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Aptamers Engineered Nanocarriers for Cancer Therapy Edited by Prashant Kesharwani Assistant Professor, Department of Pharmaceutics, SchoolofPharmaceuticalEducationandResearch, Jamia Hamdard, New Delhi, India WoodheadPublishingisanimprintofElsevier 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OX51GB,UnitedKingdom Copyright©2023ElsevierLtd.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans, electronicormechanical,includingphotocopying,recording,oranyinformationstorage andretrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowto seekpermission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandthe CopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightby thePublisher(otherthanasmaybenotedherein). 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ISBN:978-0-323-85881-6 ForinformationonallWoodheadPublishingpublicationsvisitour websiteathttps://www.elsevier.com/books-and-journals Publisher:MatthewDeans AcquisitionsEditor:SabrinaWebber EditorialProjectManager:JoshuaMearns ProductionProjectManager:PrasannaKalyanaraman CoverDesigner:MilesHitchen TypesetbyTNQTechnologies Contributors KhalilAbnous PharmaceuticalResearchCenter,PharmaceuticalTechnologyInsti- tute,Mashhad University of MedicalSciences, Mashhad, Iran MohammedA.S.Abourehab DepartmentofPharmaceutics,CollegeofPharmacy, Umm Al-QuraUniversity,Makkah,SaudiArabia;DepartmentofPharmaceutics and Industrial Pharmacy,College of Pharmacy,MiniaUniversity, Minia, Egypt Barbara Adinolfi Istituto di Fisica Applicata Nello Carrara, Consiglio Nazionale delleRicerche, Sesto Fiorentino, Italy Sara Davari Ahranjani Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran Abdulfattah Al-Kadash Cell Therapy Center, The University of Jordan, Amman, Jordan Bayan Abu Al-Ragheb Cell Therapy Center, The University of Jordan, Amman, Jordan MohammadSarwarAlam DepartmentofChemistry,SchoolofChemicalandLife Sciences, Jamia Hamdard, New Delhi, Delhi,India Walhan Alhaer CellTherapy Center, The University of Jordan,Amman, Jordan MahnazAlipour PolymerCompositeResearchLaboratory,DepartmentofApplied Chemistry,Faculty ofChemistry,University of Tabriz, Tabriz, Iran Atul Anand Animal Disease Control Program, Department of Animal Husbandry and Dairying, Ministry of Fisheries, Animal Husbandry & Dairying, Governemnt of India, NewDelhi,India PeymanAsadi DepartmentofMedicalNanotechnology,SchoolofAdvancedTech- nologiesin Medicine, Mazandaran University ofMedical Sciences, Sari, Iran MohammadBanazadeh PharmaceuticalSciencesandCosmeticProductsResearch Center, Kerman University of Medical Sciences, Kerman, Iran; Students Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran xii Contributors Mahmood Barani Medical Mycology and Bacteriology Research Center, Kerman University ofMedical Sciences, Kerman, Iran Jaleh Barar Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute,TabrizUniversityofMedicalSciences,Tabriz,EastAzerbaijan,Iran;Depart- mentofPharmaceutics,FacultyofPharmacy,TabrizUniversityofMedicalSciences, Tabriz, East Azerbaijan, Iran PayamBayat FacultyofMedicine,DepartmentofImmunologyandAllergy,Immu- nology Research Center, BuAli Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran BehzadBehnam PharmaceuticsResearchCenter,InstituteofNeuropharmacology, KermanUniversityofMedicalSciences,Kerman,Iran;FacultyofPharmacy,Students ResearchCommittee,KermanUniversity ofMedical Sciences,Kerman,Iran; Herbal andTraditionalMedicinesResearchCenter,KermanUniversityofMedicalSciences, Kerman, Iran; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University ofMedical Sciences, Kerman, Iran MagdolnaCasian DepartmentofAnalyticalChemistry,FacultyofPharmacy,Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Cecilia Cristea Department of Analytical Chemistry, Faculty of Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Carla Cruz CICS-UBIdCentro de Investigaç~ao em Ciências da Sa(cid:2)ude, Universi- dade da Beira Interior, Covilh~a, Portugal Rambabu Dandela Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indian Oil Odisha Campus, Samantapuri, Bhubaneswar, Odisha,India SapnaDevi DivisionofVeterinaryMedicine,FacultyofVeterinaryScience&Ani- malHusbandry,Sher-e-KashmirUniversityofAgriculturalSciences&Technologyof Jammu(SKUAST-J),R.S. Pura,Jammu,India Ezaldeen Esawi Cell