmentofEnvironmentalTechnology,Federal UniversityofTechnologyOwerri,Owerri,Nigeria
ChinazaGodswillAwuchi SchoolofNaturalandAppliedSciences,Kampala InternationalUniversity,Kampala,Uganda
JonathanT.Bvunzawabaya DepartmentofBiomedicalSciences,Kamuzu UniversityofHealthSciences,Blantyre,Malawi;AfricaCenterofExcellencein PublicHealthandHerbalMedicine(ACEPHEM),KamuzuUniversityofHealth Sciences,Blantyre,Malawi;DepartmentofChemicalTechnology,MidlandsState University,Gweru,Zimbabwe
YenSanChan DepartmentofChemicalEngineering,CurtinUniversity,Sarawak, Malaysia
JagadeepS.Chandra DepartmentofMicrobiology,JSSAcademyofHigher EducationandResearch,Mysuru,Karnataka,India
xvi Listofcontributors
DipakChetia DepartmentofPharmaceuticalSciences,FacultyofScienceand Engineering,DibrugarhUniversity,Dibrugarh,Assam,India
GenevieveDable-Tupas ResearchCenter,CollegeofMedicine,DavaoMedical SchoolFoundation,Inc.,DavaoCity,Philippines;DepartmentofPharmacology, CollegeofMedicine,DavaoMedicalSchoolFoundation,Inc.,DavaoCity, Philippines
AbdulkadirMohammedDanyaro DepartmentofBiochemistry,BauchiState University,Gadau,BauchiState,Nigeria
MaureenB.DeGuzman DepartmentofPharmacology,CollegeofMedicine,Davao MedicalSchoolFoundation,Inc.,DavaoCity,Philippines
ChukwuebukaEgbuna AfricaCentreofExcellenceinPublicHealthand ToxicologicalResearch(ACE-PUTOR),UniversityofPortHarcourt,Port Harcourt,Choba,Nigeria
UmarMuhammadGhali DepartmentofMedicalBiochemistry,Facultyof Medicine,NearEastUniversity,Mersin,Turkey
MaryamIdris DepartmentofMicrobiology,BayeroUniversity,Kano,Nigeria
JaisonJeevanandam CQM-CentrodeQuı´micadaMadeira,MMRG,Universidade daMadeira,CampusdaPenteada,Funchal,Portugal
DogaKavaz BioengineeringDepartment,FacultyofEngineering,Cyprus InternationalUniversity,Mersin,Turkey;BiotechnologyResearchCentre,Cyprus InternationalUniversity,Mersin,Turkey
SaravananKrishnan CreativeCarbonLabsPvt.Ltd.,Chennai,TamilNadu,India
NaveenKumar DepartmentofChemistry,SriDharmasthalaManjunatheshwara College,Ujire,Karnataka,India
FanuelLampiao DepartmentofBiomedicalSciences,KamuzuUniversityofHealth Sciences,Blantyre,Malawi;AfricaCenterofExcellenceinPublicHealthand HerbalMedicine(ACEPHEM),KamuzuUniversityofHealthSciences,Blantyre, Malawi
AbdulwahabLasisi MaidstoneandTunbridgeWellsNHSTrust,Maidstone,Kent, UnitedKingdom
FatimaAliyuMahmoud DepartmentofBiochemistry,BauchiStateUniversity, Gadau,BauchiState,Nigeria
NazariV.Mansoureh SchoolofPharmacy,UniversityAugust17,1945,Jakarta, Indonesia
AndrewG.Mtewa ChemistrySection,MalawiInstituteofTechnology,Malawi UniversityofScienceandTechnology,Thyolo,Malawi
FaqirMuhammad InstituteofPhysiologyandPharmacology,Universityof Agriculture,Faisalabad,Pakistan;DepartmentofBiosciences,Facultyof VeterinaryScience,BahauddinZakariyaUniversity,Multan,Pakistan
MuhammadMuhammad DepartmentofBiochemistry,BauchiStateUniversity, Gadau,BauchiState,Nigeria
Listofcontributors xvii
AshwinKumarN DepartmentofBiomedicalEngineering,SRMInstituteofScience andTechnology,Chennai,TamilNadu,India
ChikaC.Ogueke DepartmentofFoodScienceandTechnology,FederalUniversity ofTechnologyOwerri,Owerri,Nigeria
OluwafemiA.Ojo Phytomedicine,MolecularToxicology,andComputational BiochemistryResearchGroup,DepartmentofBiochemistry,BowenUniversity, Iwo,OsunState,Nigeria
AhmedOlatunde DepartmentofMedicalBiochemistry,AbubakarTafawaBalewa University,Bauchi,BauchiState,Nigeria
SundayA.Onikanni Phytomedicine,BiochemicalToxicologyandBiotechnology ResearchLaboratory,DepartmentofBiochemistry,CollegeofSciences,Afe BabalolaUniversity,Ado-Ekiti,EkitiState,Nigeria
