博士申请用研究计划英文模板Word文件下载.docx

博士申请用研究计划英文模板Word文件下载.docx

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A.Proposedareaofresearch

TheaimofthisproposedPhDprojectistodevelopandevaluatepHresponsive,endosomolyticpolymersforefficientintracellulardeliveryofbiologicaldrugpayloads.

Thereisaneedtobetterunderstandthemechanismsofentryintothecellcytoplasmandnucleusinordertodesignoptimaldeliverysystemsforbiologicalmolecules.Ontheonehand,thiswouldopenupsignificantopportunitiestodeliverpotentdrugpayloadsagainstintracellulartargetstopositivelyimpacthumanhealth.Inadditiontheprojectaimstodevelopamoregeneralunderstandingoftherulesgoverningtheuptakeofbiologicalmoleculesintocells.

Thisprojectproposestoinvestigatetheuseofsynthetic,biodegradablepolymersforintracellulardeliveryofdrugpayloads（includingsiRNA,therapeuticpeptideandantibody）againstawell-validatedintracellulardrugtarget,suchasBcl-2.ThenovelpH-responsivepolymershavebeendesignedbyDrRongjunChen’sLabtomimictheactivityofviruses,bothintheircellentryandendosomalescapemechanisms.Usingcancercelllines（JurkatorHL-60cells）asamodelsystem,thepolymerswouldbetestedwithavarietyofdifferentbiologicalpayloadsinaquantitativecomparisonoftheirabilitytoenterthecellandtriggerapoptosisandsubsequentlycelldeath.Withanefficientmodelsystemestablished,therewouldthenbescopetooptimizethesystemintermsofthekineticsandmechanismsofcellentry,cytoplasmicandnuclearlocalization,andthebiodegradationofthepolymers.Therewouldalsobescopetoexploretheefficiencyinothercellsystemsandwithfurtherintracellulartargets.ThismultidisciplinaryprojectisattheinterfaceofChemistry,BiologyandMedicine,andwillprovidethestudentwitharealopportunitytobeinvolvedinthedevelopmentandevaluationofnewnanomedicines.

B.Background

Advancesingenomicsandproteomicshaveenabledthedevelopmentofmacrodrugs,suchasnucleicacidsandproteins,withpotentialforthetreatmentofawidevarietyofdiseases.Amongstotherproblems,theirclinicalapplicationsmaybegreatlyimpairedbylowcellularuptakeandlysosomaldegradationbeforetheycanreachtheirtargetorganellesorcellnuclei.Inordertoachieveefficientintracellulardeliveryofsuchbiologicalmolecules,deliverysystemsarerequiredtoenablehighcellentryviaendocytosisandefficientreleaseintothecytoplasmbyendosomalmembranedisruptionundermildlyacidicconditions.

Recombinantvirusesandfusogenicviralpeptideshavebeenusedtomediategenetransfection,buttheirclinicaluseispotentiallylimitedbysafetyissuesanddifficultiesinlarge-scaleproduction.Avarietyofsyntheticpolymershavethereforebeendevelopedasnon-viralvectors.Cationicpolyethyleneimine,poly（2-（dimethylamino）ethylmethacrylate）andpolyamidoaminedendrimersmediategenedeliverythroughthe‘protonsponge’effect,butsufferfromcytotoxicityandrelativelylowtransductionefficiencies.Theintensivelystudiedvinyl-basedanionicpolymers,poly（a-alkylacrylicacid）s,displaypH-responsivemembranedisruptivebehavior,buttheyarenotbiodegradable,thuslowmolecularweightshavetobestrictlyrequiredtoallowrenalexcretionandtheirclinicalapplicationsareseriouslylimited.

DrRongjunChen’sLabhasrecentlydevelopedaclassofnovel,biodegradable,pH-responsivepolymerstomimicfactorsthatenableefficientviraltransfection,buttheyaresafe,easytomanufactureandhavemorecontrollablestructures.Theparentpolymerisapolyamide,poly（L-lysineisophthalamide）,whichwasbasedonpolycondensationofdiacylchloridesandnaturalmetabolitetri-functionalaminoacidscontainingbothα-andω-aminegroups.Hydrophobicaminoacidsand/orpoly（ethyleneglycol）weregraftedontoitspendantcarboxylicacidgroupstomanipulateitsamphiphilicityandstructure.Themetabolite-derivedbiomimeticpolymerscanundergopH-mediatedcoil-globulechangesinconformation.Thispropertyenablesthesepolymerstobesignificantlymembrane-disruptivewithinpHrangetypicalofendosomalcompartments,butnecessarilynon-toxicatphysiologicalpH.Basedonprevioussuccessfulintracellulardeliveryofthemodel-drugssuchascalcein,dextran（withmolecularweightrangingfrom3kDato70kDa）,andtherapeuticproteinapoptinandsiRNA,itisthoughtthatthesepolymersmaybeabletodeliverawidevarietyofdifferentbiologicalmolecules（nucleicacidsandproteins）intocellsforthetreatmentofvariousdiseasesincludingcancers.