Therapy Center, The University ofJordan, Amman, Jordan MortezaEskandani ResearchCenterforPharmaceuticalNanotechnology,Biome- dicineInstitute, TabrizUniversityofMedicalSciences,Tabriz,EastAzerbaijan,Iran AidaGholoobi MedicalGeneticsResearchCenter,MashhadUniversityofMedical Sciences,Mashhad,Iran;MetabolicSyndromeResearchCenter,MashhadUniversity of Medical Sciences, Mashhad,Iran Ambra Giannetti Istituto di Fisica Applicata Nello Carrara, Consiglio Nazionale delle Ricerche,Sesto Fiorentino, Italy LopamudraGiri DepartmentofIndustrialandEngineeringChemistry,Instituteof Chemical Technology, Indian Oil Odisha Campus, Samantapuri, Bhubaneswar,Odi- sha, India Contributors xiii ElaheGozali DepartmentofHealthInformationTechnology,SchoolofAlliedMed- ical Sciences, Urmia University ofMedical Sciences, Urmia, Iran Mukesh Kumar Gupta Department of Biotechnology and Medical Engineering, National Instituteof Technology, Rourkela,Odisha,India Farnaz Hosseini Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran OanaHosu DepartmentofAnalyticalChemistry,FacultyofPharmacy,IuliuHație- ganu University of Medicineand Pharmacy,Cluj-Napoca, Romania Said I. Ismail Qatar Genome Project, Qatar Foundation, Doha, Qatar; Department ofBiochemistryandPhysiology,MedicalSchool,TheUniversityofJordan,Amman, Jordan Ananya Kar Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indian Oil Odisha Campus, Samantapuri, Bhubaneswar, Odi- sha, India HarsimranKaur DepartmentofPharmaceutics,DelhiPharmaceuticalSciencesand Research University, New Delhi,Delhi, India GowthamKenguva DepartmentofIndustrialandEngineeringChemistry,Institute of Chemical Technology, Indian Oil Odisha Campus, Samantapuri, Bhubaneswar, Odisha, India Prashant Kesharwani Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, Delhi, India; University Insti- tute of Pharma Sciences, Chandigarh University, Mohali,Punjab, India MehrdadKhatami NoncommunicableDiseases ResearchCenter, BamUniversity ofMedicalSciences,Bam,Iran;FacultyofMedicalSciences,DepartmentofMedical Biotechnology, Tarbiat Modares University, Tehran, Iran ZainabLafi Facultyof Pharmacy, The Middle East University, Amman,Jordan IsmailSamiMahmoud FacultyofAppliedMedicalSciences,DepartmentofMed- ical Laboratory Sciences, The HashemiteUniversity, Zarqa,Jordan MuhammedMajeed Sabinsa Corporation,EastWindsor,NJ, United States Atena Mansouri Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand,Iran André Miranda CICS-UBIdCentro de Investigaç~ao em Ciências da Sa(cid:2)ude, Uni- versidade daBeira Interior, Covilh~a,Portugal Mohammad Mohajeri Department of Pharmacology and Toxicology, School of Pharmacy, Kerman University of Medical Sciences,Kerman, Iran xiv Contributors SeyedehAliaMoosavian NanotechnologyResearchCenter,PharmaceuticalTech- nology Institute, Mashhad University of Medical Sciences, Mashhad, Razavi Khora- san Province, Iran Hamdi Nsairat Faculty of Pharmacy, Pharmacological and Diagnostic Research Center, Al-Ahliyya Amman University, Amman, Jordan Yadollah Omidi Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, United States Hossein Omidian Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, United States Kumar Pranay Department of Biochemistry, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India AlexandraPusta Department ofAnalytical Chemistry,FacultyofPharmacy,Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Rajkumar Rajendram Department of Medicine, King Abdulaziz Medical City, King Abdulaziz International Medical Research Center, Ministry of National Guard eHealthAffairs,Riyadh,SaudiArabia;CollegeofMedicine,KingSaudBinAbdu- laziz University ofHealthSciences, Riyadh, Saudi Arabia SmrutiRekhaRout DepartmentofIndustrialandEngineeringChemistry,Institute of Chemical Technology, Indian Oil Odisha Campus, Samantapuri, Bhubaneswar, Odisha,India Pratikshya Sa Laboratory of Nanomedicine, Institute of Life Sciences, Bhubanes- war, Odisha, India; Regional Centre for Biotechnology, Faridabad, Haryana, India Amirhossein Sahebkar Biotechnology Research Center, Pharmaceutical Technol- ogy Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran;SchoolofMedicine,TheUniversityofWesternAustralia,Perth,WA,Australia; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences,Mashhad,Iran;FacultyofMedicine,DepartmentofMedicalBiotechnology and Nanotechnology, Mashhad