IfeanyiCliffordOwuamanam DepartmentofFoodScienceandTechnology, FederalUniversityofTechnologyOwerri,Owerri,Nigeria
BabatunjiE.Oyinloye Phytomedicine,BiochemicalToxicologyandBiotechnology ResearchLaboratory,DepartmentofBiochemistry,CollegeofSciences,Afe BabalolaUniversity,Ado-Ekiti,EkitiState,Nigeria;BiotechnologyandStructural Biology(BSB)Group,DepartmentofBiochemistryandMicrobiology,University ofZululand,KwaDlangezwa,KwazuluNatalState,SouthAfrica
ShashankM.Patil FacultyofLifeSciences,DepartmentofBiotechnologyand Bioinformatics,JSSAcademyofHigherEducationandResearch(JSSAHER), Mysore,Karnataka,India
RamithRamu FacultyofLifeSciences,DepartmentofBiotechnologyand Bioinformatics,JSSAcademyofHigherEducationandResearch(JSSAHER), Mysore,Karnataka,India
LakshmiV.Ranganatha DepartmentofChemistry,TheNationalInstituteof Engineering,Mysore,Karnataka,India
YousefRasmi DepartmentofBiochemistry,SchoolofMedicine,UrmiaUniversity ofMedicalSciences,Urmia,Iran;CellularandMolecularResearchCenter, CellularandMolecularMedicineInstitute,UrmiaUniversityofMedicalSciences, Urmia,Iran
PavaniRekulapally CollegeofMVLS,UniversityofGlasgow,UnitedKingdom
NahitRizaner BioengineeringDepartment,FacultyofEngineering,Cyprus InternationalUniversity,Mersin,Turkey;BiotechnologyResearchCentre,Cyprus InternationalUniversity,Mersin,Turkey
MithunRudrapal DepartmentofPharmaceuticalChemistry,RasiklalM.Dhariwal InstituteofPharmaceuticalEducationandResearch,Pune,Maharashtra,India
SureshSN InstituteofBrainScience,Chennai,TamilNadu,India
SaurabhShah DepartmentofPharmaceutics,NationalInstituteofPharmaceutical EducationandResearch(NIPER),Hyderabad,India
AliSharif InstituteofPharmacy,FacultyofPharmaceuticalandAlliedHealth Sciences,LahoreCollegeforWomenUniversity,Lahore,Pakistan
AbdullahM.Shbeer DepartmentofSurgery,FacultyofMedicine,JazanUniversity, Jazan,SaudiArabia
PrithviS.Shirahatti St.Joseph’sCollegeforWomen,Mysore,Karnataka,India
ShashiBalaSingh DepartmentofBiologicalSciences,NationalInstituteof PharmaceuticalEducationandResearch(NIPER),Hyderabad,India
VivekRanjanSinha UniversityInstituteofPharmaceuticalSciences(UIPS),Panjab University,Chandigarh,India
SaurabhSrivastava DepartmentofPharmaceutics,NationalInstituteof PharmaceuticalEducationandResearch(NIPER),Hyderabad,India
RamalingamB.Subramanian DepartmentofBiosciences,SardarPatelUniversity, Bakrol,Gujarat,India;IndukakaIpcowalaCentreforInterdisciplinaryStudiesin ScienceandTechnology,SardarPatelUniversity,Vallabhvidyanagar,Gujarat, India
AnjaliB.Thakkar DepartmentofBiosciences,SardarPatelUniversity,Bakrol, Gujarat,India;IndukakaIpcowalaCentreforInterdisciplinaryStudiesinScience andTechnology,SardarPatelUniversity,Vallabhvidyanagar,Gujarat,India
VasudevR.Thakkar DepartmentofBiosciences,SardarPatelUniversity,Bakrol, Gujarat,India
ParthThakor DepartmentofBiosciences,SardarPatelUniversity,Bakrol,Gujarat, India
HabibuTijjani DepartmentofBiochemistry,BauchiStateUniversity,Gadau, BauchiState,Nigeria
HanningtonTwinomhwezi SchoolofNaturalandAppliedSciences,Kampala InternationalUniversity,Kampala,Uganda
HuzaifaUmar BioengineeringDepartment,FacultyofEngineering,Cyprus InternationalUniversity,Mersin,Turkey;BiotechnologyResearchCentre,Cyprus InternationalUniversity,Mersin,Turkey
AbdullahiGarbaUsman DepartmentofAnalyticalChemistry,Facultyof Pharmacy,NearEastUniversity,Mersin,Turkey
SugumariVallinayagam DepartmentofBiotechnology,VelTechRangarajanDr. SagunthalaR&DInstituteofScienceandTechnology,Chennai,TamilNadu, India
SanjayG.Walode DepartmentofPharmaceuticalChemistry,RasiklalM.Dhariwal InstituteofPharmaceuticalEducationandResearch,Pune,Maharashtra,India
