Doxorubicin And Adjudin Co-Loaded PH-Sensitive Nanoparticle For The Treatment Of Drug-Resistant Cancer

Objectives: To overcome tumor resistance,we design a novel pH-sensitive graft copolymer,poly(?-amino ester)-g-?-cyclodextrin,to co-deliver doxorubicin(DOX)and adjudin(ADD),which can achieve the rapid release of drugs in tumor cells,increase the uptake of drugs in tumor cells,and overcome the drug resistance of tumors.Methods: Poly(?-amino ester)-g-?-cyclodextrin copolymers(PC)are synthesized and conjugates between 1-adamantaneacetic acid(Aa)and DOX are prepared;encapsulation of the hydrophilic drug DOX is achieved via host-guest interactions.The pH-sensitive material PBAE is used to encapsulate ADD to form the dual-drug coloaded nanoparticles.Aa-d-?-tocopheryl polyethylene glycolsuccinate(Aa-TPGS)is introduced as hydrophilic moiety to increase stability.The particle size and ?-potential of the NPs were measured by dynamic light scattering(DLS)and the morphology was observed by transmission electron microscope(TEM).The encapsulation efficiency of Aa-DOX and ADD was determined by fluorescence spectrophotometer(DMF)and high performance liquid chromatography system(HPLC).Taking breast cancer cell MCF7 and its drug-resistant strain MCF-7 /ADR as the model,the ability of Aa-DOX&ADD double-drug co-loaded nanoparticles to overcome tumor drug resistance was evaluated in vitro and in vivo.And the mechanism of overcoming drug resistance of the nanoparticles was further explored.Results: Aa-DOX+ADD dual-drug coloaded nanoparticles(Aa-DOX+ADD@PC)were prepared by a modified nano-precipitation method.The batches of drug-loaded nanoparticles formed by different copolymers exhibited comparable particle sizes(i.e.,approximately 100 nm)and a similar encapsulation efficiency of Aa-DOX(i.e.,approximately 50%).In vivo and in vitro experiments had verified that the synthesized Ad-DOX&ADD double-drug co-loaded nanoparticles can effectively increase the drug concentration in cells and increase the killing effect of adriamycin on drug-resistant tumor cells.Western blot and polymerase chain reaction(PCR)analyses showed that inhibition of P-glycoprotein(P-gp)and X-linked inhibitor of apoptosis protein(XIAP)expression may underlie inhibition of tumor resistance mediated by NPs.Conclusions: The dual-drug co-loaded NPs(Aa-DOX+ADD@PC)were prepared by a modified nano-precipitation method,which can precise ratiometric control the loaded drugs in the NPs.These pH-sensitive nanoparticles can achieve higher tumor killing effect,lower required drug dose and overcome tumor resistance.The mechanism may be related to the down-regulation of p-gp and XIAP expression.