Theadaptivetreatmenttolerance(ATT)ofcancercellsisthemainencumbrancetocancerchemotherapy.Apotentialsolutiontothisproblemistotreatcancercellswithmultipledrugsusingnanoparticles(NPs).Inthisstudy,wetestedtheco-administrationofcurcumin(Cur)anddoxorubicin(Dox)toMCF-7resistantbreastcancercellstoblocktheATTandelicitefficientcellkilling.Drugswereco-administeredtocellsbothsequentiallyandsimultaneously.Sequentialdrugco-administrationwascarriedoutbypre-treatingthecellswithalbuminnanoparticles(ANPs)loadedw让hCur(Cur@ANPs)followedbytreatmentwithDox-loadedANPs(Dox@ANPs).Simultaneousdrugco-administrationwascarriedoutbytreatingthecellswithANPsloadedwithboththedrugs(Cur/Dox@ANPs).Wefoundthatthesimultaneousdrugco-administrationledtoagreaterintra-cellularaccumulationofDoxandcellkillingwithrespecttothesequentialdrugco-administration.However;thesimultaneousdrugco-administrationledtoalowerintracellularaccumulationofCurwithrespecttothesequentialdrugco-administration.WeshowedthatthisresultwasduetotheaggregationandentrapmentofCurinthelysosomesassoonasitwasreleasedfromCur@ANPs,aphenomenoncalledlysosomotropism.Incontrast,thesimultaneousreleaseofDoxandCurfromCur/Dox@ANPsintothelysosomesledtolysosomalpHelevation,which,inturn,avoidedCuraggregation,ledtolysosomeswellinganddrugreleaseinthecytosol,andfinallyprovokedefficientcellkilling.Ourstudyshedthelightonthemolecularprocessesdrivingthetherapeuticeffectsofanti-cancerdrugsco-administeredtocancercellsindifferentmanners.