MaryamHaladuZangoma DepartmentofBiochemistry,BauchiStateUniversity, Gadau,BauchiState,Nigeria
JamesH.Zothantluanga DepartmentofPharmaceuticalSciences,Facultyof ScienceandEngineering,DibrugarhUniversity,Dibrugarh,Assam,India
Chapter1 Rolesofnanoparticlesindrug discoveryanddelivery SaurabhShah1,VivekRanjanSinha2,ShashiBalaSingh3 and SaurabhSrivastava1
1DepartmentofPharmaceutics,NationalInstituteofPharmaceuticalEducationandResearch (NIPER),Hyderabad,India, 2UniversityInstituteofPharmaceuticalSciences(UIPS),Panjab University,Chandigarh,India, 3DepartmentofBiologicalSciences,NationalInstituteof PharmaceuticalEducationandResearch(NIPER),Hyderabad,India
ChapterOutline 1.1Introduction3
1.2Typesofnanoparticles4
1.2.1Lipidnanoparticles4
1.2.2Polymer-basednanoparticles6
1.2.3Inorganiccomponent-based nanoparticles7
1.3Applicationofnanoparticles8
1.3.1Drugreleaseprofile9
1.3.2Genedelivery10
1.3.3Pulmonarydelivery11
1.1Introduction
1.3.4Antimicrobialdelivery12
1.3.5Braintargeting13
1.3.6Pharmacokineticsand biodistribution14
1.3.7Mucoadhesivedelivery14
1.3.8Skindelivery15
1.3.9Macrophageuptake16
1.3.10Nanotheranostics16
1.4Summaryandconclusion20 References21
Theemergenceofnanotechnologyasaplatformhasrevolutionizedthescienceof patienttherapy.Multifariousapplicationsofnanotechnologyindrugdiscovery, drugdelivery,anddiagnosishavepavedthewayforexcitingavenuesleading towardtheadvancementofconventionaltechniques.Nanotechnologyinvolvesthe creationandutilizationofmaterialsinthenanodimensions(1 1000nm)(Shah etal.,2020).Nanomaterialshavebeenwidelyusedfordiagnostic,therapeutic, andtheranosticapplications.Thedrugsthatarecurrentlybeingdiscoveredand clinicallyutilizedforvariousdisorders, includingcancer,diabetes,Alzheimer’s disease,andarthritis,aresynthesizedonthebasisoftheirpromisinginsilico, invitro,orinvivoactivity.Theforemostreasonbehindthefailureofalarge numberofdrugsistheirlackofoptimumabsorption,distribution,metabolism,
andelimination(ADME)characteristics(Guptaetal.,2020).Thiscontributesto severebioavailabilitychallenges,whichinturnleadtoincreasesinthedoseand dosingfrequency.Thisfurtherincreasesthepropensityofadverseeffectsandtoxicities,whichleadtothefailureofdrugsinpractice.Additionally,crossingbiologicalbarriers,suchastheskin,mucosa,andblood-brainbarrier(BBB),by conventionaldrugs,arerarelypossible.Theoccurrenceofresistanceinvarious disorders,suchascancer,microbialandinfections,rendersthedrugscaffold ineffective,leadingtothefailureofawholeclassofdrugs.Theanswertothese challengeslieswiththeadventofnanotechnology.Nanotechnologyinvolvesthe utilizationofnanoparticleswhichnotonlyaimtoaddresstheADMEissues,but alsoprovidesolutionsforahigherdoseanddosingfrequencyalongwithbioavailabilitychallenges.Nanoparticleshavetheabilitytobetargetedtospecificorgans, tissues,andcellsviasurface functionalizationprinciples(Thorpetal.,2020). Withinthelast10years,about40,450reportshavebeenpublishedonnanoparticlesfordrugdelivery,alongwith96clinicaltrials,whilefordiagnostics,about 46,233reportshavebeenpublished,along with304clinicaltrials.Awidevariety ofnanoparticlesareusedindrugdiscoveryanddrugdelivery;however,therehas beennoguidanceorprotocolsastowhichtypeofnanoparticlesaredeemedfit foraspecificfunction.Thishascausedtheemergenceofanunresolveddilemma amongstresearchers.Thescenarioexhibits aneedofinvestigatingthecharacteristicsofeachandeverytypeofnanoparticletomakethemostappropriatechoice forthedesiredattributes.Thischapteraimstoresolvetheunansweredambiguity byemphasizingthecharacteristicsofthe nanoparticlesthatdictatethechoiceof nanoparticlesfortheirbest-fitrolesin drugdiscoveryanddrugdeliverywithan attempttospeeduptheclinicaltranslationofnanotechnology-basedproducts.
