PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues 英文参考文献.docVIP

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PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues 英文参考文献.doc

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PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues 英文参考文献

D?ppetal.EJNMMIResearch2012,2:24 /content/2/1/24 ORIGINAL RESEARCH OpenAccess PEGylation,increasingspecificactivityand multipledosingasstrategiestoimprovetherisk- benefitprofileoftargetedradionuclidetherapy 177 with Lu-DOTA-bombesinanalogues SimoneD?pp1,CristinaMüller1,ElisaGarcíaGarayoa1,PeterBl?uenstein1,VeroniqueMaes2,LucBrans2, DirkATourwé2andRogerSchibli1,3* Abstract Background:Radiolabelledbombesin(BN)conjugatesarepromisingradiotracersforimagingandtherapyofbreast andprostatetumours,inwhichBN2/gastrin-releasingpeptidereceptorsareoverexpressed.Wedescribethe 177 influenceofthespecificactivityofa Lu-DOTA-PEG5k-Lys-Banalogueonitstherapeuticefficacyandcompareit withitsnon-PEGylatedcounterpart. Methods:DerivatisationofastabilisedDOTA-BN(7–14)[Cha13,Nle14]analoguewithalinearPEGmoleculeof5kDa (PEG5k)wasperformedbyPEGylationoftheE-aminogroupofaβ3hLys-βAla-βAlaspacerbetweentheBNsequence 177 andtheDOTAchelator.Thenon-PEGylatedandthePEGylatedanalogueswereradiolabelledwith Lu.Invitro evaluationwasperformedinhumanprostatecarcinomaPC-3cells,andinvivostudieswerecarriedoutinnude micebearingPC-3tumourxenografts.DifferentspecificactivitiesofthePEGylatedBNanalogueandvariousdose regimenswereevaluatedconcerningtheirtherapeuticefficacy. Results:ThespecificityandthebindingaffinityoftheBNanalogueforBN2/GRPreceptorswereonlyslightly reducedbyPEGylation.InvitrobindingkineticsofthePEGylatedanaloguewasslowersincesteady-statecondition wasreachedafter4h.PEGylationimprovedthestabilityofBNconjugateinvitroinhumanplasmabyafactorof 5.6.Thenon-PEGylatedBNanalogueshowedfavourablepharmacokineticsalready,i.e.fastbloodclearanceand renalexcretion,butPEGylationimprovedtheinvivobehaviourfurther.Onehourafterinjection,thetumouruptake ofthePEG5k-BNderivativewashighercomparedwiththatofthenon-PEGylatedanalogue(3.43±0.63%vs. 1.88±0.4%ID/g).Moreover,theincreasedtumourretentionresultedinatwofoldhighertumouraccumulationat 24hp.i.,andincreasedtumour-to-non-targetratios(tumour-to-kidney,0.6vs.0.4;tumo