University of Medical Sciences,Mashhad, Iran Sanjeeb Kumar Sahoo Laboratory of Nanomedicine, Institute of Life Sciences, Bhubaneswar, Odisha, India FatemehSalahpour-Anarjan DepartmentofMedicalNanotechnology,Facultyof Advanced Medical Sciences, Tabriz University ofMedical Sciences, Tabriz, Iran Kiarash Saleki Student Research Committee, Babol University of Medical Scien- ces, Babol,Iran; USERNOffice,BabolUniversity of Medical Sciences, Babol, Iran TiagoSantos CICS-UBIdCentrodeInvestigaç~aoemCiênciasdaSa(cid:2)ude,Universi- dade da Beira Interior, Covilh~a, Portugal Contributors xv Thozhukat Sathyapalan Department of Academic Diabetes, Endocrinology and Metabolism, Hull YorkMedical School, University ofHull, Hull, UnitedKingdom Mahsa Shahriari Department of Pharmaceutical Biotechnology, Faculty of Phar- macy,ZabolUniversityofMedicalSciences,Zabol,Iran;DepartmentofPharmaceut- ical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Pharmaceutical Research Center, Pharmaceutical Technology Insti- tute,Mashhad University of MedicalSciences, Mashhad, Iran NeeleshSharma DivisionofVeterinaryMedicine,FacultyofVeterinaryScience& Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences & Technol- ogy of Jammu (SKUAST-J), R.S. Pura, Jammu, India AfsanaSheikh DepartmentofPharmaceutics,SchoolofPharmaceuticalEducation and Research, Jamia Hamdard, New Delhi, Delhi, India VanshikhaSingh DepartmentofPharmaceutics, School ofPharmaceuticalEduca- tion and Research,Jamia Hamdard, New Delhi, India Seyed Mohammad Taghdisi Targeted Drug Delivery Research Center, Pharma- ceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran Yong Teng Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta,GA, United States Mihaela Tertis Department of Analytical Chemistry, Faculty of Pharmacy, Iuliu Hațieganu University of Medicineand Pharmacy,Cluj-Napoca, Romania SaraTombelli IstitutodiFisicaApplicataNelloCarrara,ConsiglioNazionaledelle Ricerche, Sesto Fiorentino, Italy Somayeh Vandghanooni Research Center for Pharmaceutical Nanotechnology, BiomedicineInstitute,TabrizUniversityofMedicalSciences,Tabriz,EastAzerbaijan, Iran Rezvan Yazdian-Robati Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran FatemehYazdian FacultyofNewSciencesandTechnologies,DepartmentofLife Science Engineering, University ofTehran,Tehran, Iran FatemehZahedipour StudentResearchCommittee,FacultyofMedicine,Mashhad University of Medical Sciences, Mashhad, Iran; Faculty of Medicine, Department of MedicalBiotechnologyandNanotechnology,MashhadUniversityofMedicalScien- ces, Mashhad, Iran FarazZare Faculty of Medicine, Aalborg University, Aalborg, Denmark 1 Cell-SELEX technology for aptamer selection Gowtham Kenguva1, SmrutiRekha Rout1, LopamudraGiri1, AmirhosseinSahebkar2,4,5, Prashant Kesharwani3,6 andRambabu Dandela1 1Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, IndianOil Odisha Campus, Samantapuri,Bhubaneswar, Odisha, India; 2Biotechnology Research Center, Pharmaceutical TechnologyInstitute, Mashhad University of Medical Sciences, Mashhad, Iran;3Department ofPharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, Delhi, India; 4Applied Biomedical ResearchCenter,MashhadUniversityofMedicalSciences,Mashhad,Iran;5Departmentof Biotechnology, School of Pharmacy,MashhadUniversity of Medical Sciences, Mashhad, Iran;6UniversityInstituteofPharmaSciences,ChandigarhUniversity,Mohali,Punjab,India 1.1 Introduction Aptamers are oligonucleotides (short form of RNA or DNA) having multiple applications in different fields like diagnostics, forensics, food science, research, drugdiscovery,andgenetestingandarespeciallyusedfordrugdeliverycarrieragents due to their special property affinity and target specificity [1]. The compounds with highaffinityforthetargetmolecules,whicharefoundinahugecombinatorialnucleic aciddatabase,areknownasAptamers.Theyareveryspecifictothetargetmoleculesas wellastheyhavesomeotherqualitiessuchasrobustnesswhichopposesthereduction conditionsaswellastheheat denaturation [2e6].Whencomparedtotheantibodies, aptamers offer a different set of benefits, such as the preparation of chemicals is easy, compact size, lower molecular weight, nonimmunogenicity, and simplicity of alteration and ligation to nanoparticles for therapeutic, diagnosis, and imaging applications [7]. Developing aptamers for the biomolecular