1.2Typesofnanoparticles Therearemanykindsofnanoparticlesthatcanbebroadlyclassifiedinto threemajortypes:lipid-based,polymer-based,andinorganicnanoparticles. Thetypeofnanoparticletobeusedforaprospectiveapplicationisthepreliminarystepinnanoparticleselection.Differenttypesofnanoparticles impartdistinctcharacteristicstothenanoparticulatecarriersystem.
1.2.1Lipidnanoparticles Lipidnanoparticlesincludesolidlipidnanoparticles(SLN),nanostructured lipidcarriers(NLC),lipiddrugconjugates(LDC),andnanoemulsions.The nanocarrierthatispredominantlyusedcomprisesphysiologicallyderived lipidslikeglycerylesters,triglycerides,andwaxes,whicharestabilizedby surfactants.Solidlipidnanoparticlescomprisealipidmatrixthatissolidat roomtemperature(Kanwaretal.,2021).MullerandLuckswerethefirstto discoverSLNbyhigh-pressurehomogenization(Schwarzetal.,1994). VariousapproachesthatareemployedforthepreparationofSLNinclude
Rolesofnanoparticlesindrugdiscoveryanddelivery Chapter|1 5
hothomogenization,coldhomogenization,solventemulsification,highshear homogenization,spraydrying,andcongealing(Newton&Kaur,2019). ThreemodelshavebeenutilizedtodistinguishSLNonthebasisofdrugdistribution,namely,monolithicmatrix,drug-enrichedcore,anddrug-enriched shell.Inthemonolithicmatrixmodel,thelipidactsasasolidsolutionin whichitincorporatesthedrugsuniformlythroughoutthematrix.SLNpreparedbyacoldhomogenizationtechniquegenerallyfollowsthemonolithic matrixmodel.Thedrug-enrichedshellmodelincreasestheamountofdrug distributionintheoutershell.Thisleadstoanenhancedburstreleasefollowedbyasustainedrelease.Drugdistributionintheshelloccursduringthe recrystallizationofthecore,inwhichthedrugisexpelledfromthecoreinto theshell.Thedrug-enrichedcoremodelindicatesthedistributionofthedrug inthecore.Thisispossiblewhentheamountofdrugthatisaddedisclose tosaturatingthelipid.Duringrapidcooling,thedrugprecipitatesinthe microemulsion,whichrecrystallizesandrestrictsthedruginthecore.SLN preparedbythemicroemulsionmethodfollowsthismodel(Radaicetal., 2016).SLNcanincorporatebothhydrophilicandlipophilicdrugstodeliver oligonucleotidesandgenes.Theyhavebeenwidelyusedtoincreasethepermeabilityandoralbioavailabilityofdrugs.Theyprotectthedrugsfromthe harshenvironmentofthegastrointestinal(GI)tract,enzymaticmetabolism, andserumdegradation.Theypromotecontrolledbiphasicreleaseandprolongthehalf-lifeanddurationofactionofthedrugs.Asolidlipidmatrixin whichthedrugisincorporatedisbiodegradableandpossessesbetterbiocompatibilitycomparedtoothertypesofnanoparticles.Despiteseveraladvantages,SLNsuffersfromcertaindrawbacks,suchasgelationtendency,drug expulsionduringrecrystallizationofsolidlipid,limiteddrugloading,stabilityissues,andhighpolydispersity.Toovercomethesedifficulties,NLCwas introducedinwhichpartofthesolidlipidisreplacedbyaliquidlipid(Nene etal.,2021).Theuseofaliquidlipidenhancestheencapsulationefficiency anddrugloading,reducesthecrystallizationofthesolidlipidduringstorage preventingdrugexpulsion,andattenuatestheinterfacialtensionbetweenthe lipidicandaqueousphases,decreasingthegelationtendencyandthereby improvingthestabilityofthenanoformulationcomparedtoSLN.Similarto SLN,NLChasmultifoldapplicationsindrugdeliveryandtraversingbiologicalbarrierswithlipidicexcipientsthataresafe(GRAScompliant).NLChas beenwidelyexploredforimprovingdrugbioavailability,includingtraversing biologicalbarrierssuchasskinandtheBBB.Owingtothelipophilicityof SLNandNLC,theloadingofhydrophilicdrugsintothemeltedlipidmatrix viasolubilizationisdifficult.Hydrophilicdrugsadditionallysufferfrom poorpermeabilitycharacteristicsacrosstheGItract,contributingtotheir poorbioavailability.ThereforeLDCwasfurtherintroducedtoaddressthe limitationsofthesehydrophilicdrugs(Takalanietal.,2020).Thesedrugs wereconjugatedcovalentlyorthroughthesaltformationwithalipidmolecule throughesteroramidelinkages,whichimparthighstructurallipophilicity.
