Glucose-responsive zwitterionic dialdehyde starch-based micelles with potential anti-phagocytic behavior for insulin delivery

Abstract

Both blood stability and glucose responsiveness for carriers are the most important issues in insulin controlled release studies. However, few reports focus on reducing macrophage response performance for drug carriers themselves. Zwitterionic self-assembled micelles mitigated recognition by immune cell has evolved to address this limitation. In this work, novel zwitterionic dialdehyde starch-based micelles, sulfobetaine (SB) as the hydrophilic shell, and 3-aminophenylboronic acid (APBA) as glucose-responsive groups to the dialdehyde starch (DAS) backbones (SB-DAS-APBA) with glucose-responsive behavior were developed. Insulin release from the nanocarriers is sensitive to the different concentration of the glucose, rapidly at the condition of 3 mg/mL of glucose at pH 7.4. Methyl thiazolyl tetrazoliumviability (MTT) assay confirmed that zwitterion micelles were cytobiocompatible and low cytotoxic activity with A549 cells. For comparison, PEGylation micelles, monomethyl ether (mPEG) as the hydrophilic shell, and APBA as glucose-responsive groups to the DAS backbones (mPEG-DAS-APBA), were also synthesized. Confocal laser scanning microscopy (CLSM) and flow cytometry results displayed that PEGylation and zwitterion coating micelles have different recognition processes in contact with macrophages. After 4 h, doxorubicin (Dox) fluorescence of the Dox-loaded mPEG-DAS-APBA micelle groups were mostly located in nuclei. However, SB-DAS-APBA micelle groups were slightly detected in both nuclei and cytosol. In addition, the fluorescence signals of mPEG-DAS-APBA micelles showed enhanced trend than that of SB-DAS-APBA micelles in macrophage cells. These results suggest that, as drug carriers, zwitterionic self-assembled micelles SB-DAS-APBA not only possessed glucose-responsive insulin delivery property, but also reduced macrophage response performance.