target on the cell membrane in their natural shape, like as proteins, molecular biomarkers, and receptors, has evolved as a potential helpful technique to develop effective disease-specific probes [8]. A live infectious organism, African trypanosomes also known as Trypanosoma brucei, was usedinthefirstcell-SELEXstudy.Thefindingsrevealedthediscoveryofthreeclas- sificationsofhighattractionRNAaptamerswhichareparticularfortheparasite’sin- fectious bloodstream lifespan series phase. The aptamers are chosen to target the parasite’sflagellarpocket,butnoneofthemattachtotheVSGprotein,thatisamong themostcommonpolypeptidesontheTrypanosomainterface[9].Aptamershavebeen shown in several investigations to not only attach to the cell external but also to be carriedintracellularly. AptamersEngineeredNanocarriersforCancerTherapy.https://doi.org/10.1016/B978-0-323-85881-6.00019-1 Copyright©2023ElsevierLtd.Allrightsreserved. 2 AptamersEngineeredNanocarriersforCancerTherapy Aptamers are discovered using a continuous selectioneamplification process knownasselectivegeneration ofligandsbyexponentialenrich.Intheprocess,culti- vationoftargetmoleculewithasolostrandednucleicacidpoolwhichhave1014e1015 variations of randomized 30e100-nt sequenced takes place. After that, the variants having required binding activity are redeemed, then the enriched library is amplified by reverse transcriptionepolymerase chain reaction (PCR). The single-stranded pool is then produced by deleting the template-strand, which can be done in-vitro as well, where PCR product is generated. The whole procedure is repeated more than 20 times to identify aptamers [2]. The SELEX procedure has been established in 1930 that is selection of RNA molecules that bind to certain proteins in vitro [10]. RNA ligands to bacteriophage T4 DNA polymerase, systematic development of ligands through exponential enrichment, since then the various aptamers had been created against different targets, which includes both small chemical molecules and largemoleculeslikeproteins(multidomain).VariousSELEXprocesshasbeendevel- oped by scientist which iscompatible with the requirement and makes the whole selection procedure highly efficient. Capillary electrophoresis-SELEX, microfluidic SELEX,rapid-SELEX,andcell-SELEXaresomeofthesemethods.Alloftheprevi- ousSELEXapproaches,withtheexceptionofcell-SELEX,relyontargetinformation for aptamer choice, and mostly aptamers found against pure protein targets fails to identifythesameproteininitsnativeform.Toachievehighest aptamers, theprotein must be kept in a homogeneous, naturally folded condition. SELEX has been done directlyagainstpureplasmamembranesinordertochoiceaptamersundermorephys- iologicalsettings[7].Intheyear1998,MorrisandJensenwerethefirsttousethecell- basedSELEXapproachbywhichthemembranesofhumanredbloodcellswereused as a complex mixture to identify aptamers that provides an in vitro procedure for isolating high affinitive aptamers, especially againstacompound combinationofpo- tential target compounds. Contrasting to the other SELEX approaches, cell-SELEX choosesanaptamerincontradictionoftheentirecell,ensuringthatmoleculartargets at cell membrane are in their natural condition and represent its normal folding structure [8]. Incubation, partitioning, and amplification are the primary processes of cell-SELEX,whicharecomparabletostandardSELEX(Fig.1.1).Positiveandnega- tivecollectionsareusedinthecell-SELEXprocesstodevelopaptamersthatcanfight cancer selectively. -ve selection is required to eliminate motifs that attach to normal cellswhilealso improvingthe selectivity ofpotential aptamers. Tobegin,withtheaptamer,asingle-strandedoligonucleotidecollectionwithawide variety of randomly sequenced is generated and cultured with goal cells. Following washing, the DNA fragments attached to the marked cell surface are extracted from thecellsthroughheatingcell-ssDNAcomplexesathightemperaturesandcentrifuga- tion.Andthentherestoredpoolandthenegativecontrolcellsarekeptfortheincuba- tion and after that all the ssDNA which binds with the negative control cells are separated. Utilizing a biotinylated reversing primer, unbinded motifs are enlarged byPCR, resultingintheabsorption ofaparticularbinder tothetarget.Forcapturing the separated biotinylated antisense strand as well as unlabeled ssDNA streptavidin