TheformationofLDCimprovespermeationandabsorption,reducesGImediateddrugdegradation,andenhancesbioavailability.Onceabsorbed,these LDCundergoesteroramidebondhydrolysisreleasingthedrugviadeconjugation(Irbyetal.,2017).
1.2.2Polymer-basednanoparticles Polymericnanoparticlesarecolloidaldispersionsmadeupofpolymer agglomerateswhosesizerangesbetween50and1000nm.Therearetwo typesofpolymericnanoparticles:nanocapsulesandnanospheres. Nanocapsulesaredrugdepots,owingtotheirvesicularstructure,whichhas thepotentialtoincorporatehydrophilicdrugsintheaqueousliquidcoreand hydrophobicdrugsinthesolidshell.Nanospheresaresmallagglomerated polymericmassesintowhichthedrugcouldbeencapsulatedaswellasbeing adsorbedonthesurface(Leeetal.,2015).Theyarepreparedfromnaturalas wellassyntheticpolymers.Thenaturalpolymersincludechitosan,gelatin, andalginate;syntheticpolymersincludepolylacticacid,polyglutamicacid, polyanhydrides,polycaprolactone,polycyanoacrylates,andpolyorthoesters. Variousmethodsthatareemployedforthesynthesisofnanoparticlesinclude directmonomerpolymerizationviacontrolledradicalpolymerization,emulsion,surfactant-freeemulsion,miniemulsion,microemulsion,andinterfacial polymerizationorwiththehelpofpreex istingpolymersbysolventevaporation,saltingout,supercriticalflui dexpansion,dialysismethod,andsoon ( Crucho&Barros,2017).Smartpolymericnanoparticlescouldbedesigned toreleasethedrugembeddedintheirmatrixinresponsetovariousstimuli, suchaspH,temperature,ultrasound,redox,andenzyme-catalyzed.Stimuliresponsivenanoparticlesundergoinsi tuswitchon/offbasedmechanisms fordrugrelease,owingtothemodificationinphysiologicalconditions. Theyprovideexcellentspatialandte mporalcontroloverdrugdelivery. Polymerswithorthoester,acetal, hydrazone,oriminelinkagespossessa criticalpH,wherebyachangeinionizationcausesswellingorcollapseof thepolymericmatrix,therebycontrollingthedrugrelease.Temperaturesensitivepolymers,suchaspolyN-isopropylacrylamide,polymethylvinyl ether,andpluronic,showcharacteristicchangesintheirstructuralintegrity dependingonthevolumephasetransiti ontemperature.Criticalsolution temperaturesarethemeansofmeasuringthethermalsensitivityofthe polymer;belowthecriticaltemperatur e,thepolymerwouldexistinsoluble form,whileabovethecriticaltemperaturethepolymerwouldexistina rigidinsolubleform(Q. Zhangetal.,2017 ).Magneticnanoparticlesutilize magnetite,ironoxide,nickelsalts,a ndsoon,whichareencapsulatedinto thepolymermatrix.Whenthenanoparticlesaresubjectedtoavarying magneticfield,theoscillatoryforcescausehyperthermia,whichleadsto drugreleasefromthepolymermatrix. 6 PART|1
