Redox-Responsive Star-Shaped Micelles For Actively Targeted Anticancer Drug Delivery

The design of polymeric carriers can be combined with the characters of cellular environment, for instance, stimuli-responsive and targeted carriers. The development of smart drug delivery system is a hot topic in the field of biomaterials.In cancer therapy nanocargo based on star-shaped polymer exhibits unique features such as better stability, smaller size distribution and higher drug capacity compared to linear polymeric micelles. In this study, we developed a multifunctional star-shaped micellar system by combination of the active targeting ability and the redox-responsive behavior.PEG and PCL were used as the hydrophilic and hydrophobic segments, respectively, and pentaerythritol (PER) was the core of the star-shaped copolymer.Disulfide bond was the linkage between PEG and PCL. The end groups of the hydrophilic segment were decorated with FA ligands to endow the active targeting. Finally, the star-PECLss-FA star-shaped copolymer was synthesized.Micelles were prepared through solvent evaporation method. A low CMC value was got, which ensure the well-defined core-shell structure and the resistance to dilution.The micellepossesses a uniform size distribution invested by DLS and a spherical morphology observed by TEM image. The redox-responsive behaviors of these micelles triggered by glutathionewere evaluated from the changes of micellar size, morphology and molecular weight. All of these results demonstrated that the micelles based on star-PECLss-FA possessed the reduction sensitive property.In vitro drug release profiles exhibited that in a stimulated physiological environment, the redox-responsive star-shaped micelles could maintain good stability, whereas in a reducing and acid environment similar with that of tumor cells, the encapsulated agents were promptly released. In vitro cellular uptake and subcellular localization of these micelles were further studied with confocal laser scanning microscopy and flow cytometry against the human cervical cancer cell line HeLa.The strong DOX fluorescence in celles suggested the important targeting ability of FA during cellular uptake.In vivo and ex vivo DOX fluorescence imaging displayed that these FA-functionalized star-shaped micelles possessed much better specificity to target solid tumor.The results of the antitumor effect in4T1tumor-bearing Balb/c mice demonstrated that the star-PECLss-FA has the best anti-tumor effect due to the smalles tumor volume and the longest survival rate, as well as the conclusion obtained from the histological assessments. Therefore, the multifunctional star-shaped micelles are a potential platform for targeted anticancer drug delivery.