Formulation and assessment of reduction-responsive hybrid nano-micelles containing triphenylphosphine-adriamycin and quercetin for combating drug resistance in cancer treatment
Objective To prepare a reduction-responsive hybrid nano-micelles containing triphenylphosphine-doxorubicin(TPP-DOX,TD)and quercetin(Que),and to evaluate its pharmacokinetics.Methods The redox-sensitive polymer material poly(ethylene glycol)-deoxycholic acid-disulfide-poly(aspartic acid benzyl ester),PDSP,and the non-redox-sensitive polymer material poly(ethylene glycol)-deoxycholic acid-carbon-carbon bond-poly(aspartic acid benzyl ester),PDCP,were used as the carrier.TD and Que were loaded onto the polymers by solvent evaporation,respectively,to prepare redox-sensitive nanovesicles PDSP@TD and PDSP@Que,and non-redox-sensitive nanovesicles PDCP@TD and PDCP@Que.The particle size,polydispersity index(PDI),and Zeta potential of the nanovesicles were analyzed using a laser particle size analyzer.The drug loading and encapsulation efficiency were determined by HPLC.The morphology of the nanovesicles was observed by transmission electron microscopy.The stability of the nanovesicles in storage,dilution,plasma,and freeze-dried powder reconstitution was evaluated.The effects of 10 μmol·L-1,10 mmol·L-1,and 20 mmol·L-1 GSH on the particle size of the nanovesicles were examined.The in vitro release behavior of the nanovesicles in release media containing 0,10 μmol L-1,10,and 20 mmol·L-1 GSH was also investigated.Resuits The particle size of the prepared PDSP@TD and PDCP@TD micelles was approximately 180 nm,while the particle size of PDSP@Que and PDCP@Que micelles was around 230 nm,with a zeta potential below-17.4 mV.All of four micelles exhibited LC and EE values exceeding 6.3％and 65.3％,respectively.TEM imaging revealed that all of four micelles displayed spherical morphology and demonstrated excellent physical stability under various conditions.Under the condition of 10 and 20 mmol·L-1 GSH,the particle size of PDSP@TD and PDSP@Que changes noticeably.The cumulative release rate of free drugs TD and Que in the release medium containing 20 mmol·L-1 GSH is less than 30％within 48 h,while the cumulative release rate of PDCP@TD and PDCP@Que in all mediums was around 38％within 48 h,and the cumulative release rate of PDSP@TD,PDSP@Que,and the mixed vesicle in the release medium containing 20 mmol·L-1 GSH was around 78％within 48 h.Conclusion The reduction-sensitive huydrid nano-micelles prepared exhibit excellent stability,and tumor cell-specific reduction sensitivity,rendering them suitable for subsequent investigations on in vitro and in vivo antitumor drug resistance.
antitumor drug resistancereduction sensitivityhybrid nano-micellesdoxorubicinquercetin
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