1.2.3Inorganiccomponent-basednanoparticles Concurrentlywithlipidandpolymericnanoparticles,inorganicnanoparticles havegainedtremendousattentionfromresearchersaroundtheglobe.Owing totheirapplicationsintherapeuticanddiagnosticfields,theyhavebeen widelyexploredforavarietyofpurposes.Inorganicnanoparticlesinclude theuseofmetalsaswellasnonmetalsinthenanometricdimension (Anselmo&Mitragotri,2015).TheU.S.EnvironmentalProtectionAgency classifiedinorganicnanoparticlesintofourtypes:carbon-containingnanomaterials(carbonnanotubes,fullerene,graphene),metal-containingnanomaterials (metals,metaloxides,quantumdots),dendrimers(star-shapedmacromolecules),andcomposites(combinationofseveralnanoparticles)(Sudhaetal., 2018).Thesematerialsplayanadjuvantroleincellularinternalization,leading toreactiveoxygenspeciesproductionthroughfreeradicalperoxidationand otherreactions,whichcauseDNAdamageleadingtocelldeath(Teeetal., 2015).Thispropertycouldbeusedininducingtumorcellapoptosisinwhich tumorcelldeathisbeneficialforamelioratingthehealthofthepatient. Tetheringthiol,thioacetal,thioketal,andaminefunctionalitiesenablestrong affinitytowardbiologicalligandssuchasDNA,peptides,proteins,antibodies, andvirusreceptors.Inorganicnanoparticlesincludenanoparticlessynthesized fromgold,silver,copper,silica,carbon,andsoon.Intracellularuptakeis affectedbysize,shape,andsurfacechargecharacteristics(Shahetal.,2021). However,nanoparticlesthataredispersedinthebiologicalfluidrapidlyform acoronaofproteinsandlipidsovertheirsurface.Thisleadstotheformation ofananoparticle-coronacomplex,whichisstabilizedbyionicinteraction, vanderWaalsforce,andhydrophobicinteraction.Whenthebody’scellsare exposedtosuchananoparticle-coronacomplex,anactivationenergydependentuptakeprocessenablesthetraffickingofnanoparticlesintothecell, wheretheyreachthelysosomalcompartment(Pinoetal.,2014).Inorganic nanoparticlescouldthereforebeusedasacellinternalizationvehicleforintracellulardelivery.Goldnanoparticleshavebeenwidelyexploredfortheranostic applicationsbecauseoftheirthermalconductivity,biocompatibility,easeof stabilization,andsurfacefunctionalization.Variousmethodsforfabricationof goldnanoparticlesincludeborohydridereduction,theTurkevichmethod,the Brust-Schiffrinmethod,theseedgrowthmethod,andthecitratereduction method(Kumarietal.,2019).Silvernanoparticlesdenatureenzymesofthe targetcellviaelectrostaticinteraction.Silverhasanantimicrobialandantiinflammatoryactivitiesthatiswellknownandhasbeenusedfordecadesin treatingburns(Hebeishetal.,2014).Silvernanoparticlesarepreparedby sparkdischarge,chemicalreduction,laserablation,lithography,sonodecomposition,andsoon(Zhang,Liu,etal.,2016).Carbonnanotubesarea broadclassofinorganicnanoparticlesthatperforateanddiffusethroughthe lipidbilayerwithoutpromotingcelldeath.Smallmolecules,oligonucleotides, andthelikecouldbelinkedtothesurfaceeitherbypassiveloadingvia
noncovalentinteractionssuchasvanderWaalsforce,hydrophobicinteractions,etc.orbyactiveloadingviacovalentinteractionswiththehelpofoxidationfollowedbyamideoresterlinkages(Monthiouxetal.,2017).Dendrimers areanotherclassofinorganicnanoparticlesthatarebranched,threedimensionalmoietiesthatwerediscoveredbyVogtleandco-workersin1978 (Fischer&Vo ¨ gtle,1999).Dendrimersaremadeofindividualunitscalleddendrons.Theemptyspaceswithinthedendrimernetworkpromotetheincorporationofvariousmoleculesviacovalentornoncovalentinteractions.In general,therearetwopreparationapproachesfordendrimersynthesis:convergentsynthesisordivergentsynthesis.Dendrimerspossessseveralattributes, suchasenhancedcelluptake,prolongedcirculation,improvedstability,and easeofsurfacefunctionalization(Sherjeetal.,2018).Themajorconcerns relatedtotheuseofinorganicnanoparticlesaretheirbiocompatibility,safety, andbiodegradabilityissues.Mostofthese inorganicnanoparticlesprecipitate severeorgantoxicitiesandimmunological reactions,andtheirnonbiodegradabilityhaslimitedtheirbiologicalapplicationsandclinicaltranslation. Fig.1.1 illustratesvariousnanoparticulatecarriersfordistinctapplications.