C.Applicant’sworkpreparationinChina

TheapplicantisanexpectedbachelormajoringinPolymerScienceandEngineeringfromBeijingUniversityofChemicalTechnology（BUCT）.Afterfouryearsofundergraduatestudies（2007-2011）,Ihaveobtainedastrongresearchbackgroundinorganicchemistry,polymerphysicsandchemistry,physicalchemistry,etc.WorkingintheStateKeyLaboratoryofPolymerPhysicsandChemistryintheInstituteofChemistryofChineseAcademyofScienceformorethanhalfofayearhassetupmymindinresearchingpolymerdrugcarriers.Ourgroupcastoureyestowardssynthesizinggraftcopolymerswithaminoacidsasthemainmonomers,tocreateanovelcarrierwhichisbothpHandtemperaturesensitive.

WehadsynthesizedapolymerbrushfromZ-lysineand2-Bromoisobutyrylbromidethroughring-openingpolymerization.Thenwegraftedspecifictemperaturesensitiveresiduesontothepolymerbrushviaatomictransferradicalpolymerization,followedbycharacterizationandtheoreticalanalysisofthepolymers.

Inaddition,IwasaResearchAssistantinthestatekeylaboratoryofBeijingUniversityofChemicalTechnology,workingonthecharacterizationofcopolymersbyNMR.IwasalsoaResearchAssistantintheEnvironmentalMaterialsLaboratoryofChinaBuildingMaterialsAcademy,workingonsynthesisofFEVEcoating.Theseresearchexperienceshaveenrichedmyknowledgeandexperimentalskillsforpolymersynthesisandenabledmetooperatemanyfacilitiesdeftly,suchasNMR,GPC,FTIR,vacuumgloveboxandrotaryevaporator.

Inthesummerof2010,Iwasselectedtoattendtheprogram“BUCT-CambridgeSummerSchool”intheUniversityofCambridge.DuringthethreeweeksintheUK,IvisitedtheDepartmentofChemicalEngineeringandBiotechnologyanddidexperimentsrelevanttomyresearchitslabs.InCambridge,Ialsodidacasestudyaboutthebiopharmaceuticalmarket.Thisdeepenedmyunderstandingofcommercialprospectsofdrugdeliverytechnologies,suchasthedemandsofdifferentpatientsfordrugdeliverysystemsandcompetitivenessofdifferenthealthtestingequipments.BesidestheUniversityofCambridge,IalsovisitedtheUniversityofOxford,ImperialCollegeLondon,UniversityofBirmingham,andUniversityofLoughborough.IalsoestablishedthecontactwithDrRongjunChenwhoistheGroupLeaderofBiomaterialsandDrugDeliveryGroupattheUniversityofLeedswhenIwasintheUK,andhavebeencommunicatingwithhimviaemailssincethen,discussingaboutpolymersynthesisandcharacterizationanddrugdeliveryresearch.

IbelievetheabovementionedacademicbackgroundsandvariousrelevantexperienceshavepreparedmyselfwellforthePhDstudyonpolymerdrugdeliveryresearchforthetreatmentofvariousdiseasesincludingcancersinDrRongjunChen’sLabattheUniversityofLeeds.

D.Aimofoverseasstudy

TheaimofmyPhDstudyistoapplypolymernanotechnologytodrugdeliveryinordertoimprovethesafetyandpharmaceuticalefficacyofdrugsthatneedpreciseintracellulardelivery.Iwilldesignandsynthesizebiodegradableaminoacid-basedpolymervectors,whichareefficient,safe,cost-effectiveandamenabletolarge-scalemanufacturing.Iwillthenevaluatethepolymer-basedtargetedintracellulardeliveryofbiologicaldrugpayloads（includingsiRNA,therapeuticpeptideandantibody）againstawell-validatedintracellulardrugtarget,suchasBcl-2,forcancertreatment.Theintentionistocombinethehighlynovelchemistryexpertisesurroundingthedeliverypolymerwiththebiologicalexpertisearoundthediscoveryanddevelopmentofavarietyofdrugpayloads.Thenovelpolymerdeliverytechnologytobedevelopedwillopenthedoortoawidevarietyofcytoplasmicandnucleartargets,previouslythoughttobeinaccessibletobiologicaltherapyforvariousdiseaseincludingcancers.

Inaddition,Iwillinvestigatethefundamentalmechanismsoftheinteractionbetweenpolymers/polymer-drugentitiesanddifferentmembranemodels（artificiallipidmembranes,erythrocytesandmorecomplexnucleatedmammaliancells）andobtainabetterunderstandingoftherulescontrollingtheuptakeofmacromoleculesintocells.

E.Researchmethods

Theprojectwouldbreakdownintodiscretestagesasdescribedbelow:

（1）Polymersynthesis

Aminoacidderivatives（e.g.lysinederivative）willbeusedtocarryouttheN-Carboxyanhydrideringopeningpolymerizationinordertoobtainapolymerbrush,whichcouldbethebackboneoftargetpolymer.Thenenvironmentally（e.g.pHandtemperature）responsivegroupswillbegraftedtothemainchainbyATRPorMichaelAddition,etc.Fluorescentpolymerswouldbepreparedbycouplingorganicfluorophores（e.g.fluoresceinisothiocyanateandCy5）ontothepolymers.Cleavablelinkerchemistry（e.g.disulfidebond）wouldbeintroducedontothepolymerbackbonefordrugconjugation.Polyethyleneglycolwouldbeaddedtothepolymerstoincreasetheirbiocompatibilityandbioavailability.

（2）Characterizationofpolymers

Thestructures,molecularweightsandcompositionsofthesynthesizedpeptidepolymerswillbecharacterizedbyNMR,massspectrometry,GPCandHPLCetc.Th