Self-enhancedtargeteddeliveryofacellwall–andmembrane-activeantibiotics,daptomycin,againststaphylococcalpneumonia

摘要： Consideringthatsomeantibacterialagentscanidentifytheouterstructureofpathogenslikecellwalland/orcellmembrane,weexploredaself-enhancedtargeteddeliverystrategybywhichasmallamountoftheantibioticmoleculesweremodifiedonthesurfaceofcarriersastargetingligandsofcertainbacteriawhilemoreantibioticmoleculeswereloadedinsidethecarriers,andthushasthepotentialtoimprovethedrugconcentrationattheinfectionsite,enhanceefficacyandreducepotentialtoxicity.Inthisstudy,anoveltargeteddeliverysystemagainstmethicillin-resistantStaphylococcusaureus(MRSA)pneumoniawasconstructedwithdaptomycin,alipopeptideantibiotic,whichcanbindtothecellwallofS.aureusviaitshydrophobictail.DaptomycinwasconjugatedwithN-hydroxysuccinimidyl–polyethyleneglycol–1,2-distearoyl-sn-glycero-3-phosphoethanolaminetosynthesizeatargetingcompound(Dapt–PEG–DSPE)whichcouldbeanchoredonthesurfaceofliposomes,whileadditionaldaptomycinmoleculeswereencapsulatedinsidetheliposomes.Thesedaptomycin-modified,daptomycin-loadedliposomes(DPD-L[D])showedspecificbindingtoMRSAasdetectedbyflowcytometryandgoodtargetingcapabilitiesinvivotoMRSA-infectedlungsinapneumoniamodel.DPD-L[D]exhibitedmorefavorableantibacterialefficacyagainstMRSAthanconventionalPEGylatedliposomaldaptomycinbothinvitroandinvivo.Ourstudydemonstratesthatdaptomycin-modifiedliposomescanenhanceMRSAtargeteddeliveryofencapsulatedantibiotic,suggestinganoveldrugdeliveryapproachforexistingantimicrobialagents. ... （共10頁）