1.3Applicationofnanoparticles Thenatureofadrugmoleculeinformsthechoiceofnanoparticulatecarrier foritsdelivery.Variouspropertiesofadrug,suchassolubility,partition coefficient,charge,molecularweight,physicochemicalstability,stabilityin thebiologicalfluids,interactionswiththecarriermoleculesinsitu,compatibilitywiththenanoparticlesynthesisprocess,half-life,bioavailability,dose,
FIGURE1.1 Nanoparticulatecarriersforvariousapplications.
FIGURE1.2 Application-basedselectionaccordingtothetypeofnanoparticles.
dosingfrequency,absorptionwindow,clearance,andplasmaproteinbinding, mustbeconsideredfornanoparticulatecarrierselection(Siccardietal., 2016).
Outofaplethoraofnanotherapeuticstrategies,certaintypesofnanoparticlesaresuitableforcertainapplications.Asisshownin Fig.1.2,lipidicnanoparticlesaresuitableforaburstreleaseprofile,whichpromotestherapid onsetandsustaineddurationofaction.Polymericnanoparticlesarebestsuited forstimuli-responsivereleaseandmucoadhesivedelivery.Inorganicnanoparticlesarebestsuitedfortheranosticapplications.Theirapplicationsfurther encompassotherapplications,suchasbrainandpulmonarydelivery,inwhich lipidandpolymericsystemsareappropriate;antimicrobialdelivery,inwhich polymericandinorganicsystemsaresuitable;andmacrophageuptake,in whichlipidandinorganicnanoparticlesareapplicable.
1.3.1Drugreleaseprofile Aswasdescribedearlier,eachtypeofnanoparticlehasitsowndrugrelease mechanism,whichinfluencesitsreleasebehavior.Theimportanceofdrug releaseindrugdeliveryliesinitscorrelationwiththeonsetanddurationof
action.Aburstreleasewithinashorttimepromotesarapidonset,whilea sustainedzero-orderdrugreleaseprovidesprolongedaction.Lipid-based nanoparticlessuchasSLNandNLCpossesssuchatypeofrelease,owingto thelocalizationofthedrugintheouterlayerofthelipidmatrix.Therelease isattributedtoerosionanddiffusionmechanisms(Rangarajetal.,2020). Drugswithreducedaqueoussolubility,reducedbioavailability,shorthalflife,highsystemicclearance,andhighmetabolismrequireananoparticle carriersystemthatamelioratessuchdrawbacksandreducesthedoseand dosingregimenviaprolongedaction.Lipid-andpolymer-basednanoparticlesareidealfordrugswiththesaiddrawbacks.Polymericnanoparticles releasethedrugmainlybysurfaceandbulkerosionmechanisms;however, theburstreleaseismuchlessincomparisontolipid-basednanoparticles. Additionally,polymericnanoparticlesundergoslowmetabolismandbiodegradationcomparedtolipid-basednanoparticles,makingthemidealcarriers forhighlythermolabileandchemolabiledrugs(Kamalyetal.,2016). Inorganicnanoparticlesmainlyreleasethedruginasustainedmannerafter thebreakingofthecovalentlinkages.Inorganicnanoparticlesareidealfor intracellulardrugreleaseowingtotheireasypenetrationandreducedsizeof lessthan50nmcomparedtoothernanoparticles(Bhartietal.,2019).The useofstimuli-responsivepolymerscouldenableabolusdrugreleaseata particularsiteortimethatmaybebeneficialinreducingtheadverseeffects. Inthisregard,polymericnanoparticlesarefoundtobesuperiortoother nanoparticulatesystems.Xiongandcoworkersdevelopedafour-armstar copolymerofpoly(ε-caprolactone),poly(ethyleneglycol)methylether,and methacrylicacidbyring-openingpolymerizationandelectrontransfer atom transferradicalpolymerization.Micellesthatweresynthesizedfromthis copolymerhadpH,aswellasredoxtriggereddrugreleasespecificallyinthe cancermicroenvironment(Xiongetal.,2017).
