pH響應(yīng)性可降解聚(醚酯-氨酯)的制備及在藥物緩釋領(lǐng)域的應(yīng)用

pH響應(yīng)性可降解聚(醚酯-氨酯)摘要:近年來，pH響應(yīng)性可降解聚合物在藥物緩釋領(lǐng)域備受關(guān)注。pH響應(yīng)性可降解聚(醚酯-氨酯)制備方法。pHN-丙基丙烯酰胺(AM)pH不敏感疏水性單體乙酰丙酮丙烯酸酯(AA),再通過ATPMOS引發(fā)酯交換反應(yīng)得到P(HEP-co-AM-co-制備得到pH響應(yīng)性可降解聚(醚酯-氨酯)。研究表明制備的共聚物具有良好的pH響應(yīng)性和可控的降解性能，在藥物緩釋方面有著潛在的應(yīng)用前景。關(guān)鍵詞pH響應(yīng)，可降解聚合物，藥物緩釋，醚酯，氨酯Drugdeliverysystemsplayacrucialroleinthetreatmentofvariousdiseases.Controlledreleaseofdrugshelpsinmaintainingthetherapeuticefficacyofthedrug,reducessideeffects,andensurespatientconvenience.Variouspolymericmaterialshavebeenstudiedfortheirpotentialuseindrugdeliveryduetotheirbiodegradability,biocompatibilityanddiversechemicalstructures.Amongthem,pH-responsivepolymershavedrawnattentionastheycanrespondtothechangesinpH,whichisaclinicallyrelevantfactor.pH-responsivepoly(ether-ester)polymersareoneofthemostinvestigatedtypesofpH-responsivematerials.Theycanundergohydrolysisunderacidicorbasicconditions,leadingtothecleavageofesterbondsandsubsequentdegradationofthepolymer.Therefore,thesepolymershavebeenextensivelyexploredfordrugdeliverysystems,particularlyinthegastrointestinaltract,wherepHchangesfromacidic(stomachpH1-3)toneutral(smallintestinepH6-7)andthecolon(pH7-8).Inthisstudy,wereportthesynthesisofanovelpH-responsivepoly(ether-ester-amide)copolymeranditspotentialapplicationindrugdeliverysystems.ExperimentalSectionε-caprolactone(CL),γ-aminopropyltriethoxysilane(APTMOS),hexanoylchloride,N,N-dimethylformamide(DMF),4-dimethylaminopyridine(DMAP),acetylpropionate(AA),N-isopropylacrylamide(NIPAAm),N,N′-methylenebisacrylamide(BIS),anddimethylsulfoxide(DMSO)werepurchasedfromSigma-Aldrich(St.Louis,MO,USA).N-(3-aminopropyl)methacrylamidehydrochloride(APMA)andtert-butylN-[3-(dimethylamino)propyl]carbamate(Boc-DMAP)werepurchasedfromTCIAmerica,Inc(Portland,OR,USA).Thereagentsusedintheexperimentswereallofanalyticalgrade.SynthesisofPoly(ε-caprolactone)PCLwassynthesizedviaγ-aminopropyltriethoxysilane(APTMOS)ring-openingpolymerization.SynthesisofP(ε-caprolactone)-co-P(ε-caprolactone)-co-AAwassynthesizedusingPCLandacetylpropionate(AA)viaaSteglichesterificationreaction.SynthesisofP(ε-caprolactone)-co-AA-co-P(ε-caprolactone)-co-AA-co-APMAwassynthesizedviaaMichaeladditionreaction.Thechemicalstructureofthesynthesizedpolymerswasconfirmedbyprotonnuclearmagneticresonance(^1HNMR)analysis.Thethermalpropertiesofthepolymerswerestudiedusingdifferentialscanningcalorimetry(DSC).ResultsandSynthesisofPoly(ε-caprolactone)Thering-openingpolymerizationofε-caprolactonewasinitiatedbyAPTMOStoformPCL.The^1HNMRspectrumofPCLshowedthecharacteristicpeaksofPCLatδ=1.39ppm(CH3ofPCL),2.28ppm(–CH2–ofPCL),and4.07ppm(–CH2–O–ofPCL)(Figure1).SynthesisofP(ε-caprolactone)-co-TheSteglichesterificationreactionwasperformedtointroduceAAintoPCL.The^1HNMRspectrumofP(ε-caprolactone)-co-AAshowedthecharacteristicpeaksofPCLandAAatδ=1.39ppm(CH3ofPCL),2.28ppm(–CH2–ofPCL),4.07ppm(–CH2–O–ofPCL),and2.11ppm(–CO–CH2–ofAA)(Figure2).SynthesisofP(ε-caprolactone)-co-AA-co-P(ε-caprolactone)-co-AA-co-APMAwassynthesizedviaaMichaeladditionreaction.The^1HNMRspectrumofP(ε-caprolactone)-co-AA-co-APMAshowedthecharacteristicpeaksofPCL,AA,andAPMAatδ=1.39ppm(CH3ofPCL),2.28ppm(–CH2–ofPCL),4.07ppm(–CH2–O–ofPCL),2.11ppm(–CO–CH2–ofAA),and3.39ppm(–CH2–NH–ofAPMA)(Figure3).CharacterizationoftheThethermalpropertiesofthecopolymerwerestudiedusingdifferentialscanningcalorimetry(DSC).Thecopolymerexhibitedaglasstransitiontemperature(Tg)of70°Candameltingtemperature(Tm)of45°C(Figure4).pH-ResponsiveThepH-responsivebehaviorofthecopolymerwasstudiedbymeasuringthereleaseofamodeldrug,ibuprofen,atdifferentpHvalues.ThecopolymershowedanegligiblereleaseofibuprofenatpH7.4andarapidreleaseatpH5.0andpH2.0(Figure5).ApH-responsivepoly(ether-ester-amide)copolymerwassuccessfullysynthesizedusingε-caprolactone,acetylpropionate,andN-(3-aminopropyl)methacrylamidehydrochloride.ThecopolymerexhibitedaTgof70°CandaTmof45°C.ThecopolymershowedarapiddrugreleaseatpH5.0andpH2.0,indicatingitspotentialapplicationfordrugdeliveryinthestomachandcolon.Furtherstudiesarerequiredtooptimizethecopolymerstructureanddrugloadingcapacityforclinicalapplications.Liu,H.;Li,J.;Luo,G.;Ye,J.;Chen,L.;Chen,L.;Xie,J.;Xiao,Xiong,H.;Li,Y.pH-responsivenanoparticleswithendosomeescapeandredox-sensitivityforenhancedintracellulardrugdeliverythroughefficientROSsuppression.JournalofControlledRelease2021,329,Ta?,C.;Top?u,G.;Karaca,G.;Aksen,F.;Ero?lu,P.;K?l??,?.;Baykara,T.pH-responsivenanoparticlesbearingpoly[(ethyleneglycol)-block-ε-caprolactone]andimidazolesidegroupsforthedeliveryofanticancerdrugs.EuropeanPolymerJournal2019,1