1.3.2Genedelivery Genedeliveryhasattractedtremendousattentionfromresearchers.Gene deliveryencompassesthedeliveryofnucleicacidssuchasDNA,siRNA, andmiRNAthroughnanocarriersintracellularlyintothenucleus.These nucleicacidsarehighlylabiletoextremeprocessconditionssuchastemperature,excessiveshear,andtheuseoforganicsolvents.Hencetheprocess thatisselectedforloadingthemintothenanocarriersmustbeamenableand avoidharshconditions(Kelesetal.,2016).Thesenucleicacidsarenegativelycharged,owingtothecarboxylategroups,sothecarrierswithapositivechargeimpartedbyanaminegroupwouldbebeneficialinformingionic complexes.Theseioniccomplexesarestabilizedbyionicinteractionsand promoteenhancedencapsulationefficiencyandloadingcharacteristics, therebyimprovingthestabilityofthenucleicacid.Additionally,thecationic chargeofthecarriercouldpromotetheprotonspongeeffect.Theproton
Rolesofnanoparticlesindrugdiscoveryanddelivery Chapter|1 11
1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP)
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)
FIGURE1.3 Cationicpolymersandlipidsusedforgenedelivery.
spongeeffectistheelectrostaticinteractionofthecarrierwiththehydrogen ions,resultinginswellingandendosomallysis,diminishingDNAdegradation withinthelysosomalnucleases(Vermeulenetal.,2018).Cationiclipidssuchas stearylamine,1-(2,3-dioleyloxy)propyl]-N,N,N trimethylammonium,1,2dioleoyl-sn-glycero-3-phosphoethanolamine,1,2-dioleoyl-3-trimethylammoniumpropane,1,2-dioleyloxy-3-dimethylamino-propane,andcetrimide(tetradecyltrimethylammoniumbromide)impartpositivechargeduetothepresenceofamine groupsandeasilyformcomplexeswitholigonucleotides.Similarly,cationicpolymerssuchaschitosan,polyethylenimine,polyhistidine,andpolyL-lysinecould beusedforoligonucleotidedelivery(Ullahetal.,2017).Hsuetal.prepared cationiclipidnanoparticlesconsistingofcationiclipid2-dioleyloxyN,N-dimethyl3-aminopropaneforsiRNAandmiRNAdeliveryintotheliver.Intratumoral injectionresultedinabout50%growthsuppressionofhepatocellularcarcinoma xenograftswithin30days(Hsuetal.,2013).Themajordisadvantageofthesecarriersistheirrapidsystemicclearancefromthereticuloendothelialsystem(RES). Inorganicnanoparticlessuchadendrimersandcarbonnanotubesrequiresurface functionalizationpriortoloadingoligonucleotides;however,theycouldimpart greaterprotectionagainsttheRESuptakecomparedtolipid-andpolymer-based systems.Gorzkiewiczandcoworkersdesignedstabledendriplexesusingpoly (lysine)anddemonstratedsuperiortransfectionefficiencyagainstmyeloidcells, demonstratingthepromisingpotentialofinorganicnanoparticlesingenedelivery (Gorzkiewiczetal.,2020). Fig.1.3 showsvariouscationicpolymericandlipidbasedcarrierscommonlyusedforgenedelivery.
1.3.3Pulmonarydelivery Nanomedicinehasthepotentialtoalleviatethesymptomsofvariouslungdisordersbyactingasacarrierandhasbeensuccessfulinenhancingpenetration
Chitosan
Poly (ethylenimine)
Eudragit E series
1,2-di-O-octadecenyl-3-trimethylammonium (DOTMA)
